Plant-Based Foods As a Source of Lipotropes for Human Nutrition: a Survey of in Vivo Studies Anthony Fardet, Jean-Michel Chardigny

Plant-Based Foods as a Source of Lipotropes for Human Nutrition: A Survey of In Vivo Studies Anthony Fardet, Jean-Michel Chardigny

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Anthony Fardet, Jean-Michel Chardigny. Plant-Based Foods as a Source of Lipotropes for Human Nutrition: A Survey of In Vivo Studies. Critical Reviews in Food Science and Nutrition, Taylor & Francis, 2013, 53 (6), pp.535-590. 10.1080/10408398.2010.549596. hal-02648978

HAL Id: hal-02648978 https://hal.inrae.fr/hal-02648978 Submitted on 29 May 2020

HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Version preprint Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

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Plant-Based Foods As a Source of Lipotropes for Hum For Peer Review Only ManuscriptType: Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 Manuscript ID: Keywords: Journal: Author: Comment citer cedocument: Nutrition: a Survey of In Vivo Studies Critical ReviewsinFoodScienceandNutrition

Phytochemicals,lipotropes, hepatic steatosis, huma Fardet,Anthony; Human INRA, Nutrition Review Draft CriticalReviews Nutrition in and Food Science

ns, rats ns, an 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 1of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 +33(0)4 73624704,Fax. 624755. F-63000, Clermont-Ferrand, France;CRNHAuver Genès Champanelle,France ;ClermontUnivers Address correspondencetoAnthonyFardet,INRA CRNH Auvergne,F-63000Clermont-Ferrand, France. Université, UFRMédecine,UMR1019Nutritio a ANTHONY FARDET,PhD, In Vivo Plant-Based FoodsAsaSourceofLipotrop

Studies

ité, UFRMédecine,UMR1019NutritionHumaine, E-mail: [email protected] n Humaine, F-63000,Clermont-Ferrand, France; , UMR 1019NutritionHumaine,, UMR F-63122Saint gne, F-63000Clermont-Ferrand,France,Tel. es forHumanNutrition:aSurveyof t GenèsChampanelle, France;Clermont a

1 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Keywords intervention studiesarepr as havinglipotropiceffects.Ho fiber, oligofructose, flavonoids,lignans,stilbenes, lipid metabolism suggestthatsome unsaturatedfatty The exhaustivereviewingofanimal studiesinve Magnesium, niacin,pantothenateandfolatesalso synthesis. Mainplantlipotr and up-regulationofgenesinvolv triglyceride-rich lipoprote mainly involving increasedphospholipidsynthesis removal offatfrom liverand/ortoreducehe be lipotropicinanimals. Thispropertyisdefi hypolipidemic andhypoglycemic prope physiological effects.Themost is attributedtothegreat diversity ofth Increased consumption ofplantproductsisassociat Abstract Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

: Phytochemicals, lipotrope,he URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For actically non-existent. in exportationfrom liver Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition opes arecholine, betaine, wever, this willhave tobeconfirmed inhumans for which ed inrespectively lipogenic investigated havebeenthei

rties. Yet,some compoundshavebeenveryearlyshownto patic steatosis,humans, rats eir phytochemicalsandtotheirnumerous positive ned asthecapacityofacompound tohastenthe patic lipidsynthesisth stigating theeffectof curcumin andsaponinsmay bealsoconsidered , increasedfattyacid indirectly support the overall lipotropic effect. indirectly supporttheoveralllipotropiceffect. ed withlowerchronicdiseaseprevalence.This acids,aceticacid,melatonin, phyticacid,some via myo thetransmethylation pathwayfor -inositol, methionine andcarnitine. and fattyacid oxidation enzyme r antioxidant,an phytochemicals onhepatic rough severalmechanisms, β -oxidation and/ordown- ti-carcinogenic, Page 2of267 2 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 3of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 8 7 6 5 4 3 2 1 9 been convincinglyshowntobepr with more orlessconclusiveresultsfrom prosp However, morespecifically, theef the major chronic diseases thatarecardiovascula vegetables and fruits, is generally associated with Increased consumption ofplant-basedfoods(P Epidemiological andobservational studies PHYTOCHEMICALS PLANT-BASED FOODCO mortality (Rissanenet al., 2003;Steffenet (Bazzano etal.,2008; Villegas et Nagura etal.,2009),weightgain/obe gain/obesity (Buijsseetal.,2009;He Noethlings etal.,2008),withfr all diseases, withlegumes onmort grain otherthancereal,andlegume intake(Newby, 2009). conclude foranassociationbetw reviewed: itclearly appears that,exceptforready-to the protective roleofPBFandplant-based the varietyused,populationstudied,targeted and/or vegetablesareless obviouswithbotheith De Vijveretal.,2009;VennandMann,2004;Williams 2005; Mellenetal.,2008;Murtaugh2007 2007; Jacobsetal.,1998;Koh-Bane al., 2007;Chatenoudet1998;De Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), To summarize, themost conclusive associatio

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition uits onCVD(Hungetal.,2004;Na een PBFandchildhoodobesityinrela NSUMPTION, CHRONIC DISEASE RISK AND DISEASERISK CHRONIC NSUMPTION, otective againstallmain chronic fects seem to vary according tothebotanical origin of thePBF rjee etal.,2004;Koh-Banerjeean ality risk(all-cause, CVDor al., 2008),andwithboth fruits sity (Buijsseetal.,2009;He

Munter etal.,2007;Flighta 2004), withvegetablesonCVD(Hungetal.,2004; diets againstchildhoodobesity hasbeenrecently ective studies.Thus,while al., 2003)andcancers (Pavia etal.,2006;Van ; Sahyounetal.,2006;Schatzkin etal.,2008;Van er noorpositive effectsreportedthatdependson alowerprevalence of all-causemortality andof r diseases(CVD),obesity,diabetesandcancers. BF), mainly whole-graincereals,legumes, disease ortheageofsubjects.Forexample, ns are observed with whole-grain cereals for ns areobservedwithwhole-graincerealsfor -eat cereals,thereisalack of evidence to etal.,2008),theeffect et al.,2004)andtype2diabetes nd Clifton,2006;Jacobsetal., cancers) (Nagura etal.,2009; diseases ordisorders(Chanet andvegetables onall-cause gura etal.,2009)andweight d Rimm,2003;Larssonetal., tion withfruitandvegetable, whole-grain cerealshave s oflegumes, fruits 3 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 and/or trappingoffr physiological effects(Slavin, 2003).Themechanis together withthefibrefractionofPBFwhichw phytochemicals (vitamins, minerals, traceelemen presence, especially in unrefined and/or mi The overallpotentialpositive effect of PBFonch A wholesetofphytochemicalswith benefit. increasing itsPBFconsumption isnotunhealthy,if with sausagesorotherenergy-denseseasonings not appearnegative forhealthonalongterm, pr contradictory reportedresults,oratleasttheab vegetables withimportant amount ofoilfor obesity among highconsumers ofvegetablesbut of PBFarepracticallynon-existe al., 2009).Studiesreportingincreasedprevalenceof consumption andpsychologicaldistressinaJapanese Noethlings etal.,2008)risks.Morespecific 2008), cerebrovasculardisease(Mizra berry. This isunderlined forcancer(Koloneletal cruciferous, between diseases riskand mortality Duijnhoven etal.,2009)(Table1). Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Alliaceae 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For ee oxidativeradicals( , greenleafyandyellow-orangevegetabl Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition nt exceptone Chinesestudy that withspecific vegetable orfru Moreover, some authorshaveobs numerousphysiologicaleffects hi etal.,2009)andall-cause

i.e. theantioxidantcapacity) (Fang et al., 2002;Pellegrini sence ofsignificanteffect,PBFconsumption does nimally-processed PBF,ofagreatvariety ally, the inverse associ ould actsynergisticallyto ., 2000;Wu etal.,2009), di ovided they arenotsystematically accompanied stir-frying (Shi et al., 2008). Despite some stir-frying (Shietal.,2008).Despitesome theculinaryhabitsinvolvedcookingof ts, carotenoids, polyphenols,phytosterols,…) and snackfoods.Itisthereforecertainthat ms mayinvolve(1)thechelation, reduction ronic diseases wouldbeassociated withthe cohort hasbeen recently chronic diseaseswithincreasedconsumption not alwaysreflectedinasignificanthealth es, rootvegetables it sub-family consumption such as reported increased prevalence of mortality (Naguraetal.,2009; erved asignificantassociation ation betweengreentea favourvariouspositive abetes (Bazzanoetal., reported (Hozawaet , citrusorfruit- Page 4of267 4 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 5of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 doses asrecently demonstrated in healthywomen consuming either 18botanicalfamilies of phytomicronutrients wouldbemore beneficialth (Fardet, 2009). recently revieweditfortheprot synergistically tocounteractth words, onecompound may exertseveralprotective very differentcompounds suchaspolyphenols,v For example, theantioxidant capacity offruits,vege phytochemicals areinvolved ineachofthesephysio 2009; HsuandYen,2008),wouldal 2006), notablythroughtheactionofpolyphenolsand/ development ofchronicdiseases(Azzi andStoc signalling-related mechanisms, ofglutathione 2005). Asdemonstrated more recently,theup- Stocker, 2000; Eastwood, 1999;Fardet, 2009;Lotito and germ fractionsofcerealsbutalsoinwhole- Rahman etal.,2006)propertiesofpolyphenolsandot and/or (7)theanti-aggregability or thecapacitytoinduceapoptosis(AzziandSt 1997; Sammanetal.,2002)andforcarcinogenesis (5) thereductionofhyperhomocysteinemia recogni damaging lipid fractions ( the glucoseuptakebyinsulin)(VennandMann,2004) 1998; Mantovanietal.,2008),(3)there et al.,2003;Wu etal.,2004a),(2) Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), It isthereforemore andmore admitte

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: e.g. Critical ReviewsinFoodScienceandNutrition LDL-cholesterol)(Leeetal., 2005;OkazakiandKatayama, 2008), e development ofonedamaging physiologicalprocessaswehave ective mechanisms associatedwithwhole-graincerealconsumption (Shechteretal.,1999)andanti- the stimulation/modulation ofth

so beinvolved.Today,oneagreestoadvancethatseveral gulation ofglucos ocker, 2000;Rubisetal.,2008;Shamsuddin,2002), itamins EandC,selenium, phyticacid...Inother ker, 2000;Moskaugetal.,2005;Rahman etal., an onlyoneortwophytomicronutrients athigh grain legumes, fruitsandvegetables(Azzi ordown-regulation ofcellredoxstatus synthesis and/orofgenesinvolvedinthe (Wu andWu, 2002), (6)th logical mechanisms throughasynergeticeffect. d thatasmall amount ofacocktail functions andseveralphytochemicals may act zed asariskfactorforCVD(Grahametal., andFrei,2006;Prior, 2003;Thompsonetal., tables andwhole-graince her micronutrients richlycontainedinthebran or theirmetabolites (Horev-Azariaetal., , (4) the lowering of circulating or liver , (4)theloweringofcirculatingorliver e homeostasis ( inflammatory (Liuetal.,2004; e immunefunction(Barretal., e.g. magnesium stimulates e anti-carcinogenicity reals isattributed to via 5

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 19 18 17 16 15 14 13 12 11 26 25 24 23 22 21 20 10 9 8 7 6 5 4 3 2 1 studied asisolatedcompounds andoftenatnon-nutri natural isomer ofglucosethatbe recently polyphenols.Thesecompounds arecholine, betaine and compared tostudiesrelatedhealthpotential Although discoveredaverylongtime Betaine, choline, myo-inositol and methionine inplants The mainlipotropes:betaine, cho PLANT-BASED FOODSASDIETAR whole-grain pseudocereals such 1993). Among ( PBF,beetroot Wyse, 1982;Hitzetal.,Ladyman etal., and temperature-stressed envir play aregulatoryroleinsituation precursor. Betaine andcholinearewatersoluble cy the elucidationofallmechanisms invol plasma orliver. However,thenumber ofdifferent increased inflammation,immuno- orglucosehomeos other impaired physiologicalmechanisms may beco and Nair,2006,CastelaoGago-Dominguez, 2008; stress that has beenshown tobeinvolved in most vivo vegetables and fruits withamodest antioxidant ef Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), antioxidantactivity

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For (Thompson etal.,2006).Moreover, Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition onments (Caldasetal.,1999;Ha onments asamaranth andquinoa) Beta vulgaris of stressfortheplant,notably longs tothecyclitolfamily(Fi line, myo-inositol andmethionine ago inplants,some ofthem ha

ved willbealonglastinganddifficulttask. ), Y SOURCESOFLIPOTROPES 1980; Nolteetal.,1997; Summers andWeretilnyk, Chenopodiaceae fect or5botanical families with a high reported of minerals, traceelements, vitamins andmore ofthepreviouslycited phytochemicals containedin toplasmic osmolytes andthermoprotectants that mmon todifferentmetabolic disorders,suchas tional doses.Inplants, tasis dysregulation,and/orhyperlipidemia in Keaney etal.,2002;Ma Gramineae similarly tothe in water-depressed(drought),saline - ( nson andHitz,1982;Hanson gure 1).Theyhavebeenmostly e.g. myo ve beenratherneglectedwhen spinach,lambsquarters and -inositol, this latter being a - ( chronic diseases(Bartsch i.e. betaine hascholineas whole-graincereals) PBFissohighthat increased oxidative increased oxidative iese etal.,2007), Page 6of267 in in 6 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 7of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Reynertson, 1977;Fuxet al.,1996;S In humans, betaine(Craig,2004),c The lipotropiceffectofbetaine, cereals, legumes, nutsandseeds(USDA, 2005b,2005c,2005d). et al.,2004). Koziol, 1992) al., 1982),wheatgerm (HorbowiczandObendorf, sources offreeorconjugated in freshjuicefrom kiwifruit(San nearly 7%oftotalsugarsinlemon (Masudaet or galactinol)solublecompound,as other hand, highest levelsofphytate(HarlandandOberleas, levels (Lottetal.,2000).Among PBF,whole-grai myo basic constituentof precursors ofphosphatidylcholineand vegetables andsoybean(USDA,2008). are generallyagoodsourceofcholine,particularly for betaineandcholinecontents 1982; Hitzetal., 1982;YokoishiandTanimoto, environmental stress(Craig,2004;Hanson andH derived plantsarewellrecognized Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), -inositol storesusedforfutureseeddevelopmen Concerning methionine, itisan Otherwise, cholineand

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

myo

and fruits(Clements andDarnell,1980),espe For Peer Review Only -inositol may bealsopresentasfreeorconjugated( Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 myo -inositol phosphateorphytate(IP6)th Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition myo choline, myo-inositolandmethionine confirmed theseobservations(USDA,2008).Exceptfruits,PBF myo -inositol appeartobelegumes (Sch z etal.,2004).Althoughliteratu fortheirhighbetainecontent,as holine (ZeiselandCosta, 2009)and in citrusfruitswherefree undkvist etal.,2000)have beenshowntoexertmulti-factorial -inositol areimportant constituents of cellmembranes as

phosphatidylinositol. In manyphosphatidylinositol. Inplants, essentialaminoacid especiallyfoundinhighamounts in al.,2003)andconcentrationsupto153mg/100 mL 1987; Lott et al., 2000; Reddy et al., 1982). On the 1987; Lottetal.,2000;Reddy1982).Onthe itz, 1982;Hansonetal.,1985;andWyse, 1994). The database recently releasedbyUSDA whole-grain cereals,wheat n cereals,legumes, nutsandseedscontainthe t, but also asregulatorofinorganicphosphate t, butalso 1994), pseudo-cereals (Becker et al., 1981; 1994),pseudo-cereals(Beckeretal.,1981; cially citrus (Masuda et al., 2003; Sanz cially citrus(Masudaetal.,2003;Sanz myo at playsaroleasphosphorusand -inositol content mayreachupto weizer et al., 1978; Sosulski et weizer etal.,1978;Sosulski re dataarescarce,therichest e.g. aresult ofanadaptation to myo glycosylated -inositol (Clements and myo branandgerm, leafy -inositol is also the myo -inositol 7 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 generally observedinsituations Excessive hepaticfatdeposits indeedleadstofa The fatty liver orhepatic steatosi preventing excessivefatdeposits( metabolism bypreventing fataccumulation withinth transport andturnover(Best,1935).Today,one de primarily due todeficiency insomeessentialsf prevent and curefattylivers inrats andthat the term “lipotropic”wasfirst century inrespectivelybeet 1956) (Supplemental Table1).Althoughbetaineandcholinewerediscoveredduringthe19 Huntsman, 1935;GavinandMchenry,1941a;Owens, to exertlipotropiceff et al.,1997). Zeisel, 2007),hyperhomocysteinemy beingariskf stabilize theplasma homocysteinelevel(Cra not inscientificliterature.Be These compounds, notablybetaine,ar to leavecholineunclassi been veryearlydebatedanditwas et al.,1960;Ournac,1970;Scriban,Seifert, in some scientific articles, especially (vitamin Ifor physiological effects.Beingessent Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Betaine, choline and

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] myo For Peer Review Only Review Peer For -inositol, vitamin B10forbetaineandvita 535-590. DOI :10.1080/10408398.2010.549596 ect withinanimal liver(Best,1934; fied” duetothelackof Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition juiceandoxbile(1862)- myo used onlyin1935byBestetal taine andcholinearefirstwell ofalcoholexcess(Lieber, 1997) s: impairedphysiologicalmechanisms -inositol e.g. ial nutrientsfor human organism, concluded in1944that“itwouldap myo accumulation ofcholesterol). e yetstilltodaypresentedasv

/ have beenfirstveryearlys meso increased liver fat infiltration andaccumulation was ig, 2004;OlthofandVerhoef,2005;Sanders scientificevidences(M -inositol andcholine(Cal actors whosetheprincipal role istoassurelipid tty liver or steatosis, ametabolic dysregulation actor forCVD(Eikelboom etal.,1999;Graham fines lipotropesascompounds thatactonlipid 1972). Yet,thevitaminic 1942; PerraultandDormard, 1966;Thuillier, e liverthrough hastening fatremoval orby chole BestandHuntsman, 1932;Bestand min J for choline) for a quite long time min foraquitelongtime Jforcholine) isbileingreek(LiandVance,2008), . whoshowed thatcholine isable to -known asmethyl donorsableto , obesity,overweightand diabetes itamins onsome web sites,but hown tohavetheparticularity

chenry andPatterson,1944). they werecitedasvitamins pear tobemoresatisfactory houn etal.,1958;Calhoun status ofcholinehas Page 8of267 th 8

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 9of267 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 (Adams etal.,2005). these mechanisms areparticularly decreased ApoB ormicrosomal TG from liver(thatnotablynaturallyoccurs increased transformationofFAinto inhibition orimpairment ofmitochondrial FA enhancement of fatty acid (FA)synthesis, 2) incr hepatocytes areaffected(A (grade 1), moderate(grade 2)or severe (grade fatty liver (NAFL) (Neuschwander-Tetri andCald hepatic steatosisorfataccumulation byweightis 2009), andhepatocarcinogenesis(Shimada etal., Patrick, 2002;Yorketal Chalasani, 2009),metabolic syndro et al.,2005;James andDay,1998; James, 1998a; DayandJames, 1998b;Kwonet 2002; Seppala-Lindroos etal.,2002; insulin resistance(Gastaldelliet fatty liverisoftenassociatedw hepatic steatosispresentanincreas Angulo andLindor,2001;Day (hepatocellular inflammation), fibrosis orcirrhosi al., 1990;Silverman etal.,1989).Afa (James andDay,1998;Patrick,2002; Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), The development of fatty livermainly result

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For ., 2009),endothelialdysfuncti Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition ngulo, 2002;Bruntetal.,1999). ith aclusterofseveralimpaired al.,2009;Mamoneet TG transfert protein(MTP)synt TG involvedinsituationofinsulin ed riskofdevelopingCVD(Manna Sharabi andEldad,2000;Shimada me symptoms (Cortez-Pintoet triglycerides(TG)byesterification,and5)decreased releaseof James, 1998a; James andDay, Valtuenaetal.,2006),increased SharabiandEldad,2000;Shimad tty liverisvulnerableandsteatos

via 3)whenrespectively< al., 2009a;Reid,2001),hyperlipidemia (Brouwers eased mobilization of FAfrom adiposetissues, 3) 2002; Yatsujietal.,2006) β VLDL in a healthy liver) that can result from VLDLinahealthyliver)thatcanresultfrom generally considered to diagnose non-alcoholic generallyconsideredtodiagnosenon-alcoholic -oxidation (Fromenty andPessayre,1995),4) s, butnot systematically s from thefollowingmetabolic dysfunctions:1) well, 2003).Andsteatosis on andarterialstiffne physiological mechanisms including heses (Jamil etal.,1998).Allof al., 1999; Mannarino et al., 2009; al., 1999;Mannarinoet2009; Marchesini etal.,1999;Patrick, resistance or hyperinsulinaemia resistanceorhyperinsulinaemia 1998). Moreover,patientswith rino etal.,2009).Inaddition, et al.,2002;Vuppalanchiand is may leadto steatohepatitis oxidativestress(Dayand a etal.,2002;Silverman et 33%, 33-66%or>66%of . Aminimum of5-10% (Adams et al., 2005; (Adamsetal.,2005; ss (Mannarinoetal., is considered mild 9 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 13 12 11 25 24 23 22 21 20 19 18 17 16 15 14 10 7 6 9 8 5 4 3 2 1 lipogenesis tothedetriment ofFA as compared tonon-obesesubjects, werereported with aconcomitant reduced level of hepaticlo and TGsynthesis(Arayaetal.,2004 degradation (thatmeans areducti significant increasedinhepatic micr deficient diet)-thatismorphologically sim nutritional modelof hepaticsteatosis withinfl mitochondrial furtherlipid DNAdamages andinhibit level oflipidperoxidationinhe plasma excess fatthataccumulates inTGstoredwithin excess FA,themitochondrial case ofobesity,increasedamounts ofFFAsimply (FFA) synthesisfrom glucosenotuptookbyperiphera andfattyacidsynthase SREBP-1c (+33%) and inadequateintake(Arayaetal.,2004).In might notablyresultfromboththeirincreasedperoxi leading torespectivelydecrea increases SREBP-1 (sterolregulatoryelement imbalanced diets generallyleadtoincreas “condition may favourlipidsynthesi chain poly-unsaturatedFA (PUFA) Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), In thecase ofNAFLassociatedwithinsulinre Otherwise, inhumans withnon-alcoholicfa via

VLDLleadingtohypertrigly URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition sed peroxisomal/mitochondrial β -oxidation pathwaythusbecomes an on ofTGexportationfromliver oxidation (Pettinellietal.,2009). patosteatosis generatesmorefr n-6/n-3 ratiowasalsoobserveda osomal CYP2E1(cytochrome P4502E1 ). Thedepletioninlong-chain s overoxidationandsecretion”

ceridemia (Paganoetal.,2002) ed PUFAn-6/n-3ratiothatreducesPPAR (FAS)(+70%),higherSREBP-1c/PPAR ammation (followinga4-w ng-chain PUFAn-3(-53%) ilar tonon-alcoholicsteat obesepatients,higherhepaticmRNAlevelsof binding protein) expression, both mechanisms binding protein)expression,bothmechanisms cytoplasm. ExcessTG may bealsosecreted in and proposed asconditionsthatwouldfavour enter theliver(Patric dation in situation of in tty liverdiseases(NAFLD),increasedlong- sistance, the increasedhepaticfreefattyacid l adipocytesisalsoi β -oxydation (Patrick,2002).Thus,inarat β -oxidation andincreasedApoB-100 via PUFA of the n-3 and n-6 series PUFA ofthen-3andn-6series ee radicalsthatmay leadto nd authorsconcludedthatsuch insufficientwayofdegrading VLDL),andtoenhancedFA (Araya etal.,2004).Indeed, . Intheend,increased k, 2002).Inpresenceof eek methionine-choline- ohepatitis inhumans - and insulino-resistance, creased oxidativestress ) nvolved; while, in the nvolved; while,inthe content wasreported, α α activation and ratio(+62%) Page 10of267 10 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 11of267 11 10 12 19 18 17 16 15 14 13 26 25 24 23 22 21 20 9 8 7 6 5 4 3 2 1 the down-regulationofPPAR hepatic lipogenesis from excessacetyl-CoAgenera arachidonic acids(Morin,1967). compounds tothebenefitsofothe that cholesterol may have selectiv compounds beingessentialforPLsynthesis,then on hepatocytesinpresenceof after i.p.injectionof[1- depressed activitiesofmitochondrial phosphati 1996). this effectgenerating more reactiveoxygenspecies alteration ofhepaticmethylation Other mechanisms beenunravelledinratsa have oxygen radicalsfollowingmitochondrial changesin suggested tobethefactorleadingincreasedlipidperoxidation thus, bymeasuringethaneexhalationinhigh-a liver (Fromentyetal.,1995).Inaddition,increased mitochondrial DNAdeletionshavebeenobservedin (Halsted etal.,2002), andasuppressive as targetgenes(Esfandi expression thathasacetyl-CoA phosphatidylcholine synthesis(F methionine ( synthesis fromhomocysteine (Baraketal., Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), In thecaseofalcohol-inducedfattyliver,ex In thecaseofhigh-cholesteroldiet

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

i.e. abnormal/altered methionine metabolism) thatleads todepressed Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 ari etal.,2007),decreased methionine 14 Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition C]acetate (respectively around-84% ethanol(Gallietal.,2001) carboxylase (ACC),FASandglycer ely decreased rateofsynthesis andturnover from acetate forthese α r phospholipids(PL)containinglin via igure 2A)(Esfandiarietal

(peroxisome proliferato inhibitionofmethionione synt

, ithasbeenshownin 1997; Baraketal.,1987), dylcholine andphosphatidyl nd minipigs chronicallyfe effectonthephosphatidylethanolamine- LDLexportationfrom lcohol consumers, hepaticfatdepositswere ted byethanolmetabolism. Morespecifically, that may damage liver oxidative stressisalsoparticularly involved: the respiratorychain patientswithmicrovesi cess ethanolconsumption leadtoincreased

r-activated receptor)- appear tobespecificallyinvolved;and ratsthatcholesterol leadtospecific synthase activity and -64%) (Morin,1967),both ., 2007),increasedSREBP-1C ol-3-phosphate acyltransferase decreased levelsof oleic, eicosatrienoic acid, and oleic, eicosatrienoicacid,and hase that allows methionine via increasedproductionof liver. Authorssuggested d alcohol.Theyinvolve: (Lettéron etal.,1993). ethanolamine 24hours cells (Weltman etal., cular alcoholicfatty

(MS, Figure2A) as shown S -adenosyl in vitro 11 N -

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 19 18 17 16 15 14 13 12 11 10 26 25 24 23 22 21 20 9 8 7 6 5 4 3 2 1 tetrachloride (CCl Song etal.,2008).Fattylivermay Cam, 1990;Vaishwanaretal.,1972) resulting from ApoBsynthesisimpairment) (Fu (Goheen etal.,1983;Keim andMares-Perlman, 1984), al., 1958a;Rosenfeld,1973;Ryuand (Felmlee etal.,2009),high-fructo 2008; Olsonetal.,1958a;Ryuand diets (Lombardi etal.,1968;Ols In animals -mainly ratsandmice, fattyliver mutations in rats( 2006). Therearestillother animal models ofsteatos use ofspecificmice strainsthatmimic choline-defi 2003) or such asmildronate orTHP (trimethylhydraziniump ethane) (Okazakietal.,2006)injections, Fatty liverorhepaticsteatosismodels deficiency (Halstedetal.,2002). alcohol upon 14weeks, but,in this case,only methionine synthaseandincrease for an adaptationtomethionine synt methyltransferase (BHMT)activity anddecreased be period ofalcoholconsumption, concomitant methyltransferase pathway(PEMT,Figure2A) Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), S -adenosylmethionine synthesis(F

via

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] hypercaloricandfat-free parenteralnut 4 Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 e.g. ) (Vaishwanaretal.,1972)orDDT(1 obese fa/faZucker rats)andmice ( Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition hetase deficiencyinordertoyi inBHMThavebeenalsoobser se/glucose/sucrose diet( on etal.,1958a),high-fatdiet( be alsoprovokedbysingleethanol Cha, 2003;SingalandEckstein,

igure 2A)(Baraketal.,1987). or ethanol-richdiet(Balkanet

Cha, 2003;Sanchez-Lozadaet via depletinghepaticcarnitinelevelsbyusingchemicals kuwatari etal.,2002;Nagi is generallyprovokedbyus when ethanol feedingwasaccompanied by folate (Zivkovic etal.,2009).However,uponprolonged ropionate) (Degraceetal cient diet hasalsobeen increased hepaticbe taine levels were also observed, resulting from taine levelswerealsoobserved,resultingfrom is, notablyinrelationwith naturallyoccuring rition (Keim andMare orotic acid-supplemented ≈ db 60%)(Hammondetal.,2003;Olson ,1,1-trichloro-2,2-bi / db eld sufficientamount ofmethionine mice - diabetic dyslipidemia - or ved inmicropigs chronicallyfed ≈ 20-40%)(Borgschulteetal., al.,2004;Baraket1997; Both significantdecreasesin (Baker etal.,1973),carbone 1939), high-cholesterol diet 1939), high-cholesteroldiet al., 2010),low-PUFAdiet el-Ostaszewski andLau- taine homocysteine reported(Dumas etal., s-Perlman, 1984).The ing lipotrope-deficient ., 2007;Spanioletal., s (p-chlorophenyl) diet(fattyliver Page 12of267 12 s - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 13of267 21 20 19 18 26 25 24 23 22 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Betaine, choline,myo-inositol, methionine and where theymaysynthesize benewly promote TGhydrolysisintoadi et al.,1996a; Baraketal.,1996b; Best etal.,195 enriched dietsinratsas exhaus demonstrated sincealongtime byusinglipotrope The lipotropic efficiency ofbetaine, cholineand gene inrelationwithFA regulation oflipidmetabolism, notablybyinhib with lipotropedepletion,andal Nieminen etal.,2009;Yasuhara1991).Possi et al.,1992;Neuschwander-TetriandCaldwell, deprivation may alsoleadtoNAFLDinbothhu solutions might bealsoinvolved(Liangetal.,1999). al., 2001;Buchman etal.,1995),but parenteral nutritionmay exhibitcholinedeficiencies obesity, diabetes,hyperlipidemia oralcoholexce mice, mtGPAT catalysing the rate-limiting step development offattyliver, Conversely, KOmice forspecificenzymes invol tamoxifen, valproicacidoretomoxir -aCPT- environmental inhibitorsofhepaticFAoxidation( ob Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), / ob mice -leptin-deficient), genetically modi

In theend,protein-caloriemalnutrition, ra In humans, aspresentedpreviously,hepaticstea

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For β Comment citer cedocument: -oxidation. Inaddition, starvinglead specific hormonal profiles thatcan Critical ReviewsinFoodScienceandNutrition e.g. tively reviewedinSupplemental Ta mitochondrial glycerol-3-phosphate pose tissues,FAproductsbeingth so n-3PUFAdepletion.Indeed, d intoTG(Kerstenetal.,1999).

thehighcontentindextrose 1 inhibitor)(Angulo,2002;Ko inTGsynthesis(Hammond etal.,2003). in vivo 0; Carroll and Williams, 1982;ChahlandKratzing, iting transcriptionoflip mans (Adams etal.,20 2003)andanimals (Ginnekenetal.,2007; myo ved inlipogenesismay beusedtolimit the witharesulting hepatic steatosis (Buchman et ss. Otherwise,humans insituationoftotal fied mice orratsandmice treated with pid weightlossorchronicstarvation/food ble involvedmechanisms may beinrelation lipotrope-relatedstudies -deficient, high-fat/hi tosis isobservedinsituationsofoverweight, e.g. -inositol towards fatty glucocorticoids, estrogenantagonists, ble 1(Baraketal.,1997; Barak acyltransferase(mtGPAT) -/- ereafter takenupbytheliver n-3 PUFA contribute to the n-3 PUFAcontributetothe andglucoseofparenteral 05; Angulo,2002;Doherty ogenic genesandinducing gh-sucrose orethanol- teish andDiehl,2001).

liver hasthusbeen 13 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 (Broun, 1948)oracombination ofcholineandcy administered alowfat,high-pr decreased liversize,werereported inpatient with and Cooke,1945).In1946-1948,improvement ofliver bronchial secretionandpainfulabdominal cramps,…) side-effects relatedtothecholine treatment ( choline chlorideduringmorethan one day)andintravenously(6-8g) receiving largedosesof case ofa27years-oldman whohaddevelopedse decreased liversize(BrounandMe elimination of ascites– (Broun andMeuther,1942).Theynotablyobserved 1941b) -totestcholinechloridefo of GriffithandMulford-obtain our knowledge,werethoseofBrounandMuetherin and Holub,1980). previously reported efficiencyra accumulation inratsfed abasal diet mmol/kg ofdiet,cholineand choline (Ball,1964).However,AndersenandHol 1965). Microscopicalobservations methionine andbetainebeingmore efficientthan notably determined throughdose-responsecurves,c 1966a; Gavin andMchenry, 1940;Halliday, 1938;Haya Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), In humans, publishedresultswere

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For i.e. barbiturates for anxiety state; and whowastreated both orally (2-5 gfor Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition accumulation offluidintoperitoneal myo tios woulddifferaccordingtoth otein/carbohydrate diet supplemente ed inratsand released oneye onemonth: recoveryofthepa r morethan2yearsinhumans (1 withhighdosesofcholinechlori confirmed the lowerlipotropicpot uther, 1942).Threeyearslatter,BarclayandCookereportedthe -inositol hadthesame lipotropi not supplemented with choline or

scarcer. The firstresults reporte i.e. cirrhosis of theliverwithascitesandthatwere ub showedthat,onasame molar basisof5.4 stine (1-3gdailyeach) (Beams, 1946). Inthe vere liverdysfunction(andrenalfailure)after myo holine being3-foldthe fall inredcells-anemia, sweating, severe 1942:authorsapparentlybasedontheresults , probablyduetothehighdosesused(Barclay decreases inbloodbilir -inositol (Bestetal.,1950;Young functions,notablyas shi etal.,1974a). Theefficiencywas cavity thatmay beTG-rich-and e experimental scheme (Andersen tient wasnoteddespiteimportant ar before(GriffithandMulford, g daily) with hepatic cirrhosis gdaily)withhepaticcirrhosis de, thenmethionine (6g)and c effecttowardshepaticTG ential ofbetainecompared to d withcholine(1gdaily) myo d inascientific journal, to -inositol suggestingthat potency ofbetaineand ubin andcholesterol, cite clearanceand Page 14of267 14 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 15of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 choline andPL-bound were (Buchman al.,2001; Zeisel et et deficiency leadtothedevelopment ofhepatost estimating hepaticfat content)inpatients rece More recently, itwas shown ( alanin aminotransferase (ALT)andadecreasein developed upon3weekssymptoms ofincipientliv Warembourg andBertrand,1964).In1991,Zeiseletal sorbitol and 2lipotropes that are betaine and containing ornithinechlorhydratean Ornitaine markers inhumans withhepaticand/orcardio al., 1954).In1964,severalauthors Popper andSchaffner,1952)-mightsignifi bea being notablyshownindogstobetightlyrela rapid improvement ofhepaticfunction-bydecreasing has leadto cholinedeficiency, andthey observed th Nadeau etal Nadeau etal.,1954;Navarranne1964; humans exhibiting varioushepati Blumberg,(Russakoff and 1944).Latter,thepositivee emphasized inthedevelopment ofcirrhosisasso and cystinewasthereforeproposed than whenliversaresmall and probablycontracted more effective“whentherearefattychangesinthe latter study,hepaticfattychangesweresuspectedbasedontheagreement thatsuchtreatment is Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), ®

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] (10.045 formula,JacquesLogeaislaborat . suggestedthatfattyliverin 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition via al., 1991).However,itwas alsoshownthatplasma leveloffree c dysfunctionsand/oratheroscle theuseofcomputed tomogr (Beams, 1946).Prolongedhepatic reported improvements ofhepatic d otherassociatedsubstancessu not differentbetweenpatients

alcoholicpatientsmay resu Warembourg andBertrand,1964).Thus,in1954, vascular dysfunctionsfollowingadmisnitration of ted to hepatic fatty overload (Hough et al., 1943; ted tohepaticfattyoverload(Houghetal.,1943; plasma phosphatidylcholine(Zeiseletal.,1991). iving parenteralnutritionthatdietarycholine eatosis, as itwasreported inanimal models byfibroustissue:alipot magnesium citrate(Navarranneetal.,1964; liver” andwhenthereisanenlargedliverrather at the administration of lipotrope tablets leadto ciated withdiabetes cant supplement toanade er dysfunction,notablyan ffects ofalipotropicther values of thebromosulphalein test,thislatter . ory, Issy-Les-Moulin reportedthatcholine-deficientsubjects aphy, anon-invasivemethod for rosis (Colson and Gallay, 1964; rosis (ColsonandGallay,1964; ch aspyridoxinechlorhydrate, with andwithoutsevere liver lt from adietarycarencethat functionandatherosclerotic fatty infiltrationwasindeed and chronicalcoholism ropic action of choline ropic actionofcholine quate diet(Nadeauet apy werereportedin increasedinserum eaux), acocktail 15 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 methionine among theessentialamino-acids appears although proteinplaya role in amino-acid ( product ofhomocysteine methylation bybetaine(Fi up to3-foldlowerasshownin potency wouldbeweaker through methyl donationtophosphatidylethanolamine confirmed thatmethionine doesnot synthesis (seeFigure2A)(DuVigneaudetal., lipotropic effectofmethionine wa 1937) andwoulddirectlyaccountforthelipotr Caballero etal.,2008;ChahlandKratzing,1966b; steatohepatitis ascompared toaplacebow significantly reduceshepatic combined withdiethanolamine glucuronate(used betaine treatment (Abdelmalek et steatosis, necroinflammatorygrade liver functions suchasadecreasedinlevelof alcoholic steatohepatitishasbeen from adeficitincystathionine of cholinedeficiency deprived ofdietarycholinehave More recently, men (40%ofthe20 tested)and fibrosis, and was notcorrelated with thedegree of Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Methionine hasbeenalsoearlyrecognized Betaine hasaboveallbeenusedinhuman fo

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] e.g. threonine)may leadtofataccumulation Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 (Fischer etal.,2007). than thatofcholineat Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition steatosisscoresandliverenlarg weanling rats(GriffithandMulfor controlling liverfatcontent synthase (Berlowetal.,1989).It been reportedtodevelophepatic howevershown inhumans tolead al., 2001);andtheuse s demonstrated tobenotablyba directlyactuponlipidmetabolism and stageoffibrosis(observed

ithout adverseeffects(Miglioetal.,2000). serum ALTduringtreatment andalowerdegreeof equivalentquantities(C 1940; DuVigneaudetal.,1941).Thiswaslatter as a lipotrope compound (Best andRidout,1940; as alipotropecompound(Best postmenopausal women(80%ofthe15 tested) opic effectofproteins(Eckstein,1952).The fat infiltration within liver (Nehra etal., 2001). gure 2A).Althoughpartialdeficienciesofsome for PLsynthesis)and Shils andStewart,1954;TuckerEckstein, r treatinghomocystinuria to exertadirectlipotropic effect(Eckstein, (Figure2A)(Labadie,1974).Itslipotropic during 8weeksoforal into ratliver(Har (Channon andWilkinson, 1935),only ement inpatientswithnon-alcoholic d, 1941a).Methionine sed onmethyl supplyforcholine steatosis, themost common sign s use inthetreatment of non- via tosignificantimprovementof but asaprecursorofcholine biopsies)afteroneyearof hahl andKratzing, 1966b), nicotinamide ascorbate per etal.,1954a)and betaineglucuronate that notablyresults is also the isalsothe Page 16of267 16 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 17of267 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 4 3 9 8 7 6 5 2 1 lipotrope doseusedwhateverthecompound consid liver tobloodstream (Figur thereafter usedforlipoproteinformation inreti lipotropic effectismainly basedonitsabilit where theyare compounds inchargeofregulating to transfertheirlabilemethyl al., 1992;Katayama, 1997b). lipid synthesisintheliverbyareducedFASand/ rate ofFAmobilization from ad Lombardi, 1971;Mookerjea,YaoandVance, PL) andtheirincreased and Miller,1989),animprovement and Borgström, 1963;YagiandKotaki,1969),adecreas fatty liveris mainly inrelationw The mechanisms bywhichbetaine,choline, methionine andmyo-inositol Detailed physiologicalmechanisms lipotropes at moderate dose might bethebest equilibrium toreach-as wewilldiscuss later. diet (Supplemental Table1) of acetateinto liver lipids (+118%)af 1952). However,highdosesofmethionine (2.5%of Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), More generally, this tends toemphasize th More generally,lipotropiceffect

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β -oxidized (Figure2B)(Labadie,1974). Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 secretion from theliver(Burtona Comment citer cedocument: e 2A)(YagiandKotaki, 1969). Critical ReviewsinFoodScienceandNutrition (Yokota etal.,1974) (Yokota groups, thusparticipatinginach ith afacilitatedtransf ipose tissuetotheliver(Hayashi fat transitoutsideth of TG-richlipoproteinformati ter 7daysof treatment inrats fedastandard 9%casein-based associated withthelipotropic

is related tothe abilityfor be . myo culum endoplasmic orforlipoproteintransportfrom y tofavourphosphatidylinosit or ACCactivities(Beach -inositol andmethionine 1990; Zilversmit andDiluzio,1958),areduced the diet)wereshowntoincreaseincorporation at lipotropic effect seems to depend on the at lipotropiceffectseems todependonthe ered andthatabalan er ofFAfrom livertobloodstream(Arvidson e liver(Figure2A)or ed neutrallipidcontent Myo nd Wells, 1977;Kotakietal.,1968; -inositol beingnotamethyl donor,its on (VLDL and LDL that include on (VLDLandLDLthatinclude etal., 1974b),and/or areduced ain reactionthat taine, choline andmethionine effect ofbetaine,choline, and Flick,1982;Ikedaet prevent development of ced amount of various ced amountofvarious towardsmitochondria ol synthesisthatis in theliver(Leclerc finally yields 17 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 reduction, decreaseinphosphatidyl choline-deficient rats,Yao andVanceobservedhe cytosol, leading tofatty liverasshown incholin In the absence ofadequate phosphatidylcholine, this latterbeingthefirstFA al., 1958a),TGbeingcharacterized byincreasedpa rats deprivedofcholine(Lombardi etal.,1968; PL levels(lecithinsandsphingomyelins) ofchil hepatic TGsynthesis- Accordingly, theimpairment oflipoproteinandTGs VLDL secretioninhibitioninitiatedbychol phosphatidylcholine, cholinefavoursTGexcreti synthesis - i.e. important mechanisms thatareinvol directly proportionaltodosesinge turnover buttheeffectwould belessthancholine lipoproteins (YaoandVance,1988,1989).Ascholin been showntolimit excessTGincultured fat exportationfrom liverbyallowingformation latter beingindispensabletoexpor and Patterson,1944;Mookerjea,19 phosphatidylethanolamine -notablyoflecithint Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), : normal hepaticsecretionof In culturehepatocytesfromratsfedacho Thus, cholineparticipates inand accelera

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acholineheadgroupmoiety -,choline 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For i.e. increasedactivityofFAS(Rosenfe Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition produced duringlipogenesisandfrom sted (Perlman andChaikoff,1939). VLDL(aTG-richlipoprotei t fatoutsidehepatocytesandmeth choline andTGcontent ofVLDL ved inthelipotropiceffectof 71; Nadeauetal.,1954;Tokm

rat hepatocytesbyfavour Mookerjea,1971;Mookerje ype likephosphatidylcholin ine deficiency(YaoandVance,1988,1989). omicrons, VLDLandLDL e-deficient rats(DaCosta of choline.Accordingly,phosphatidylcholinehas patic TGaccumulation, plasmatic TGandVLDL in dosesupto50mg perratandtheincreasenot cholesterol and TGarelikely to move towards on from hepatocytesandbetainemay correct line-deficient diet,YaoandVanceunravelled ecretions from liver,the lmitic acid(16:0) content(Rosenfeld, 1973)- e, betainewasearlyshowntoacceleratePL tes thesynthesis offatinto PLfrom and methionine stimulate thesynthesisof ld, 1973) - and the decreased plasma ld, 1973)-andthedecreasedplasma n) requiresphosphatidylcholine choline, betaineandmethionine, which longerFAaregenerated. which akjian and Haines, 1979), this akjian andHaines,1979),this ionine indirectlycontributeto butnochangeinplasmatic ing theirexportation e (Figure2A)(Mchenry et al.,1995).Latter,in a et al., 1975; Olson et a etal.,1975;Olson subsequent increasein have been reported in have beenreportedin Page 18of267 via 18

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 19of267 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 inositol supplementation ondecreasing theseenzyme activitieswaslessmarked, theirresultswould G6PDH (Glucose-6-phosphatedehydrogenase) and inositol may alsodepresstheact not contributetoreducetheextentoffattyliv and inositol-deficientmice, itwasdemonstratedthat myo such asphosphatidylcholine( Mookerje.S, 1965;Recknagel,1967).Lipoproteinsin plasma andhepaticPLconsequentlytoredu lipoprotein synthesisandleadstoim depletion activities anddecreasedexpressi ( phosphatidylcholine homeostasis that phosphatidylcholine depletion,eff choline-deficient deficient Mdr2 secreted withinbile( methyltransferase: phosphatidylethanolamine intophosphatidylcholine( and Cactivity,theenzymes thatreleasesFFA 1990).Cholinemay al HDL level(YaoandVance, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), e.g. -inositol (MchenryandPatterson,1944;Yagi upregulationofphospholipaseA -/- / Choline deficiency therefor To go further, KO mice for the hepaticenzymeallowtransformation KOmice forthe that of To gofurther, Pemt

Pemt via URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

-/- biliarysecretion(Lietal.,2005). mice) wereproducedbybreedi -/- For Peer Review Only Review Peer within5daysafteranhepatic mice died For Mdr2 535-590. DOI :10.1080/10408398.2010.549596 Pemt i.e. -/- -/- / mice) and/orforthehepaticenzyme thatallowphosphatidylcholinetobe Pemt phosphatidylcholine-specific flippase, multiple drug-resistant protein 2: Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition i.e. - /- mice survived until more than90 days withthe same 50% ivity ofseveralenzymes involvedinhepaticlipogenesis, lecithin) tothe formation of wh on ofcholineoxidase)andthelackphosphatidylcholine e doesnotallowsupplyingthe ect beingattributedtoan paired releasedofhe isactivationofvarioushepa

2 , cholinekinaseandphosph from membrane PL(Singhetal.,1990). ng (Lietal.,2005).Itwas er (Ikeda et al., 1992). Same authors showed that er (Ikedaetal.,1992).Same authorsshowedthat ced lipoproteinsecretionfromliver(Hainesand and Kotaki,1969).However,byusinggerm-free so preventfrom anincreasedphospholipasesA inositolsynthetizedbyin ACC (Ikedaetal.,1992).Sincetheeffectof deed includeamembrane thatcontainsPL patic TGintoplasma, phosphatidyldepletionof50%butthat i.e. phosphatidylethanolamine ich participatech important adaptationofthe tic cholinerecy adequate amount ofPLfor ocholine cytidyltransferase ocholine cytidyltransferase clearly shown thatcholine- testinal microflora do to reducedlevelsof oline, butalso cling pathway i.e. FAS, N 19 - 2

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 plays amajor role inFAsynthesis.Inthe female ratsfed amethyl-deficient diet andin rats consuminglipotrope-deficient DNA hypomethylation andcancers(G transfer theirmethyl groups(lab specifically inliver(Christman etal.,1993).This lipotrope-deficient dietshaveof (Henning andSwendseid,1996,Moon It hasbeenreportedthatlipotr Lipotropes ormethyldonors? positive effectsuponlipidmetabolism andfatliver content(Figure 2A). of betaine,choline and inverse effects(Häussinger,1996).Wemay theref (Guzmán al.,1994).Conversely,tr et lipid transferwithinmitochondr that increases theirvolume -wasshowntoinhibits 1991; Hue,1994),thisenzyme allowingfo swelling inrathepatocytes wasshown toincrease cellular metabolism all osmolytes andmay participate incellvolume re with cellularproteinfunctions-evenathi of betaine,cholineand the intestinallevel(Ikedaetal.,1992). also suggestedthatafractionof Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), In theend,anotherunexpected

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For via myo geneexpressionmodifications (Häu myo Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition -insoitol. Indeed,assmall hydrosol -inositol might contributetocell ope-deficient dietsmay becarcinoge ten beenusedtofavourcarcinogene dietary inositolmay bedegradedor ile methyls) andontheassociati ia) whosedeficitleadtodef diets(Christman etal.,1993;Lo ansfert ofosmolytes intocellw cellular mechanism might beinvol

oelz et al., 1985; Van Den Veyver, 2002) as it was shown in oelz etal.,1985;VanDenVeyver,2002)asitwas shownin et al.,1998,PoirierandWh gh concentrations -,betaine, choline and same way, hypo-osmotic incubationofhepatocytes- rmation ofthemeta whichmammary carcinogenesis was inducedwere CPT-1(carnitinepalmitoy lipogenesis andtoactivateACC(Baquetetal., isbasedonthepropertyofsome lipotropesto gulation, thelevelofce ore hypothesizedthatincreasedcellularcontent ssinger, 1996). Thus, increased cell ssinger, 1996).Thus,increasedcell bolic intermediate uble molecules thatdonotinterfere uble molecules ective FAoxidatio shrinkage withpossiblepotential on betweenanincr nic in the absence of carcinogens nic intheabsenceofcarcinogens cker etal.,1986).Forexemple, sis inrats(Rogers,1975),more usedforfuelbymicrobiota at ill leadtocellshrinkageand itehead, 1973):th ved inthelipotropiceffect llular hydrationaffecting ltransferase-1) (allows

malonyl-CoA that myo n (Figure2B) eased levelof -inositol are is why Page 20of267 i.e. 20 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 21of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 results were furthercriticized by Best etal caseinogen may beconvertedw increasing whileTGpercentage decreasing; andth lipids wasaltereduponhigh-prot (Channon andWilkinson, 1935). counteracted thedevelopment offattyliverinra 17.5 mg gattheexpenseofcar choline/100 that increasingtheproteincontent and linkedtoproteinmetabolism (BestandHunt Patterson, 1944).In1935,ithasbeennotablysuggested The lipotropiceffectofproteinshasbeenve Are proteinslipotropic? inositol), allmethyl donorshavenot used than confounded untilnow(Wuetal.,1998).Theterm the reasonswhybothlipotrope-andmethyl donor-d carcinogenic (GhoshalandFarber,1984;Lockeretal 1986). function andxenobiotic( groups withinorganism wouldfavouranincreased highest number oftumors (Moonetal.,1998).More also characterizedbyDNA hypomet Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), The lipotrope/methyl donor-deficie

lipotrope-deficient diet URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For e.g. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition carcinogens)metabolism (Naussetal.,1982;NewberneandRogers, ithin cholineandbetaine (Cha In thesame study,authorsalsos . Yet,whilealllipotropesarenotmethyl donors( (caseinogen, from 0to50%)ofa beenshowntobelipotropic( ein dietwithphosphatideand hylation inmammarytissuesth

nt dietisthereforetheonl . thatfoundhigherliv ry earlydiscussed and reviewed(McHenryand ts, andtheeffectwasapparentlydose-dependent bohydrates (glucosehydrate,from 50to0%) sman, 1935).Thus,thesame year,itwasshown sensibility towards cancers by altering immune sensibilitytowardscancersbyalteringimmune methyl donor-deficientdiet ey finallysuggested thatsome aminoacids of eficiencies have been, purposely or not, often eficiencies havebeen,purposelyornot,often ., 1986;Wu et al.,1998).Maybethisisoneof generally, adecreasein that hepaticfatdepositswasinfluencedby nnon andWilkinson, 1935).Their e.g. er fatpercentages howed that the quality of liver howed thatthequalityofliver high-fat diet(4

S y dietary deficiency to be y dietarydeficiencytobe free cholesterolpercentage -adenosyl-methionine). at was associated with the at wasassociatedwiththe theamountofmethyl istodaymost often 0%) containing in ratswithin e.g. myo 21 - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 higher hepatic total FAcontent compared tonormal diet-together withalowerlevel of liverPL of activity (Singala (Tucker andEckstein,1938).Thus it wasnotedthatthelipotropice beef muscle proteinandedestin>fibring was obtained bydeceasingintensity: gromax and acids includingthreon except methionine, itwasalsoobservedinratsa cholesterol-liver, notwithhigh-FA-liver-wasot et al.,1953).Asmall lipotropice depending ontheamount oftryptophane,glycineor was alsosuggested(Beveridge etal.,1945)th and Eckstein,1938).Inadditionto in rats(BeestonandCh shown tobelipotropicwhilecystinesupplementati acid wasmore particularlyinvolvedinthelipotropic and cholineintheliver(ChannonWilkin Huntsman, 1932),itwashypothesized increased fattyliver that returntonormality re-feeding rats withanadequate shown tocausehepaticfataccumulation inratsby factor” (Best,1935).Thelackof similar conditions ofdietandtheyarguedthatth Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

In 1969,itwassimply demonstrated thatrats A seriesofproteinswasalso Based onthepreviouslydemonstrated lipotropi

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] nd Eckstein,1939). Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 ine (Eckstein,1952). annon, 1936;TuckerandEcks Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition diet containing18%caseinleadto ffect oftheseproteinscorrelate ffect oftryptophaneandglutam , arachin,aproteinoflowmeth the lipotropiceffectofmethioni an adequateamount ofprotein tested fortheirlipotropicac

that amino-acids from casein after 3weeksofthedi liadin >gelatineandzein(Channonetal.,1938); and son, 1935).Onethereafterwonderedwhichamino- eir dietwouldcontainot herwise reported(Channonetal.,1943).However, en confirmed (Harperetal.,1953)butpartly whale muscle protein >caseinogenalbumin > on by 0.5% in the diet increased fat liver content on by0.5%inthedietincreasedfatlivercontent lack oflipotropic effectforallessential amino- these same authors(Bestetal.,1955); however, effect ofproteins.Meth protein inthediet(H fed a low-protein diet (5% casein only) had a fed alow-proteindiet(5% caseinonly)hada tein, 1937)andlysineha c effectofbetaine and choline(Best and et (Bestal.,1955). d withtheir methionine content tivity andthefollowingranking ne from casein,thatofthreonine ionine contenthadnolipotropic the development ofa“transient” in the diet was however latter in thedietwashoweverlatter ic acid-butonlywithhigh- were converted into betaine were convertedintobetaine her non-protein“lipotropic arper et al., 1954b,Singal arper etal.,1954b,Singal ionine wast d no effect (Tucker d noeffect(Tucker hus rapidly Page 22of267 22 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 23of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 8 7 6 5 9 4 3 2 1 absorption withinsmall intestine the transcription factor liverr Both anincreasedexpressionof level ofhepatictotalcholesterol (Sugano etal.,1982). difference insecretion being not (apolipoprotein A-1)secretionfromisolatedrat casein, soybean proteins werealso shownto and reduced hepaticTGaccumulation (Yangand reduced secretionofhepaticcholes growing andadultsratsfedor Compared tocasein,riceandsoy pr soybean proteinsaffectenzy cholesterol turnover(Iwami etal.,1986).Moreover, hydrophobic peptidesofsoybeanproteinbindingbile effect may beattributable to the lowerdiges cholesterol synthesisinresponsetoincreasedfaecal soy proteincompared tocaseinwass synthesis (Brandsch etal.,2006).In 1c (sterolregulatoryelement binding casein, ratsfedporkprot cholesterol (Boyd etal.,1986).Lipotropiceffect vitamin B12)variedaccordingtotheamount rats andwoodchucksforwhichtheeffectoflipot 27% after6weeks(Osumi etal., Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

vs URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

high-fatandfishproteinspluscholestero 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For ein hadlower hepaticlevelsofTG(-46%) Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition eceptor homologue-1 -andaninhibiti mes involvedincholesterolme not withhigh-choleste hepaticCYP7A1(cholesterol7 and TGwiththefishprotein-cont are notablyinvolved(H 1969). Thelipotropicactionofprot observedwithcorresponding equivalentamino acidmixtures terol intocirculation, hown tobeantihypercholesterolemic of proteinshasalsobeenemphasi ratsreceivingcholesterolintr

oteins were alsoshowntoex protein) andG6PDHconcentrations, ofsoyproteinisolateinthediet( significantly reducecholes tibility ofsoybeanproteincompared tocasein, Kadowaki, 2009;Yangetal.,2007). Compared to ropic factors(choline,me liver, andcholesterol steroidexcretion(Nagat acidsandconsequently rol diet,protectivemechanisms involvinga itwasshowninratsthathighlypurified l diet,resultsshowing osomi etal.,2009). Similarly, compared to an increasedexcretion α tabolism (Madanietal.,1998). aining diet(Hosomi etal.,2009). -hydroxylase) - avenously andintragastrically, on of cholesterol and bileacid via eins wasfurtherunderlinedin ert lipotropic effect inboth zed inratsfedahigh-fatplus decreased mRNASREBP- via terol, TG andApoA-1 thionine, folicacidand a etal.,1982). Suchan stimulation ofhepatic i.e. TG contentsinliver; a significantly lower stimulating hepatic of biliarybileacids

via via i.e. areducedFA activationof 10 vs 20%) 20%) 23 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 The lipotropiceffectofin 2009) spectroscopy: abluntingeffect high-animal proteindietbymeasuri effect ofproteinshasbeenrecentlyc concentrate) restauredserum cholesteroltoits of asupplement oflipotropicf lipid metabolism withinliver,notablyforcholeste decreases inlipid(chole fatty material accumulation uponthelow-protein normal dietcontaining100gprotein made withamildly hypercholeterolemic andhe (Sugiyama etal.,1996). correlated withthelivermicrosomal phospha relative to totalPLthan soybean methionine concentrationinratliver,thatca 1996). Inaddition, authors reported thatlactalbumi accumulation whilesoybean proteins leading to cholesterol, TGandPL egg albumin, sardine, soybeanandwheatgluten,its Lipotropic effectofproteinsseems therefore methionine content.Thus,inratsfed25%either Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), In humans, thelipotropiceffectofproteinswa

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For sterol, PL and TG) and lipoprotein concentrations suggesting impairment of sterol, PLandTG)lipoproteinconcentrationssuggestingimpairment of ositol isomersandphytate concentrations,wheatglutenprot Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition of proteinsuponliverlipids( proteins,andthatmethionine actors (choline,methionine, i or alow-proteindietof25g: ng the intrahepatocellular lipids by onfirmed inhealthyhumans fedahigh-fat

sein leadtoaround10%morephosphatidylcholine normal level(Olsonetal.,1958b).Thelipotropic althy middle-aged alcoholicwoman uponeithera caseinorproteinsfrom rol (Olsonetal.,1958b). the lowest TGaccumulation (Sugiyama etal., has been shown significant variations in hepatic has beenshownsignificantvariationsinhepatic ne andwholeeggproteins to dependonproteinorig diet butitwasobservedin serum important tidylcholine/phosphatidylethanolamine ratio s apparently very littlestudied. Areport was ≈ -22%)wasobserved(Bortolottietal., eins leadingto nositol, vitamin B12andliver content of dietary proteins was content ofdietaryproteinswas liver biopsiesdidnotrevealany lactalbumin,wholeegg, Then theadministration 1 H-magnetic resonance H-magnetic resonance in -andprobablyalso leadtothehighest the highest lipid the highestlipid vs ahigh-fatand Page 24of267 24 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 25of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 shown tohaveasimilar lipotropicaction thanfree dehydrogenase (Katayama, 1995,Okazaki et al.,2003,O importantlyNADPH being usedfor FAsynt involve adepressedactivityof rats withincreasinglevelof and G6PDH,malic enzyme -MEandFASactivi decreased dose-dependenteffecton triacylglycerols, choles al., 2004)andinDDT-fedrats(Okazaki etal., 2003) ICR mice (Leeetal.,2005;Lee important issue. seeds -,thequestionwhetherorno content innumerous PBF,es IP4, etc.(Chen, 2004;HelfrichandBettmer, 2004). ( al., 1982,Steadman etal.,2000)or monoglycosylated regulation andisusedindiabetes (Okazaki etal., 2006). Actually, Conversely, (Andersen andHolub,1980;BeachFlick,1982; 2004). However,toourknowledge,only also present inPBF,butat Besides Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), i.e. IP6)orphyticacidthatisgenerallythemost abundant Phytic acidhasbeenreportedto Myo myo

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] -inositol ispresent inPBFmainly asfree -inositol, inositolpossess8otherisomers, notably chiro For Peer Review Only Review Peer For -inositol consumptionhasb 535-590. DOI :10.1080/10408398.2010.549596 myo -inositol), di-glycosylated terol andbileacidcontents(Leeet Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition a largely lowerlevels than phytae from0.1to2.5%ofthediet pecially grainproducts- lipogenic enzymes suchasFAS andNADPH-generatingenzymes - management (Kim etal.,2005). al.,2007b),inhigh-sucrosefedra t phyticacidhastobe chiro myo several hepaticlipidparameters

-inositol phosphatessuchas reduce hepatic andserum lipid levels indiabetic and aged -inositol isrecognized for it myo hesis -likeME,G6PDHand6-phosphogluconate een reported to increase fat depositsinrat liver -inositol wasshowntoha myo myo ties) wasotherwiseshowninhigh-sucrosefed Okazaki etal.,2006; Yagiand Kotaki,1969). -inositol (Horbowiczetal.,1998,Sosulski -inositol insucrose-fed ratsinrelation witha However, asregardswithhighphyticacid or conjugatedforms suchasgalactinol( i.e. myo via nomi etal.,2004).Phyticacidwas also considered asasourceoflipotropes isan whole-graincereals myo al.,2007b)(Supplemental Table3).A notablyasignificant increase in fecal -inositol (Kim etal., -inositol phosphatefollowedbyIP5, chiro (Katayama, 1997a).Mechanisms myo ts (Katayama, 1995;Onomiet (total lipids and TGcontents, s ability toimprove insulin - and -inositol hexakisphosphate ve lipotropicproperties scyllo , legumes, nutsand 2005; Sanzetal., -inositol that are i.e. 25

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 phosphates from ratstohuman remains highlyuncertainorprematured. source oflipotropesin humans; and theex today, resultsarethereforenotsu myo (Vucenik andShamsuddin, 1994).However,nohuman st adenocarcinoma) showedthatphyticacidmay be within 3 cell lines ( 2002).Another microbial phytaseswithinthecolon(SandbergandAndlid, with phytase-deactivatedwheatbran(Sandberg low pHencounteredinthestomach (as to bemainly duetodietaryphytasesofplantand/or phosphatases arepresentinhumans (BitarandRei been reportedinileostomates (Sandbergetal 60% degradationofwheat ingested phytin (calcium-magne is reportedtobe30-foldlessth phytate inhumans. Thishasprobablytoberelate myo rats, andthenmetabolized anddistributedtova has beenpreviouslyshownthatph phytic acidbefermented withinthecolon(Lopez hydrolysis intofree suggesting ametabolisation ofphyticacidinrats was identical for rats fed either phytic acid or free decreased hepaticlipogenesis(Katayam Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), -inositol contentorimproved liverFAme -inositol and/orIP1(Sakamoto et Yet, phytatewasshownveryearl

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For myo i.e. -inositol bysmall intestinephytasesth mouse Tcellleukemia, human erythroleukemia andhuman colon Comment citer cedocument: branphytateinto Critical ReviewsinFoodScienceandNutrition an inratduodenum(Iqbaletal.,1994). sium saltofphytate) fficiently convincing toconsider ytic acid israpidly absorbed in al.,1993).However,nostudies

y tobedegradedinhumans ba e.g. a, 1997b).Interestingly,hepaticfree forcerealphytases),assh myo trapolation oftheli ., 1987). Although mucosal phytases and alkaline ., 1987).Althoughmucosal phytasesandalkaline tabolism followinghigh-phytateconsumption. Up and Andersson,1988),butalsoduetoendogenous rious tissues,probablyma d totheweakerphytase -inositol penta-, tetra- a uptookassuchand/orpartlydephosphorylated nhold, 1972),thedegrada et al.,2002;Lopez2000).Accordingly,it and mice. Thisisprobablytheresultofphytate microbial originsthatc infaeces(McCanceandWiddowson, 1935).A myo udies havereportedincreasedhepaticfree -inositol (OkazakiandKatayama, 2008), rough anadaptativeresponsebefore stomach andsmall intestine of potropic effectof myo sed ona20-60%recoveryof reportedlipotropiceffectof

own inhealthyileostomates -inositol phosphates as a -inositol phosphatesasa nd triphosphateshasalso activity inhumans which ould beactivatedatthe inly undertheform of tion ofphytateappears myo in vitro -inositol content myo studylead -inositol -inositol Page 26of267 26 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 27of267 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 notably dietcomposition. Such apparentcontradictory result labile andcannotbetransferredtoform methi allow preventingfattyliverwhereascholinedid, 1965). Inaddition, inratsfeda20%-proteinandc demonstrated tobesignificantlylowerinratth (Degrace etal.,2007).However,atequimolar content (>+250%)andasignifican unravelled incarnitine-deficient et al.,2002). reduce liver lipid(TG,PLandcholesterol) contents compared tolowlevel (40mg/kg) (Blanchard and Jeevaratnam, 2009);andinobesecats,highleve saturated ormonounsaturatedFA,pr increase hepatic cholesterolcontent insedentary nonesterified FA(Supplemental Table2)(Rhewa and apparently more marked withTG thanwithot 1989).Theeffectis restrictions (Hu,1975,Ortega, Wolf, 1965),orinratssubmitted toprotein a lipotropic effectinratsfedc As betaineandcholine,carnitine The lipotropic effect ofcarnitine Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), As choline,betaine and

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition holine-methionine-deficient andhi myo rats thatnotablydevelopanim isatrimethylated molecule that hasbeenshown tohavea t decreaseinPLcontent(-22 s haveprobablytobeattribut obably asaresultofanincreased -inositol, thelipotropiceffectof

onine from homocysteine an thatofcholine(Hu,1975;KhairallahandWolf, holine deficientdiet,carnitinesurprisingly didnot nd Sachan, 1986). Indeed, carnitine was shown to nd Sachan,1986).Indeed,carnitinewasshownto vs dose-dependent between0.1and0.8%ofthediet probably sincemethyl groupofcarnitineisnot her classesoflipidsthatarePL,cholesterol and nd/or methionine/lysine (carnitine precursors) excersized rats fed high-fat dietrich ineither amounts, lipotropic effectofcarnitinewas l ofcarnitine inthediet(1000mg/kg)didnot gh-fat (30%)diet(Khairallahand and -36%;Supplemental Table2) portant increaseinhepaticTG ed toexperimental conditions, cholesterolturnover(Karanth carnitinecanbealsosimply (FritzandDupont,1957). 27 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 the bestsourceofcarnitine bothona100gfresh 2.62 and4.98mg/100 gforrespectivelychanterelle, comparing animal- andplant-basedfoods(Bourdi based foods(SelineandJohein,2007),thus for 17liquiddairyproducts,and0.014(orange) - mg/100(Norwegian goatcheese) pheasant) –166.0(kangaroosteak)mg/100 gfor20animal products,0.64(Babybel contents of74foodproductsandobtainedthefo choline, al., 2007),valuesthatarecloser and 0.27mg/100 gdryweight(dw)havebeenrepor and, toalesserextent,milk products(Selinea thousand times lower(Bourdinetal.,2007)andbests and acylcarnitine (2%of thetotalcarnitinepool) contentsinplanttissues isaround ahundredand sesame, cabbage,commonbean,apricotsandbanana (fermented soya), some nuts,seeds,le (Figure 2C)andfrom naturalcarnitine found of carnitineisthereforeto increase exerciseperformances (Decombaz et increased fatoxidationrateasshowninoverweight (Mccarty, 1994). acyltransferase, therate-limiting enzyme inFA mitochondria where theyare Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Body carnitineresultsfrom bot Carnitine ismandatory forth

myo

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] -inositol andmethionine. More For Peer Review Only Review Peer For In humans, itisproposedascommercial 535-590. DOI :10.1080/10408398.2010.549596 stimulate FAoxidation(Hu,1975). Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition β -oxidized toproduce energy (Fi to rangesfoundforBvitaminsin g for20cheeses,2.2(yogurt)- gumes, vegetables,fruitsetcereals( e uptakeoflong-chainFAacyl-CoAfrom thecytosolto

h synthesisfrom dietarylysi generally, Seline andJohein determined total carnitine al., 1992;Lennonet1983). nd Johein,2007).Valuesofrespectively0.32,0.51 confirming conclusionsofBourdinetal in lowamount inPBFsuchasavocado, llowing rangesonafreshweight-basis:3.2(breast food- anddryweight-bas β n etal.,2007).Among PB 4.98 (oystermushroom) mg/100 gfor13plant- -oxidation isactivatedbyexogenouscarnitine subjects (WutzkeandLore ted forrapessed,flaxa mushroom andoystermushroom) appearsas ). Comparedto animal tissues, the carnitine ources areofanimal originsuchasredmeat fat burners gure 2B). Accordingly, carnitine gure 2B).Accordingly,carnitine PBF thanthosefoundforbetaine, 42.8 (condensed milk) mg/100 g tohelploose ne andmethionine contents e.g. is followedbyavocado nd tobacco (Bourdin et nd tobacco(Bourdinet pumpkin, sunflower, F, mushrooms (1.32, nz, 2004),butalsoto The lipotropiceffect weight through ® ) -14.9 . tempeh when Page 28of267 28

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 29of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 animal-based food(ABF)products, andtoalesserextentinsome fermented cereals( combination withcholine andfolates(Laird 1954; QuanandLeBreton,1973;St literature isnotenoughconvinci although itisusedwithinthecomposition ofcommerciallipotrope supplements, one believesthat Suzuki, 1974;Suzukietal.,1976). high proteindietwithoutpyri confirmed untiltodaydespite several studies showing thedevelopment of fatty liver inrats fed a Saheb andDemers, 1972);andthelipotropiceff and Lupien,1974;GavinMchenry,1940;J considered asalipotrope (Carte shown toexertalipotropeeffectinrats(H lipotropic effect ofPBFhasbeenalsoemphasi and Gallay,1964;Navarranne al., 1955),folates(vitamin B9)(K Hoorn etal.,2008),pantothenicaci and betaine,thecontributionofmicronutrients In additiontothewell-recognizedli Magnesium andBvitamins The contribution ofmagnesium and vitamin banana (0.10mg/100 g)andapple(0.05 (0.43 mg/100 g),carrot(0.40mg/100 g),cauliflowe Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Lipotrope effect hasalso beenreported for

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition doxin (AbeandKishino,1982;OkadaOchi,1971; r andPhizackerley,1951)duetofurt ng tovalidateitasalipotro et al.,1964;Warembourg and elley etal.,1950;LairdandDrill, d (vitamin B5)(Catolla Therefore, althoughsome haveconsidereditasalipotrope and potrope compoundsthatarecholine, . GreifandWenning, 1954;Shils

mg/100 g)(SelineandJohein,2007) alliday, 1938),pyridoxin(vitamin B6)wasnolonger s Btotheoveralllipotropiceffect such asniacin(vitamin B3)(Perry,1960,VanDer zed (Supplemental Table1).Althoughveryearly ohnston etal.,1961;Mc Drill, 1971),thisBvitamin beingonly presentin r (0.36mg/100g),cucumber (0.19mg/100 g), vitamin B12(cobalamine) eitheralone(Drill, ect ofpyridoxinhasnot CavalcantiandLevis, pe, especiallyinhumans. Bertrand, 1964)totheoverall her contradictory results(Audet 1971) andmagnesium (Colson andStewart,1954)orin myo henry andGavin,1941; -inositol, methionine beenconvincingly 1950;Turchettoet e.g. beer) 29 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 19 18 17 16 15 14 13 12 11 10 25 24 23 22 21 20 26 9 8 7 6 5 4 3 2 1 methionine depletionwereof-39and-68%for liver histopathology and byaccentuationof chronically ethanolfedmicropigs th (Zeisel, 1981),thusimportantly formation from homocysteine is itsactionasprecursorofth For folates(orfolicacid),themechanism involvedin Folates (vitaminB9) especially for niacin. The mechanisms bywhichmagnesium andBvitamins may limit fat deposits are multi-factorial, Physiological mechanismsassociatedwiththe and Newberne,1969;Wuetal.,1998). vitamin B12deficiency(Christman etal.,1993;M Accordingly, carcinogeniclipotrope 2A) (GillisandNorris,1951; allowing methionine formation inawaysimilar to corresponds tothetransfertofa where itissupplied by yeast. It is notably invo lipotropic effectoffolic acid hasbeenalsoempha chronically ethanolornot fed compounds ACC(key inlipogenesis) SREBP-1c and on geneexpression in relation with lipid meta the same researchteam showedthatfolatedefi nopn-alcoholic andfolate-sufficien Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

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Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition via e methyl donor5-methyl tetrahydrof micropigs (Supplemental Table1)(Esfandiari etal.,2005). The participating inthelipotropic e methyl donation,andlatterto Jaenicke andRudiger,1971; methyl groupfrom5-methyltetr t micropigs; Supplemental Table1) at folatedeficiency accelerated -deficient ormethyl donor-defic

lipotropic effectofB ciency wasalso accompanied bysignificanteffects bolism, notably anincr respectively folates-sufficient andfolate-depleted abnormal methionine metabolism ( lved withinthe process of transmethylation that sized inrats(Drill,195 the action of betaine withhomocysteine (Figure oon etal.,1998;Newberne1971;Rogers itscontributiontothe - butnoeffectonFAS ffect. Thus, it has been shown in ffect. Thus,ithasbeenshownin choline regenera Newberne andRogers,1986). vitamins andmagnesium alcoholic steatosis asshownby ahydrofolates tohomocysteine olate thatleadstomethionine (Halstedetal.,2002).Latter, ient diets generally include ient dietsgenerallyinclude eased mRNA expressionof 4; Kelleyetal.,1950),but overall lipotropiceffect mRNA expression–in tion (Figure2A) i.e. hepatic Page 30of267 30 vs

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 31of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 (decreased totalfat, neutral fat andnon-esterified diet (Schön,1958).Then, Bakeretal that arelativelackofCoenzyme partly reversedincreasedhepaticcholesterol showed thatincorporationof3- cholesterol contentinrabbits addition of0.4%nicotinicacidtoaninitial2 FFA contents(Orbetsovaetal.,1977).Conversely, atherogenic diet(2%cholesterol) increased hepatic nicotinic acid(250mg/kg b.w.)inspontaneously chloride (HandlerandDann,1942);adaily acid wasshowntoinducefattyliverinrats,the i.e. diet (18%fat),theincreasedrangebeingmore ma around 4%inratsfedduring8daysaniacin-supplem Rikans etal.,1965):forexample, GriffithandMulf et al.,1960;GriffithandMulford,1941b;Merrilla effect ofthisvitamin Bonhepaticlipidmetabolis to theoverall lipotropic effect of PBF,first report Although wechosetoconsiderniacin(vitamin B3 Niacin (vitamin B3) 2003), aCVDriskfactor. concomitant withtheirabilitytoreducehyperhomocys initially presentinthediet(L it appearstobeeffectiveonlywhenadequateam Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), from 12.5to19.9%(GriffithandMulford,1941b)

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Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition from 6.55to1.51%(MerrillandLemley-Stone,1957).In1958, Schön aird etal.,1965).Thissupportive 4% nicotinicacidinahypolipot A(CoA)may beresponsiblefor

. showedthatnicotinic acidmay preventhepatic steatosis concentration byaround42-46%inrats,advancing effect beingcounteracted %-cholesterol dietlargelyloweredaverageliver ed results werequitecontradictory as regards with FA levelstothenormality) inethanol-treated rats m (Bakeretal.,1977;Bake rked inthepresenceof0.04%cholinechloride- ord observedanincreased injection duringonem Merrill andLemley-Stone lattershowedthatthe nd Lemley-Stone, 1957;Orbetsovaetal.,1977; or vitamin PPornicotinicacid)ascontributing ounts ofotherlipotropes,notablycholine,are cholesterol, TG,total hypertensive ratsfedeithernormal dietor ; inaddition, a2%-supplementation nicotinic ented diet(22.3%fat)ascomparedtobasal teinemia (Brouweretal ropic dietfree the effect ofth lipotropic effect of folates is lipotropic effectoffolatesis when adding0.4%choline lipid, andesterified onth ofahighdose liver fatpercentageof r etal.,1973;Gaylor ., 1999;Moatetal., from cholesterol cholesterol from e hypolipotropic 31 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 17 16 15 14 13 12 11 10 18 9 8 7 6 5 4 3 2 1 due totheimportantneed in hypothesized thattheantilipotropic methionine (Bakeretal.,1977;Rikans and byblockingvitamin B12fromactingasaco-f transmethylation processbypreventingmethionine although plasma TGlevelisgene the potentiatedhepaticstea al (Baker etal., 1977).Although0.1%niacin-supplement also forPLcontent(-52%),indicating“that forTG(-26%)andeffect becoming chol significant 0.5% cholinedihydrogencitratetoth esters andnon-esterifiedFAcontentsbuteffect -40, +94,-14,+116and+33%changesinrespectively the studyofBakeretal 0.1% havebeenobserveddespitethepresenceofcho excess fat deposits inhigh-fat- ornormal-diet-fed ra effect wasnotsignificantduetoa supplemented withniacin,50mg reduced niacin/kg synthesis havebeenhypothesizedinthisstudy lipogenesis) andapossibleinhibition offatdepot fatty liversinducedwithCCl importantly reducedifferentlipidfr adipose tissuethatwasinducedbyethanol(Baker and hypothesizedthatnicotinic acidmay havedepr methionine) andthermophilic yeast Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), . interestingly s

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] For Peer Review Only howed byusingthe Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 . , the0.1%niacin-supplementation ofrats Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition tosis inducedbyhighdosesofnico methyl groupsofitsdetoxifica 4 andoroticacid: competitiveness high variabilityindata actions (totallipids,cholestero rally decreased-may beascribed effect ofnicotinicacidat hi Torulopsis pintolopessi e 0.1%nicotinicacidleadtoreductionforalllipidclasses,

in vitro models al., 1964).Accordingly,ithadbeenpreviously s werenotsignificant(Baker etal.,1977).Adding niacin interferes withcholine-inducedlipotropism” (Vaishwanar et al., 1972). And in laying hens (Vaishwanaretal.,1972).Andinlayinghens mobilization andTG/FFA et al.,1973).Nicotinicacidwasalsoshownto ess themobilization of to providemethyl groups line (Bakeretal.,1977;Rikans1965).In ts supplemented withni esterol ester(-7%) contents,but surprisingly actor inthemethylati fatinfiltrationinliverbyaround29%,but hepatic PL, TG, free cholesterol, cholesterol hepaticPL,TG,freecholesterol,cholesterol ation wasnotnutritionally realistic,Bakeret Escherichia coli (HartfielandKirchne (requiringcholineormethionine) that tion products(Schön,1958) -notably gh doses(from 1to4%)might be fed a choline-deficient dietleadto fed acholine-deficient tinic acid (Sorrell et al., 1976) - tinic acid(Sorrelletal.,1976)- with CoA synthesis(involved in l, lipidphosphorusandTG)inrat (requiring vitamin B12 or (requiringvitamin B12or toitsinterf non-esterified FAfrom on ofhomocysteinein acin atahighlevelof forcholinesynthesis r, 1973).Conversely, availability forlipid erence in the erence inthe Page 32of267 32 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 33of267 19 18 17 16 15 14 13 12 11 10 26 25 24 23 22 21 20 9 8 7 6 5 4 3 2 1 the lattercase.Authorss former casenochangeswereobserved whileastim incubation medium ofliversli injected inrats during 21days in 2-C rate ofacetateincorporation into cholesterol synt in thecholesterolsynthesispathway,asforFA Other advancedthatnicotinicacidwoulddivertc nicotinuric acidathighdosesof CoA neededforcholesterol synthesis, CoAcompe 1957; Perry,1960;SchadeandSaltman, 1959;Schön,1958), authors tosignificantlyreduceitscontentand liver inducedbyexcessniacin(Baker 1951,Handler, 1944;Perlzweigetal., deficiency” andleadingtoimpaired secretionoflip off methylgroupsfromcholine (Institute of Medicine,1998);whichl excess niacin beingmethylated intheliver to nicotinamide thatrequiresmore methyl groupsfo to partlyresultfrom marked redu lowered serum cholesterollevels(Miller etal (Orbetsova, 1977).Inhumans, nicoti b.w.) adecreasedhepaticcholes (Orbetsova etal.,1976). or singleinjectionwouldnotinflue Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), 14 More specifically, concerning liver cholesterol, sodium acetateaccording to themode ofadmini

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Accordingly, theyobservedinratsinj uggested thatchronicadmini Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition ces ataconcentration of10 nicotinicacid-andlipids ction inhepaticcholes before killingatalevelof20 terol andTGcontentafter6hour nce cholesterolsynthesisatthesame levelofthemetabolic chain and/or methionine synthesisl nic acidadministration -from 1 etal.,1977;Rikans1965). 1943). Indeed,additionofcholine ead toassimilate nicotinicacid

., 1960;Parsons,1961b), suchreductionbeinglikely formation (Perry,1960).Inanotherstudy,different holesterol precursorstowardsoxidationratherthan r excretionthannicotinicacid(Milleretal.,1960), hesis wereobtainedwithra ting withdetoxication systems -notablytowards rate ofbiosynthesis(M N ulation of acetateincorporationwasreportedin ids from theliver(Bakeretal.,1977;Cantoni, -methyl-nicotinamide thenexcretedinurine stration ofnicotinicacid nicotinicacidhasbe terol synthesis(Parsons, 1961b).Thus,from stration ofnicotinicacid,eitherchronically ynthesis (SchadeandSaltman, 1959). -3 an effectattributed M(Orbetsovaetal.,1976).Inthe ected withnicotinic mg/kg b.w.ordirectlyaddedto eading toafunctionalcholine s with increaseafter3hours s with to 2g3times daily-leadto to a“methyl trapthatdrains generally revers errill andLemley-Stone, t liverslices incubated en shown by different en shownbydifferent vs to alackofacetyl- directincubation acid(250mg/kg es thefatty 33 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 22 21 20 19 18 17 16 15 14 13 12 11 10 25 24 23 9 8 7 6 5 4 3 2 1 mitochondria beingthesiteofFA levels ofreactiveoxygen species(ROS)th non-alcoholic steatohep a decreased expression of superoxi oxidative stress decreasing totallipidcontentandincreasinganti apparently nutritional doses - fed ratsthatacoppernicotinic the hypolipidemic capacityofniacin,Salama etal mg/kg bodyweight(Mayoretal.,1967).Basedonth lack ofeffectnicotinic acidon hepaticacet CoA arenotaffectedby nicotinicacid(Yeh,19 oxidation, suggestingthatenzymes requiredforpalmitate carnitine (Figure2C). with pyridoxin,vitamin C,ironandotherenzymes, with palmitic acid,CoA, carnitine and nicotinicaci mechanisms bywhich nicotinicacidi enzyme involved inFAsynthesis(Fomenko etal (from 19to100%forrespectively metabolism. results betweenstudies. i.e. or more other lipotropes withvariationsaccordi these studies,itseems thatnicotinicacidinducesfa Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), singleinjection Other mechanisms might beinvolvedinthe

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] In vitro via Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 accumulation offreeradicals beingacausethatmay leadtofatty liver.Indeed, vs , nicotinic acid hasbeen chronicadministration. Thatwouldpa atitis (Sreekumar etal.,2001).Such Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition i.e. acid complex (atherapeuticdrug), 400mg/kg -,isabletocorrect de dismutase hasbeenobserved β 10 to100mkmoles ofnicotini -oxidation (Sreekumar etal.,2001

nhibits ketogenesis,whenincubating thus showntoimportantly at may yieldmutation inmitochondrial DNA, ng toanimalspeciesandmodes ofadministration, 76). Thiswouldconfirm previousresultsshowing yl-CoA concentration atan . interestinglydemonstrat tty liver only at high doses and in absence of one tty liveronlyathighdosesandinabsenceofone oxidant status(Salama etal.,2007),increased ., 1979).Yet,withthe d, thislatterhadnoinfl participates inthe synthesisof thelipotrope e antioxidantpropertyofcopper(Cu)and positive effectofniacinonhepaticlipid β -oxidation andthepr a decreasegenerallyleadtoincreased rtly explainapparentcontradictory fatty liverbynotab administered bystomach tubingat c acid) ACC activity, the main c acid)ACCactivity,themain in patients with cirrhotic stage ). Finally,niacin,together objective ofunravelling inhibit at various doses inhibit atvariousdoses ed inhigh-carbohydrate uence ontherateof injectionlevelof50 in vitro oduction of acetyl oduction ofacetyl ly significantly mitochondria Page 34of267 34 β - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 35of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 (around 1-3gdaily)may behepatotoxic-andalso of niacin(Grundy etal.,1981).Howeve al., 2001).A similar reductionwasobservedwithhype was showntodecreasebothacutelyandchronica 1979). Theeffectofnicotinicacid cholesterol levelsandraisingplasma HDLcholeste hyperlipidemia (Figgeetal.,1988;Grundy clinically asadrugathighdoses(generally3-6g hypocholesterolemic (Altschuletal.,1955,Parsons 2003); andconsequently9°)reduceHDL expression ofATPsynthase reduction of hepaticatherogenicli acyltransferase), thekey enzyme forthesynthesis of triglycerides, finally resulting inapotential from HDLtopro-atherogenicap Protein) mRNA (VanDerHoornetal to ApoA-1form nascentHDL expression (SiripurkpongandNa-Bangehang,2009) Bangehang, 2009);5°)up-regulateABCA1(ATP-B (PPAR reduce intracellular cholesterol (total, free al., 1997;Van DerHoornetal.,2008);2°)increas accelerated ApoB(aTG-richlipoprotein) degradati HepG2 cellsshowedthatniacinmay: 1°)inhibi positive effect of niacin onhepatic lipidmetabo Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), α In thefifties,Niacinwasotherwisereporte Recent studies allowed unravelling newmechan

regulates FAoxidationandstimulates regulates pe

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition β chain-thislattermediatinghepa was alsotestedinhealthywome oB-lipoproteins; 7°)inhibithe poprotein secretion(G ; 6°)reduceexpressionofCETP

., 2008)-CETPmediates thetransfer r, withinclinicalth uptake byHepG2cell(Zhangetal.,2008). and esters);4°)induceexpressionofPPAR t TGproductionandFA synthesiscombined with lly VLDL-TGproductionratefromliver(Wang et al., 1981)bynotablyreduc daily) inthetreatment of lipiddisorders suchas rol level(Chapman etal.,2010;Shepherd lism (Figure 2C). Thus, results obtained with on (Jin et al., 1999; Jin et al., 1996; Kashyap et on (Jinetal.,1999;Jin1996; Kashyapet e efflux of HDL ApoA-1 (Jin et al., 1997); 3°) e effluxofHDLApoA-1(Jinetal.,1997);3°) roxysome proliferation)(SiripurkpongandNa- - ABCA1effluxesexcesscellularcholesterol and Flinn,1959),istodaywidelyused d tobehypolipidemic inhumans, notably rlipidemic patientsgiven1gthreetime daily leadtovariousundesi inding CassetteTransporter1)mRNA anji etal.,2002);a isms thatmay contribute totheoverall erapy context,such tic HDLendocytose(Martinezetal., patocyte DGAT(diacylglycerol n atthehighdoseof2g/dayand (Cholesteryl Ester Transfer nd 8°) inhibit surface nd 8°)inhibitsurface

ing plasma TG and ing plasma TGand of rable, butgenerally high-dose ofniacin

cholesteryl α mRNA mRNA

esters 35 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 a studyinhyperlipidemic subjects nicotinic acidduring2weeks reducescholeste al., 1998).Othershaveshownin liver oradirectinhibitionofhepaticsecretion/ concentrations (Grundyet production (Chapman etal.,2010;Figge etal.,1 1999), asnotablyshown plasma throughinhibitionofcatecholamine stimulati and skintemperature(Schweikartet mg-dose (Schweikartetal.,2009). observed thata16.7mg-doseniacindoesnotcausefl lower dosesofniacinupto50.1mg dailyhaveb studies 2yearslaterin10hyperc Flinn, 1959)althoughsignifican several livertests, andneedle biopsies didnot sh nicotinic acidtherapyin17patients, nicotinic acidisnotcontraindicate histological alterationsthatwere hypercholesterolemic humans chronicallyadminister side effects(Welsh andEde, of or methionine (Aronovetal.,1999)decreasedhepato 1994; SchwenkandFisher, 1994;Stern,2007);but the Etchason etal.,1991;Lawrence,1993;Pardue, slow/sustained-release niacinas reversible, side-effectsli Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), myo -inositol hexanicotinateinsteadofniacinalone,

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For ke blushing/flushing,itching,gastroin Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition al., 1981).Thismay occur in vitro 1961);andBaggenstosetal alsoreportedinhealthypatients,andconcludedthattheuseof compared toimmediate-releaseni t alterationsinhepaticfunction (Carlson,1963),leadingtore holesterolemic patientsamong that wereadministered1 to2g d incarefully supervised patient In addition,nochangeoccurs al.,2009).Inaddition, nondiabetic patientsth

no significanthepaticalterationwasfound rol synthesisbyaround50% (Nunnetal.,1961).And synthesis of ApoB-containing lipoproteins (Tato et synthesis ofApoB-containinglipoproteins(Tato et ow anyfatty changesor abnormalities (Parsons and 988) andresulting indecreasedplasma VLDL-TG 1961; Raderetal.,1992;Reimund andRamos, een testedinhealthyvol ed 1.5to6gnicotinic via on ofTGlipolysisinadiposetissue(Arner, ushing symptoms, thataresporadicata50.1 toxic risk.Othersreportedthebeneficialuse co-administration ofbetaine(Mccarty, 2000) myo eitherareduced transport ofFFAtothe niacinmay reducethereleaseofFFAin -inositol hexanicotinatebeingfreefrom at theadministrati testinal irritation,… . (1967), concerning bloodpressure,pulse 36 (Parsons, 1961a).Recently, tests were reported in another tests werereportedinanother daily nicotinicacidhas lead to acin (DaltonandBerry,1992; duction ofhepaticVLDL-TG s. Similarly, afteroneyearof unteers andithasbeen via acid, observedminor on of2gdaily liverbiopsiesin -, notablywith via theuseof Page 36of267 36 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 37of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 6 5 4 3 9 8 7 2 1 Pantothenic acid(vitamin B5) 2C basedonreferencescitedpreviously niacin therefore appear multifactorial as wehave te compared topantothenicacid-supplemented and observed inpantothenic acid-defici and progressiveincreaseinlipid was shownthatpantothenicacidde the rolethatpantothenicacidmay playinfatt amounts ofbothinositolandcholinetodietscontai and Lewis,1953).However,fattyli synthetized from cholesteroland fat metabolism seriouslyimpaired inpantothe (Guggenheim andOlson,1952).Otherssuggestedthat explanation fortheobserved reducedliverfat being constitutiveofthe transformation ofacetateintochol cholesterol fedrats(Guehringetal.,1952),pant (Engel, 1942;MorganandLewis,1953),notably acid andpyridoxine)orapantotheni First, iswasfoundthatfeedingratswithaB and Hockaday,1962;GriffithMulford,1941b;Morg As forniacin,apparentcontradict the hepaticlevel(Parsons,1961a). suggest thatserum cholesterolreduc Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Compared tootherlipotropes,physiologicalmech

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globulesinratliver(Wirtschaf pantothenic acidbeinginvolved ory resultshavebeenalsorepor esterol (BlochandRittenberg, 1942) ent andhigh-fatfedrats areducedhepaticneutralfatcontent ficiency may leadtofattyliverindogs(Schaeferet al.,1942) ver wasreducedtonormal level tion hastobeattributedreduc c acid-deficientdietprevented

andonthosefrom Supplemental Table1. y liverdevelopment (Engel,1942).Thesame year,it vitamin- (includingthiamine, riboflavin,pantothenic nic acid-deficientrats,adrenalhormone being high-fat fed rats, with no difference for hepatic high-fat fedrats,withno differenceforhepatic ning Bvitamins thusmode ntatively summarized andillustrated itinFigure othenic acidbeingindirectlyinvolvedinthe content ofpantothenic adrenalhormone productionisreducedand an increasedcholesterolcontentinhigh- an andLewis,1953;Schaeferetal.,1942). anisms involvedinthe ke hasbeennotably ter and Walsh, 1962). It was also ter andWalsh, 1962).Itwasalso in cholesterolsynthesis(Morgan ted forpantothenicacid(Carter tion of cholesterol synthesis at tion ofcholesterolsynthesisat the development offattyliver in ratswhenaddingadequate via acetyl-CoA actionand rating andrelativising acid-deficient rats lipotropic effectof proposedasan 37 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 process (MahboobandEstes, 1978). gain inratswithprobable hepaticmitochondrial (Ueshima etal.,1956,Ueshima etal.,1958),andpant being hypothesizedaspossiblem and cholesterolesterreductionby content withnoeffectontotalPLandfreecholes (phosphopantothenate, pantethinea hypothalamic obesityinducedbyaurothiogl content of40%compared tonon-deficientrats acid-deficient ratskeptondietformore than significantly, thetotallipidconten fed rats(Fidanzaetal.,1970).Latt 1969) whilenochangeinhepati reduced thehighhepaticTGconten in TG(Williams etal.,1968).In1969,Osumi etal considered, increased liverweightandFAcont 1968, Williams etal the dietfrom 5to20mgdespitealargelyhighe were reported,nohistologicalch hepatic fattymetamorphosis andfinecoarse Levis, 1950,Turchettoetal.,1955).Inpantothenicaci Italian research teams reportedlipot tendencies werereportedwithlo total cholesterol,freecholes Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

More generally,pantothenicacid

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] e.g. For Peer Review Only Review higher levelsofstearateandarachidonate Peer For 535-590. DOI :10.1080/10408398.2010.549596 . showedthatsupplementing low-fator Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition terol andPLcontents(CarterHockaday,1962).Thesame c lipidcontentwas observedw w-fat diets (Carter andHockaday, anges beingobservedwhenincreasi echanisms (NarutaandBuko,2001). t ofliverinducklings(Saheb er, pantothenicacidcarencehasb panthenol, reducedresistanceto nd panthenol)importantly andsi ropic actionofpantothenicacidin t initiallydeveloped ents but not that of PLwith

isrecognized asmaintain wasalsoobserved(Mahboob,1975).Inmice with 75days,significantlylowerphosphatidylcholine terol, andsignificanteff r weightgain(Gersho dysfunctions likeaslower vacuolar formation withlipids evenly deposited d-deficient cats(only0to3mg/kg diet),some . othenic aciddeficiency showed inratsthatCa-pantothenatepartly ucose, pantothenicacidderivatives through alow-proteindi in PLandhigherproportionoflinoleate high-fat fedratswithpantothenicacid ith pantothenic-deficient- and Demers, 1972).Inpantothenic 1962). Conversely,inthefifties, variations accordingtotheFA gnificantly reducedhepaticTG insulin andlipolysisactivation een showntoincrease,butnot ng pantothenicacidcontentof ing normalhepaticfunctions rats(Catolla Cavalcantiand ff andGottlieb,1964).In ect upontotalcholesterol rateoftheoxidation lead tolowerweight et (Osumi etal., vs normal- Page 38of267 38 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 39of267 25 24 23 22 21 20 19 18 26 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 main lipotropes-choline, obtained withbothniacin andpantothenicacidproba Supplemental Table1thatreportsmo to theiracyl-CoAthioesters”(Youssefetal.,1994). that such an effectmay resultfrom an“adaptation chain acyl-CoAsynthetasethat low-protein diet(Osumi etal.,1969 The liveracyl-CoAcontentwas always lowerwiththehigh-fatdiet(18%)than pantothenic acidsupplementation fo the hepaticCoAcontent(total CoA activityinratliverforthefirst2dayscomp Accordingly, anincreased inpantothenic acid regulation ofperoxisomal peroxisomal Hauhart, 1992).Inaddition,pant alone, theincrease inCoAcontentbeingalso pantothenate plus valproate –thatinhibitsFAoxi et al.,1987).Latter,thehepa total CoAcontent wassignificantly reducedinpant Song, 1996)thatisactivein acid activeform)(Kaplan andLipmann, 1948;Lipmann Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Such resultsemphasized differentpantothenic Pantothenic acidisotherwisebothpr

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β -oxidation thatwasrestauredtonormal 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For L -carnitine and Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition betaine, methionine and β -oxidation wasparalleled withareducedactivity of thehepaticlong- tic freeCoAcontentreductionof dation -wasshowntobepartly activates FAdegradation(Yousse β otherwise increasedbyCa-pantoth -oxidation, themain pathwayto , acid-solubleandlong-chain othenic acid-deficient ratsexhi L r bothlow-andhigh-fatdietsin ). Similarly totheseresults,ithasbeenshownthatthehepatic -cysteine withnoeffectwhen st relevantstudies).We believe

ecursor andconstitutiveofCoA( consumption (5mg daily)wasshowntoenhance with thelow-fat diet(6%) (Williams etal.,1968). observed inabsenceofvalproate(Thurstonand ared toacontrolgroup(Causietal.,1958).And to thereduced abilityof theliver toactivate FA othenic acid-deficient weanling rats (Moiseenok myo bly depends on the presence or not of the other bly dependsonthepresence ornotoftheother acid effectsonhepatic level followingsupplementation: thisdown- -inositol -orotherBvitamins, butalsoon et al.,1947;Novelli1949;Smith and reversed whensupplemented with f etal.,1994).Authorssuggested developpingmice treatedwith acyl) wasincreasedfollowing enate after being decreased by a enate afterbeingdecreasedbya bited alower level of hepatic rats whilethe CoAvalues were FA degradation(Figure2B). that the contradictarory results that thecontradictaroryresults L -carnitine was administered lipid metabolism (see i.e. thepantothenic 39 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 17 16 15 14 13 12 11 10 21 20 19 18 26 25 24 23 22 9 8 7 6 5 4 3 2 1 ATP. Allof theseproperties of magnesium playa role in the overall FA presence ofATP.Itisalsorequiredbymito acyl-CoA (Figure2B),anditactivatesCoAsynt also particularly involved inthereaction of 1993). Magnesium hasbeenalsoshowntore 1997), andalowmagnesium dietwas low plasma levelofmagnesium alsobeenasso has hypomagnesemia associated withNAFLD andnon-alc concentration from 0.01to5mM increase ofpalmitate oxidation and Green,1958).Theroleofmagnesium onFA 2B) (Andrieux-Domont andLeVan,1970;Berg,1959; Concerning magnesium, itsdepletion contributing tothe overall lipotropic effect of PBF. and insulin resistancemay beassociated with Supplemental Table1)(Fritz,1959). Magnesium used inlipotropicsupplements. normal doses andincludingthepr considered ascontributingto This is the reasonwhy inthe e B-vitamins, notablyniacinandpant doses andanimal speciesused,andonexperimental Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), More specifically,magnesium iswellknownas As regardswiththesespecific properties of

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535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition the overall lipotropic effect of PBFinnormal dietary conditions, reached inheartmuscle mitoc nd wehaveconsideredthatniac inpresenceof carnitine( esence ofotherlipotropes.Nowa othenic acid-probablyexertsin has beenassociatedwithcirr otherwise showntodecreaseinsu

duce hyperlipidemia (Kis CoA withATP(Mg-ATPcomplex) andFFAtoyield chondria for oxidative phosphorylations that produce chondria foroxidativephosphorylationsthatproduce hesis from pantothenic fatty liver,magnesium maybeconsideredas magnesium andsinceincreasedoxidativestress oxidation waswellillustrated by thedramatic Ithasmoreoverbeencited aslipotropeinthe scheme. Inother words,thelipotropicactionof ciated withinsulinresistance (Rosolovaetal., oholic steatohepatitis antioxidant(Freedman etal.,1992).Itis GarfinkelandGarfi ≈ +800%)oracetylcarnitine ( hondria whenincreasingmagnesium in andpantothenicacidmay be hosis (Koivistoetal.,2002),and days, itisotherwisecommonly synergywithotherlipotropes. ters etal.,1993). lin sensitivity(Nadleretal., β -oxidation process(Figure acid proportionallytothe (Hanje etal.,2006).A nkel, 1985; Ingraham nkel, 1985;Ingraham ≈ +950%; i.e. Page 40of267 40 at 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 41of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 around respectively1965, 1970,1990and1995(Supplemental Table2). and melatonin, theirpositive effect onhepaticlipidmetabolism appeartohavebeenputforward begins inthenineties.Finally,concerningunsat Interest fortheeffectofpolyphenolsandderi seventies, greatinterestwasbroughttofibe rate oflipogenesisandFAsynthe high-cholesterol fedmice (BeherandAnthony, 4). Theexceptionwas polyphenols, saponins,unsaturatedandshort-chainFA other phytochemicals, notablyhydroxycitric lipid metabolism, itappearsthat this isnotbefore theendof thesixties thatresearch focused on and high-fat(30%)fedrats(seeSupplemental and carnitinewasshown toimporta 1950). Theeffectofcarnitine onFAoxidation wasre emphasized around1950(CatollaCavalcantiandLe Eckstein, 1937);then,alwaysinrats,thelipotr early between1932and1941(BestHuntsman, Lipotropic effectofcholine,betaine,methionine and Other phytochemicalsandplantextracts effects of amagnesium therapyinpatients withfatty liver. current commercial lipotrope complexes. There clinical reportofColsonandGa Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), From thesurveyandanalysisofstudiesdea

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For β -sitosterol thatwasreport Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition llay (ColsonandGallay,1964)iscommonly assuchin used sis inratliver(Lowen ntly reducehepaticTGcontentin

Tables 1and2)(Khair r andderivedcompounds (Supplemental Table3). ved compounds onhepaticlipidmetabolism really urated FA,organosulfurcompounds, FA short-chain 1955). Around1970,HCAwasshowntodecrease opic potential of vitamins B was apparently first opic potentialofvitamins Bwasapparently ed in1955toreducehepatic are howevernohuman studiesinvestigatingthe acid (HCA),organosulfurcompounds,fiber, ling witheffectofplantcompoundsonhepatic 1932; Gavin andMchenry,1941b;Tucker myo vis, 1950;Kelleyetal.,Tyner ported inratliverslice1959 (Fritz,1959) ormelatonin (Supplemental Tables2,3and stein, 1971;Sullivanet -inositol hasbeenunravelledinratsquite allah and Wolf,allah and 1965). choline-methionine-deficient cholesterolcontentin al., 1972); and in the al.,1972);andinthe 41 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 15 14 13 12 11 10 21 20 19 18 17 16 26 25 24 23 22 9 8 7 6 5 4 3 2 1 mainly isolated from fruits of the effects onhepaticlipid metabolism: theywere phytochemicals thatcome fromspecificbotanical magnesium, niacin,pantothenicacidandfolatesa Besides the8previouslydefinedlipot Specific plantcompounds:hydroxycitric (Adams etal.,2005). lipotrope sincesteatosisismos lipid orTGcontents.Thosedecreasingonlyhepatic considered aslipotropiccompounds oflipogenesis(SupplementalSREBP, orrate Tables Hydroxycitric acid 2). Allium loosing weight,andcysteine-c 1998; LewisandNeelakantan,1965)usedinco lipogenesis inratliverfollowing ei high-fructose fedratsupplemented withHCA(B contradictory resultsobtained,astheincreased pos The lipotropic effect of HCAmay howeverappear on lipogenicenzyme activities,FAoxidationen positive effect onlipid metabolism hasbeen reported, myo Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), -inositol, vitamins B,magnesium, carnitinea

Now, wethereforeconsidere allphytochemicals species (

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s-ethylcysteineands-methyl cysteine Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition ontaining compounds astheorganosulfuredcompounds foundin tly concernedby TGaccumulationorretention withinhepatocytes Garcinia ther i.v./i.p.HCAinjection or sensu stricto

ropes that arebetaine,choline, acidandorganosulfurcompounds family, notably

onlythosethatsignifica zyme activities, gene HCA (Lowenstein, 1971; Sullivan et al., 1972) HCA (Lowenstein,1971;Sullivanetal.,1972) nd phytate-forwhichat 1-4). However,inthe followingsectionwillbe families havebeencitedashavingpositive t-prandial hepaticlipid nd that are quite ubiquitous in plants, other nd thatarequiteubiquitousinplants,other cholesterolcontentmay notbeconsideredas mmercial nutritionalsupplements thataim at controversial asillustrated by the apparent randt etal.,2006),th be on total lipid, TGorcholesterol contents, - otherthanbetaine,choline,methionine, in onionorgarlic)(Supplemental Table Garcinia cambogia ally ingestedHCA(Lowenstein, expression ofPPAR myo ntly reduce hepatictotal content of chronically -inositol, methionine, e decreasedrateof least one significant least onesignificant (Heymsfield etal., α and Page 42of267 42 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 43of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 effect wereobservedin overwei subjects aftera8week-HCA treatment (750mg daily, supplementation (-0.5to-1.5kg)(Kovacsetal (Preuss etal.,2004a), reduce weightgainandBMIinobesesubjects infusion (Supplemental Table2) lipogenesis followinghigh-doseHCA consumption(6 1986). FA oxidationinthemetabolic c inhibition ofATPCL)(McCarty,1994) (Leonhardt andLanghans,2002)th notably attributedto the a Nageswara RaoandSakariah,1988; rats (Brandtetal.,2006;Greenwood1981; accumulation withinmuscles and liver (Supplemental Table 2)(Watson etal.,1969). for FA:this inhibitionoftheconversionca enzyme thatcatalyzes the splitof citratetooxa shown et al.,1974b;Sullivanal hi reduction ofhepaticFAsynthesisratebyHCAin prandial lipidcontent( experimentally inducedobesity(S following HCAsupplementation innormal rats(S 1971,Sullivan etal.,1974b,Sullivan etal.,1972), th Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), The rarestudyleadinhuman failedto showntosigni Conversely, HCAwasconvincingly in vitro

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toinhibit ATPCL/CCE(ATP-citrate lyas 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For ≈ +67%)inhigh-fructosefedrats(B in normal/overweight subjects Comment citer cedocument: norectic propertyofHCAinre Critical ReviewsinFoodScienceandNutrition ., 1977)(Table2andSupplementa ght subjectsthatweregive ontrol offoodintakeathigh ullivan andTriscari,1977),theim (Schwarz etal.,1999).Yet,HCA at wouldresultfrom reducti Sharaetal.,2004; etal

, an inhibitor of CPT-1 (Figure 1b), and to the role that plays , aninhibitorofCPT-1(Figure1b),andtotherolethatplays after 8weeksHCAtreatment(-5%,2800mg daily) loacetate and acetylCoA,theconstruction material Kangetal.,2007;LeonhardtandLanghans,2002; ., 2001a,Kovacsetal.,2001b)andinoverweight rbohydrate metabolites intofatfavours glycogen show anysignificantdecreasedhepatic gh-fructose andhigh-glucosefedrats(Sullivan e absenceofeffect ≈ ullivan etal.,1974a) -4.5kg)(Badmaevetal., 2002),whileno g daily),eitherafter upon 2weeksof lation withanincreased FA e/citrate cleavageenzyme) activity,the ficantly reduceweightgainorregainin n 1500mg HCAdailyfor12weeks randt etal.,2006)orthesignificant on inmalonylCoAproduction( l Table 2). In addition, HCA was l Table 2). Inaddition,HCAwas fat dose(ScharrerandLanghans, portant increaseinhepaticpost- ., 2003). This effect might be ., 2003).Thiseffect was reportedto on liverlipidcontent daily 500mg-HCA fasting orfructose or inratswith significantly β -oxidation de novo via 43

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Augusti, 2007;Linetal., 2004).Similar resultswere but alsotoreducehepatic biosynthesisofTGa protect liverfrom inducedhepato (Lin andYin,2008)orhigh-cholesterol(Kumari an they havebeenshowninmice orratsfedameth cysteine) and lipid-soluble ( Concerning water-soluble( Cysteine-containing compounds Further studies arethereforeneededbefo to ourknowledge,nostudy CCE activity,thisdoesnotreflectinlowertotal hepatic rateoflipogenesisinchroni HCA supplementation inratsappearscontradictory oxidation, eitheratrestoruponexercisi exchange ratio,chronicHCAadmi al., 2000).Inmice, whileasingleHCAtreatmen given HCAsolutionof19g/Latalevel3.1mL/ significant increasedtotalfatoxidationwasregist in sedentaryadultsatrestor al., 2002)oruntrainedmen(Tomita etal.,2003)a relation with anincreased short-term rateof fat oxidationasdemonstrated in eitherathletes (Lim et cholesterol (Badmaev et (Kovacs etal.,2001a;Kovacs2001b)but (Heymsfield etal.,1998).Inaddition,HCAsupp Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), The lackofeffectortheincreasepost-prandi

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For al., 2002;Preusset2004b).Theeff Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition e.g. e.g. has investigatedthesp duringmoderately intenseexerci

diallylsulphideanddipropyl

toxicity andfrom highsaturated s -allyl cysteine, nistration (10mg twicea HCA nistration cally fedrats.Thismeans thatif,

ng conditions(Ishiharaetal.,2000). re concludingornotHCAisalipotrope nd cholesterol(Supplemental Table2) (Kumari and lipid contentuponalongperiodoftime. However, ionine-choline deficient(L lthough othershavereported lementation doesnotincr kg b.w.beforeandafterexercise(VanLoonet ered inenduranced-trainedhumansthatwere s may decrease bloodlevelsinTG,LDLand t of10-30mg hadnoeffectonrespiratory ecific effectofHCA -ethyl cysteine, al content of hepatic lipid contents following to theabilityofHCA reportedindiabeticmice (Hsuet al.,2004). d Augusti,2007)dietto sulphide) organosulfur compounds, ect onbodyweight se (Kriketosetal.,1999);andno fat-associated oxidativedamages, day for25days)promote lipid in vivo n -acetyl cysteine, on hepaticTGcontent. in etal.,2008),high-fat ease satietyinhumans to importantly inhibit to importantly , HCAreallyinhibits nosignificanteffect sensu stricto alleviate and/orto loss might bein s -propyl -propyl . Page 44of267 44 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 45of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 no precisionweregiven (Spadaro 2006; Spadaroetal.,2008). However,PUFAwereeith degree ofsteatosiswith24-30% (Capanni etal.,2006;Spadaro2008).Results Mostofstudieswereleadinratsormi wereadmini who concerns patientwithNAFLD Table 2toallowcomparisons. and oilsspecifictoanimal products( Unsaturated FAarecommontobothPBFandABF.Re Mono-unsaturated andpoly- Unsaturated andshort-chainfattyacids,melatoninpara-aminobenzoicacid organosulfur compounds. 2001). Onemay thereforeconcludethatresults not lipid-solublecompounds thatma of hepaticcholesterolsynthesiswouldmainly organosulfur compounds ( reaching ahigherinhibition ofacet HepG2 cellssuggestthatthe reductase andSREBP-2(Supplementa This hasbeenlinkedtosignificantdepresse 1995; Linetal.,2008; andYi lipids (Supplemental Table2)(GebhardtandBec activity ofHMG-CoAreductaseand relation with adecreased activity of twolipogen Some ofthe mechanisms involved-notablyasunra Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: i.e. Critical ReviewsinFoodScienceandNutrition unsaturated fattyacids

s concerted actionofseveralor -allyl or n, 2008;Linetal., subjectshavingnomore steatos etal.,2008).Acco e.g. y become toxicathighdoses( ate incorporation into cholesterol ascompared toisolated

a reducedrateofacetateormevalonate incorporationinto l Table2)(LinandYin,2008). s -propyl cysteine)(Lee andYeh,2003)thatinhibition fish)havebeenthereforealsopresentedinSupplemental ce (Supplemental Table2).Theonlyhuman studies d mRNA forME,FAS,HMG-CoA expressions result from water-solubleorganosulfurcompounds k, 1996;Kumari andAugusti,

ic enzymes thatareME andFAS,adecreased stered 1-2gdailyof velled byusingrathepato 2004; Liu andYeh,2000; convincinglysupport clearlyshowedasigni er ofanimal origin(Capannietal.,2006) or sults from studies leadwithunsaturated FA rdingly, n-3PUFAhave beenrecently ganosulfur compounds wouldallow is diagnosed(Capannietal., i.e. In addition,studiesleadin 1-4mM) (YehandLiu, PUFA for6-12months cytes -areprobablyin ficant decreaseinthe YehandYeh,1994). lipotropic effectof 2007;Kumari etal., 45 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 22 21 20 19 18 26 25 24 23 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 (with hyperlipidemic, diabeticandobese 2009) butthismay beexplainedbythespecifi some studiesreported no effectorincreased expre by Clarke(Clarke,2001).However,concerning SR and inhibitTGFAsynthesis enzymes (aldehydedehydrogenase, ATPsynthase, DHA andAAprevent from fattyliverdevelopment, mice (Moriseetal.,2009).Inadditiontothesemech which PUFAmay favourper CPT andacyl-CoAoxidase(ACO)(Supplemental Ta G6PDH, HMG-CoAreductaseandMEtoincreas al., 2010),toinhibitactivitiesof al., 2009)andtodecrease 2008). PUFAwerealso “negative regulatorofhepaticlipog (Supplemental Table2)(Moriseet 1977) andwith polyunsaturated in high-fructose oil from safflower dietary long-chainn-3FA-containi Among mechanisms involved,PUFAareknownto al., 2002)asshownwithconjugatedlinoleicacid(C secretion”, n otherwise observed inliver of NAFLDpatients proposed asatherapeuticliverdrug Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), − 6/ n −

3 ratio,suchaconditionbei

thereby leadingtostea URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] For Peer Review Only Review α Peer For vs -linolenic acid(18:3 535-590. DOI :10.1080/10408398.2010.549596 long-chainsaturatedFAgiventoratsfe shown toincreasePPAR SREBP mRNAexpression(Sekiyaetal., Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition oxisomal andmitochondrialFA tosis (Arayaetal.,2004) severallipogenic(TGandcholes via ng krilloilinhigh-fat-fedmice enesis” (Alwaynetal.,2005;Sekiya /glucose fedrats(Toussantetal al.,2009).Andseveralauthors totreatpatientswithNAFLD etal.,2008).Ithasbeen (Xin SREBP1down-regulationhave

n-3)-rich dietinbot ng likelyto“favourlipid symptoms) (Gotohetal.,2009)andPPAR c strainsofmice usedinthesestudies, α ssion ofSREBP(Gotohetal mRNA expression(Choiet and 3-ketoacyl-CoAthiolase) from oxidation by LA) inhigh-fat-fedrats(Choietal.,2007),with a marked enhancement inlong-chainPUFA EBP, resultsare not alwaysconsistent since anisms, itwasshowninethanol-fedratsthat anisms, e activitiesofFAoxidationenzymes thatare and that protection of some mitochondrial andthatprotectionof some ble 2).Cellularandnuc .

h wildtypeandPPAR inhibittheexpressionofFAS(Moonet d fat-freediet for7 days (Clarke et al., β -oxidation (Tandy etal.,2009),withPUFA 2003)oractivity ., 1981),withmethylestersof synthesis overoxidationand terol) enzymes thatareACC, have described n-3 PUFA as have describedn-3PUFAas been describedandreviewed et al.,2003;Spadaro via PPARup-regulation ., 2009;Moriseetal., al.,2007;Moriseet lear mechanisms by α -null (KO)mice i.e. (Di Nunzioet α

db -null (KO) / db mice mice Page 46of267 46 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 47of267 26 25 24 22 21 20 19 18 17 16 23 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 2009). However,results do notappear fed a10%-fat(commercial shortening, 53.4% significant lipotropiceffects,among whichadecreas trans in theprimary preventionofNAFLD(Assyet generally MUFA-richfoods,isamain contributorof lignans andhydroxytyrosol,whichpr also contributetotheoveralllipotropiceffect increased hepaticFAoxidation(A oxidation of96%andanincreasedCPTactivity of88%inApoE the endleadtodow-andup-regula is abletodecrease NF- prevent steatosisinNAFLDpatientshasbeenlatter (Supplemental Table5)(Husseinet consumption significantlyreducedhepaticTG degree of steatosis inmethionine-choline-deficient ra HUFA (Seallsetal.,2008).Yet,MU from plantorigin (canolaoil)althoughli animal origin(menhaden/fish/fungal oil)aremore menhaden fish/fungaloils(highinHUFA, and ca unsaturated FA,HUFA), (Goheen etal.,1983,KeimandMares-Perlman, 1984). ( parenteral nutrition,ithasbeensu PUFA mightbeinvolved (Songet Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), i.e. impaired formation oflipoprotei structured fatsynthesized from flaxseedoil, As shownrecentlyinmice fedsyntheticdiet

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For κ B activation andLDLoxidationwhilein Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition nola oil(highinPUFA, ggested thatalackofPUFAmay ssy etal.,2009).However,seve al.,2007).Accordingly,therole al., 2008).Andinratssubmitted ns thatexportslipid FA-rich olive oilwas alwaysconsistent.Thus, there tion ofrespectivelySREBPandPPAR

ompted Assyetal.tosuggestthatoliveoiland,more noleic andlinolenicaci of oliveoil,suchasphenoliccompounds, squalene, trans i.e. al., 2009).Besidesoliveo butter fat and palm stearin contentbyaround29%,fishoilfailedto efficient inpreventingfr AA, EPA andDHA),itseems AA,EPA thatHUFAfrom discussed (Assyetal., i.e. FA)diet(Supplemental Table5)(Cho etal., ed hepaticTGcontentof16%,anincreased ts thanPUFA-richfishoil;andwhileolive oil the beneficialeffectof containing lard(lowin PUFAandhighly linoleicandlinolenicacids)oramixture of s outsideliver)and shown tobemoree -/- creasing insulinresistance that in ds arebothprecursors mice compared toApoE ral otherphytochemicals would lead toimpaired lipidtransport spective efficacity of different spective efficacityofdifferent to hypercaloric andfat-free of oleicacidinoliveoilto 2009). Indeed,oleicacid om steatosisthanPUFA was alo shown to exert wasaloshowntoexert il, PUFA/n-3rich/low- theMediterraneandiet enhanced lipogenesis α fficient inreducing andPPAR in vivo -/- γ mice and of 47 β - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 23 22 21 20 19 18 17 16 15 14 26 25 24 12 11 10 13 5 4 3 2 9 8 7 6 1 6) andn-3( to models andFAchosen.Secondly,onemay wonderwhethern-6( 2 inbothanimals andhumans tendtosupportalipot not: if results appear still insufficient todefinitiv (Supplemental Table2). also observed, whichisalsosupportive andindicativeofadecreasedlipogenic activity (Clarke etal.,1977;Toussant1981).Ina enzyme activitieswerealsorepor (Supplemental Table2).AlthoughFAarenotfrom na least +100%),oliveoilremaini 2001). However,alloilsimportant G6PDH activities,olive oil(oleic acid-rich) failed linolenic acid) orsardine (n-3 PUFA-rich)oils consumption beingpro-inflammatory (Leeet al only n-3PUFAhavebeen proposed arachidonic acidinethanol show alipotropiceffectofunsaturatedFA,with is difficulttotesteachone asregards withhepati choline deficient (Hussein etal.,2007).Discrepe somewhat contradictorywiththos 10%-fat dietrichinsaturatedlipids:whiles oils inimproving variousmarkers of in Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), α -linolenic acid) inPPAR

In theend,onemay firstwonderwhetherallunsat As forfiberandpolyphenols,unsaturatedFA

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] e.g. α Only Review Peer For vs -linolenic acid,C18:3n-3)wouldhaveth 535-590. DOI :10.1080/10408398.2010.549596 10%-fatfedrats. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition fed rats(Goheenetal α ncies may be ascribedtothedifferentmodels tested, ng thelessefficient(Takeuchiet -null (KO) female micehigh- -null (KO)female fed ted withethyl linoleate andmethyl linolenate/linoleate/oleate ly andsignificantlyincreased e ofHusseinetal.reporteda hepaticlipidmetabolism hasbeen totreatpatientswithNAFLD

unflower (n-6PUFA-rich),linseed (enrichedwith ddition, decreased SREBP and increased PPAR were ddition, decreasedSREBPandincreased PPARwere ely conclude,thosereported c steatosisimprovement.However,resultstendsto importantly decreased TG ., 2007a)andbeinglikely tobeinvolvedinthe ., 1983)andofaround-49% notablyimportantTG reductionsof-83%with ropic effect whosesignificancevaryaccording are composed ofnumerous compounds andit to (Supplemental Table5)(Takeuchietal., tural origin,important urated FAofplantoriginarelipotropicor e same lipotropicpotential.Inhumans, al.,2001).These β -oxidation and CPT activity (at bove witholiveandfishoils fat diet(Moriseetal.,2009) e.g. (Xin etal.,2008), excessn-6 (Xin tested inrats fed initially a arachidonic acid,C20:4n- content,andACC inSupplemental Table reduction inlipogenic with linseedoil(rich i.e. results appear methionine- Page 48of267 48 α - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 49of267 19 18 17 16 15 14 13 12 11 10 25 24 23 22 21 20 9 8 7 6 5 4 3 2 1 Melatonin hepatic cholesterolcontentin 2). Andhepaticacetateandpropion with SCFAmixture ofacetic,propionic andbuty synthesis asshowninisolatedhe playing aroleinthesemechanisms. being produced regulation ofFASgeneexpressionweredemons However, hazelnuts and walnutsareconsidered for themelatonin contentofPBF,andmelat is astrongantioxidantandalsoplaysrolein the centralhormone thatregulateschronobiological In human, melatonin issynthesized 2009). Amongmechanisms involved,up-regulationofPPAR decrease inhepaticTGconten on hepaticlipidmetabolism (Supplemental Tabl have beenshown, eitherasisolatedcompound orin the most areacetate,propionateandbut important Short-chain fatty acids (SCFA) mainly result in Short-chain fattyacids into non-alcoholicsteatohepatitis. promotion ofhepaticnecro-infl Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

Other studiesmainly reportedtheinhibition

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Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition rats(Kosekietal.,1991). t (around 16%)withaceticacidin ammation (Cortez-Pintoetal., patocytes withpropionicacid(Wright ate concentrationswereshownto from serotonininpinealgland

onin contentofsome PB its growth. To our knowledge, there is no database its growth.Toourknowledge,thereisnodatabase humans andanimals from fiberfermentation and trated (Kondoetal.,2009).Consequently,SCFA yrate. AsforthepreviouslyPBFcompounds,they ric acids(Hara etal.,1999) (Supplemental Table e 2).Butonlyonestudyreportedasignificant asgoodvegetablesources ofmelatonin; and mixture, toexertpositive and significant effects rhythms, notablysleeping.Inplants,melatonin effect ofSCFAuponratecholesterol y beconsideredaspossiblyindirectly 2006) thatmay transform NAFLD α high-fat fedmice (Kondoetal., , ACOandCPT-1,down- and isbeforeallknownasbeing benegativelycorrelatedwith etal.,1990)or F stillremains unknown. in liver slices in liverslices 49 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 22 21 20 19 18 17 16 15 14 13 12 11 10 26 25 24 23 9 8 7 6 5 4 3 2 1 Para 2005). TG from liverare notably mainly involved in such Deficiency inMTPanddecreasedsy then uptookingreatamountbytheliverandre-s accelerate TG hydrolysiswithinadi important parameter intheethiology of fatty live insulin resistance(Kuzuetal.,2007;Sener Mechanims involvedinthislipotrope effect - increasedoxidativestressandlip daily (Nieminen etal.,2001). 2006; Seneretal.,2004).Thestudyleadin physiological ( 2009; Subramanian etal.,2007).However,dosesus Table 2)(Kuzu etal.,2007;Nieminen etal.,2001; minks toimportantlyredu would helpintheproduction of ability tostimulateproduction offolicacidbybacter Para 2003) (Catala etal.,2007;Leon2004;Seneral Severalstudies havereported aprotective effect of melatonin againstliver injury inrelation with itsantoxidantpropertyandeffectonge tomatoes, potatoes andgreenvegetables. melatonin is also foundinalgae, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), -aminobenzoic acid -aminobenzoic acid(PABA)isalsocitedasa . More specifically,altoughstudiesarescarce,me

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i.e. For Peer Review Only Review from 0.5-10mg/kg b.w.injectedi.p.and10 Peer For 535-590. DOI :10.1080/10408398.2010.549596

ce hepaticTGcontentsandtoimpr Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition pantothenic acid,thislatter cont id peroxidationbeingassociated ginger,grape,cocoa,cereals( pose tissuesreleasingFFA within nthesis ofApoBthatareinvolve

minks usedmore physio ne expressioninrelationwithantioxidantstatus r. Indeed, suchdecreased insulin sensitivity may Panetal.,2006;Sener2004;Shieh al., 2004).Increasedinsu might notablyincludea ., 2004;Subramanian etal.,2007;Taysi ynthesized inTGforming excessfatdeposits. animpaired metabolic lipotrope withinsome websitesbasedonits ed inratandmice studieswerehighandun- ia withinintestine,a latonin hasbeenreportedinrats,mice and ove gradeforsteatosis(Supplemental mg/L ofdrinkingwater)(Panetal., ributing as CoA precursor to the ributing asCoAprecursor tothe d inVLDLassemblytoexport with steatosis -anddecreased e.g. bloodstream, thislatterbeing logical dosesaround10 maize, riceand wheat), condition thatintheend reduced oxidativestress context (Adams etal., line resistanceisan Page 50of267 50 μ g 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 51of267 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 fiber wouldbelessconclusive cholesterol (1%)fedrats(Storyet hepatic TGcontentreduction hasbeenreached lipid/fat contentsinra hemicellulose from bran)havebeenconvinci wheat Both soluble( Soluble andinsolublefiber according to variousmechanisms. However,they compounds havebeenshown topositively affect polyphenols andphenolic-derivedcompounds that Plant-based foodsarealsowell-known sourcesof Fiber-type andpolyphenol-typecompounds 1953). FA oxidation,thisbeingreflected shown inratsthatsteatosis wasa lipid content,hasneverbeendemonstrated, neit commercial lipotropiccomplexes, thelipotropic eff was showntoleadfolicaciddeficiency are foundinhuman intestine,fola stimulating bacteriagrowth (Briggs andDaft, 1955; intermediate inthebact and Childress,1962),toplayaroleinfolate lipotropic effect. Indeed,PABAha Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

e.g. 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For pectinfrom sugarbeetfiber)andinsolublefiber( ts fedvarioussteatoge erial synthesisoffolates(Wegkamp et Comment citer cedocument:

Critical ReviewsinFoodScienceandNutrition (Schneeman andRichter,1993). ssociated withanincreased levelof with increasedlevelof al.,1981).However,inratsfed tes arelipotropes,andPABA omi s beenshowntodecreaseserum

n diets(Supplemental Table3).Forexample, 85% (Woodruff etal.,1953).Yet,althoughusedin haveneverbeen citedaslipotropes. her inanimals norinhu by supplementing dietwith5%lignininhigh- lipid metabolism inbothhumans andanimals fiber(solubleandinsoluble),oligosaccharides, formation (Barbierietal.,1995),notablyas ect ofPABA,notablya ngly reportedtoreducehepaticTG and/ortotal Pfiffner andBird,1956).Inaddition, bacteria Pfiffner cannotbefoundinABF.Allofthese acetylatedPABAin al.,2007)andhasbeenrecognizedas normal diet,lipotr cholesterol level in men (Failey acetylationduetoinhibitionof ssion inthedietofguineapig e.g. cellulose andinsoluble mans. Ithas onlybeen reduced hepaticTGor rat urine(VanHung, opic effectof 51 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 24 23 22 21 20 19 11 10 18 17 16 12 15 14 13 9 8 7 6 5 4 3 2 1 fiber-associated compounds likepo unlikely thatfibercompounds actdirectlyongene cholesterol andTGlevels”(ChanHeng,2008). Ho was observedafter10weekssugges oxidation andlipogenesiswerere studied. Thus,recently,ithasbeenshowninmi μ lipid-lowering effect.For exempl respectively 80and258% that incorporation of[U- with supplemented diet a11%-fat fed for1month of cholesterolsynthesis(Fi ranging from16.2 definition), havebeen early shown toadsorb and/or sequestrate bileacid conjugates by increasingitssynthesisandtu trapping withinsolublea and itsprecursors( et al.,1983). Thismay beattributedtoanadapta with higherHMG-CoAreductaseactivityandra Latter, MongeauandBrassardevaluatedthebile 1968; EastwoodandHamilton, 1968) thuspotentiall hydrophobic bounds(EastwoodandMowbray,1976; Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), mol glycocholate/0.2gNDFforspoon-sizesh Physico-chemical propertiesoffi Thanks tonewtechnicaltools, Concerning cholesterol,appare

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For μ mol glycocholate/0.2gofne i.e. bileacids) withinintestine nd viscousfiber.Conseque (Thomas etal.,1983). Comment citer cedocument: 14 Critical ReviewsinFoodScienceandNutrition gure 2D).Thus,Thomas etal C]glucose or[1,2- rnover throughanenhancedHMG- spectively up-anddown-regulated e, fiber,especially lyphenols andtheirre ting a“regulatory mechanism torestore the loweredplasma

nt contradictory results - results contradictory nt theeffectoffiberonhepati ber havethereforetobeconsideredexplaintheirhepatic redded wheat(MongeauandBrassard,1982). 14 ce feda10%huskdietthat tion resulting from thehigherrelease ofcholesterol utral detergentfiber(NDF C]Na-acetate intocholesterol was increased by salt bindingcapacityof 30% of neutral detergent fiber from blackgram fromblackgram fiber detergent 30% ofneutral ntly, the liver compensates losses incholesterol and explanationshaveprobablytobefoundin via hydrophobiclignin(incl y stimulating cholesteroleffluxfrom liver. te ofsynthesis-were Eastwood, 1975;EastwoodandGirdwood, hydrophobicbindingto . havenotablyshownon sulting conjugatedandmetabolized forms wever, atthehepaticcellularlevel,itis i.e. lowerhepatic content together CoA reductaseactivityandrate c geneexpressioncanbenow after 3weeks butthe inverse ) for wheat germ) forwheat to34.2 genesencodingforFA various cerealproducts also reported (Thomas alsoreported(Thomas uding inthefiber insoluble fiberor liver slices of rats Page 52of267 via 52

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 53of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 5 4 9 8 7 6 3 2 1 of lipidmetabolism aswell(Delzenne andDaubi al., 1998)andsinceGLP-1 may increase insulinsensit 2°) sinceoligofructosemay increase GLP-1caecalc indirectly modulateTGlevels,insu Daubioul alsoproposedthat1°)fructans,by than from ahigherclearanceof “hypotriglyceridaemic actionoffruc (Supplemental Table2)(Demigné etal.,1995,Wright colonic fermentation offructans-thatwassh Daubioul, 2000).Othermechanism possiblyincl within colonandthat Oligosaccharides from PBFareconsidered asfi secretion observedinratswoul Kok, 1999).Suchdatatendtoexplainthat and G6PDH(Figure2D, Table3andSupplemental expression and/orresultingactiv (Beylot, 2005).Among mechanisms involved,fructans inulin-type fructanson TGandcholesterolme Daubioul etal.,2000;Kokal in obeseZucker rats(Supplemental Table3)(B oligofructoses likefructans( raffinose; but,toourknowledge,hepaticlipid-l Oligosacharides to reachliveranddirectlyimpact cel and/or fiberfermentation products Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] For Peer Review Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 include oligofructoses Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition e.g. d beinrelationwith adecrease TG-rich lipoproteins”(Beylot,2005) inulin) inratsfed standard, hi ities oflipogenicenzymes that ., 1996a;Koketal.,1996b;Sugata that areSCFA,especiallypropioni lin participatingintheregulation lular metabolism andgene expression. tans resultsratherfrom adecr

own toinhibitlipogenes the reductionofTG-richlipoproteins( ber-type compounds thatarecompletely fermented and galactosideslike tabolism hasbeenrecentlyreviewed byBeylot oul, 2000).Thislasthypot affecting glycemic andinsulinemic responses, usserolles etal.,2003; owering effecthasbeenmainly reportedfor ude theproductionof oncentration inratsfedoligofructose(Kok et Table 3)(Aghellietal.,1998;Delzenneand ivity, thishormone islikelytobeamodulator etal.,1990).Beylotot havebeennotablyshowntodecreasegene d hepaticlipogenesis(Delzenneand gh-sucrose orhigh-fructosedietand are ME,FAS,AC ease inthehepaticTGsynthesis . Intheirreview,Delzenneand ni etal.,2006).Theactionof c acid, all of them being able c acid,allofthembeingable of TGsynthesis;and/orthat is inrat hepatocytes verbascose, stachyoseand Daubioul etal.,2002; hesis is supported by a a hesis issupportedby proprionate -through herwise suggests that herwise suggeststhat C, ATPCL/CCE i.e. VLDL) VLDL) in vitro 53

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 this isnotsufficient toconsidere phen acyltransferase (thatforms cholesterylestersfrom al., 2003).Inthisstudy,ferulicacidwasalsos effect wastheinhibitionofHMG- was showntohavenoeffectonFASactivity acid, didnotsupportaconvinglipotr lignans, andsecondarilywithphenolicacidst Nakamura andTonogai,2002).In no significanteffectonhepaticc the fewonethatinvestigatedeffect (Supplemental Table4).From studies significant hepaticTGreductionswe classes ofpolyphenols,especiallyflavonoids polyphenols inhumans. specific hepaticlipidmetabolism, toourknowledge quite recentandmost ofstudieshave positive effectsonhepaticlipid metabolism (Supplem compounds), lignans( Polyphenols includesphenolicacid( Polyphenols in plasma GLP-1 concentrationupon recent study showinginhyperinsulinaemic subjects fed Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Compared toflavonoidsandlignans,thefewstudi In animal models,hepaticlipidmetabolism improvement hasbeenobservedforthe4four

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535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For e.g. sesamin) andstilbenes( Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition holesterol andTGcontentswere CoA reductasebyferulicacidinhi of polyphenolsinnon-steatosismodels ( addition, mostofstudiesare re reportedonlyforlignans,and beenperformed forthelastfifteenyears. Yet,as regardswith 12 months12 (Freelandetal.,2010). olic acidsashavingalipotropic effect. opic effect(Supplemental Table4).Forexemple, gallicacid reviewedinSupplemental Tabl

e.g. ferulicacid),flavonoids( in vitro hown tosignificantlyreduceacyl-CoA:cholesterol and lignans(SupplementalTable4).However, ilbenes (onlyonestudy)(Supplemental Table4). cholesterol) activity(Kim e.g. , nostudyhasreported ental Table4).Theinterestinpolyphenols is resveratrol) andmay also exertimportant + (Wang etal.,2003).Themostsignificant 20 g/dofwheatfibera es leadwithphenolicacids,mainly ferulic observed (Nakamura et al., 2001; observed(Nakamuraetal.,2001; concerned withflavonoidsand gh-cholesterol fed rats (Kimet in lesser extent for flavonoids in lesserextentforflavonoids e 4,onecanobservethatfor i.e. etal.,2003).However, e.g. a lipotropiceffectof with standarddiets), significant increase catechin-derived Page 54of267 54 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 55of267 17 16 15 14 13 12 11 10 26 25 24 23 22 21 20 19 18 9 8 7 6 5 4 3 2 1 hydrolase activityand (cAMP) level, activation of prot Indeed, phosphodiesteraseinhibi 2000), wouldnotablystimulate lipol Briefly, flavonoids, the modulation oflipidhomeostasis byflavonoids strongly inhibit SREBP geneexpression(Figure2DandSupplemen not alipotropic effect probabledifferenteffect different compoundswith contents inhypercholesterolemic by mice supplemented atalevelof200mg/kg b.w.allowedsi Stilbenes ( only onereportedinSupplemental Table4broughtin and FAoxidationenzymes, andtheirresul ability ofpolyphenolstodown-regulateandup-regul Shimotoyodome etal.,2005;Vena (Dulloo etal.,1999;Klaus (Bose etal.,2008);andvarioustypesofflavonoïds polyphenols ( hepatic lipidaccumulation in high-cholesterol fe and theflaxseed lignan secoisolariciresinol (SECO) inducer ofhepaticFAoxidation Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), However, polyphenolsareahuge Concerning thefourthclassof Concerning flavonoidsandlignans,sesamin (a i.e.

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] e.g.

cajanin,andlongistylinCA) in vitro For Peer Review Only Review Peer For (-)-epigallocatechin-3-gallate) may prevent 535-590. DOI :10.1080/10408398.2010.549596 via sensu stricto β phosphodiesteraseinhibition(Koet FAS activity (Wang etal., 2003;Wa -oxidation oflipidichydrol Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition et al.,2005;Rumpler etal in 10-15%-fatfedrat tion wouldfavourincreaseof eine kinaseA,subsequentincr . Inliterature,polyphenol content bles etal.,2008).Mechanisms ysis productsfrom TGandchol

polyphebnols thatarestilbenes,desp respectively 14and23%(Luoetal.,2008). phytochemical family, composed ofseveralhundreds ting activities, but alsotoincrease PPAR containingextract/fractionfrom ysis products(Peluso,2006). d rats(Felmlee etal., s onhepaticlipidmetabolism: allhaveprobably wasrecentlyshowntodose-dependentlyreduce tal Table2).Flavonoidswerenotablyshown to withinliverwasde ate geneexpressionofrespectivelylipogenic havebeenshowntopreventliversteatosis gnificantly reducingTGandtotalcholesterol (Ashakumary etal.,1999; teresting resultsforleadingfuturestudies. lignan) hasbeenrepor al., 2004;NicholsandMorimoto, 1999, ng andTian,2001).In arecentreview, fatty liver disease in high-fat fed mice ., 2001;SachanandHongu,2000; cyclic adenosine monophosphate cyclic adenosinemonophosphate ease inhepatic triacylglycerol involved wouldbenotablythe of PBFismostly expressedby esteryl esters 2009).Majorgreen tea scribed (Peluso,2006). ite rarityofstudies,the ted tobeapotent Ide et al., 2001), Ideetal.,2001), (Peluso, 2006). α Cajanus cajan anddecrease 55

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 reduced hepatic TGcontents byrespectively -40/- 1995). Forexample, plantsaponins from hepatic fatdepositsorlipidcontents(TGandc with polyphenols(Supplemental Table4).Theirc structure (Figure 1).Theyaregenerallyincluded As curcumin, saponinsarenot Saponins fed rats(Seetharamaiah a was interestinglyshowntosignificantlydecrease derived compound(Figure1).Among thetwostudies Curcumin notclassifiedasapolyphenol is Curcumin deficient ( respectively hamsters feda10%-fatand0.2%-choles polyphenol extractssignificantlyreduceddegree metabolism invariousanimal models (Supplemental investigate theeffectofethanol with apotential lipotropic effect. to exertapotentiallipotropicaction.One found thosethemost likelytobe include onlyonetypeof method). The TPCcontentcorrespondstotheea the TotalPhenolicCompound Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Accordingly, ratherthantofocuseonan

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/ ob

) mice (Brunoetal.,2008). 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For polyphenol. However,thisisamong this nd Chandrasekhara,1993). Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition - and/orwater-extractablepolyphenol sensu stricto (TPC) content(estimated absorbed withinsmall intestinea

may therefore consider TPCcontentasa Aralia mandshurica sensu stricto polyphenolsbutpossessa holesterol) (Khanalet isolated compound, more andmorestudiesnow in thefiberfraction.Studiesarelessrecent than sily extractable fraction and obviously does not sily extractablefractionandobviouslydoesnot hepatic TG contentby22%inhigh-cholesterol 35% and-39/-20%inhigh- onsumption orinjectionmay leadtoreduced Table 4).Forexample,sylimarin andgreentea reportedinSupplemen of steatosisandhepaticTG contentsin terol diet(Lin etal.,2009)andinleptin- butmay beconsideredasapolyphenol- via the Folin Ciocalteu’s colorimetric andcommercialwhite saponins polyphenol fraction nd, consequently,themost likely s fromplantsonhepaticlipid al., 2009; Onning and Asp, al., 2009;OnningandAsp, polyphenol-like chemical tal Table4,curcumin fat (Wojcickietal., whole compound that aretobe Page 56of267 56

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 57of267 21 20 26 25 24 23 22 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Gamma-oryzanol significant onlyatthe highlevelof1.2% oryzanol wasshownto reducehepaticTGcontents extracted from ricebranoil.Among thefour Gamma-oryzanol isamixture offerulicacid plasma level.Theyare Several phytochemicals aregenerallytestedforthei Cholesterol-lowering phytochemicals alkylresorcinol onTGortotallipidcontent. et al.,2004a).Butfurtherstudiesar addition, theywerereportedtosignificantlydecreas Kozubek, 2003),suggestingthatal enzyme inTGsynthesis andtoreduceTG directly exhibit apolyphenol-likechemical structure Alkylresorcinols aremainly foundinwheatand Alkylresorcinols (Figure 2D).Indeed,saponinsaremost ofthe saponins withindigestivetractth asforfiber, has probablytobeattributedthesame effect ginsenosides purifiedfrom ginse saponin supplementation alsoleadtoanincreasedra 1977) andhigh-cholesterol(Oakenfulletal.,1979) Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), in vivo

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, alkylresorcinolswereshown For Peer Review Only Review Peer For

535-590. DOI :10.1080/10408398.2010.549596 γ -oryzanol, tocotrienols,polic Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition ng inrats(Supplemental Table4) at thereafterstimulatescholestero kylresorcinols might exert e neededtotestinanimal mode

time associatedwithfiberwithinfoodmatrix. in vitro estersoftriterpenealcoholsandsterols (Ross etal.,2004b).Although notdemonstrated rye inarangeofaround30-150mg/100 gandalso accumulation within3T3-L1 cells (Rejman and studies wereportedinSupplemental Table4, supplementation (-33%)(Seetharamaiah and r cholesterol-loweringpr fed rats(Supplemental Table4).Paradoxically, e totalhepaticcholestero osanol andphystosterols. te oflivercholesterol toimportantly inhibitGPDHactivity, thekey inhigh-cholesterolfe in vivo i.e. l turnover and hepatic synthesis l turnoverandhepaticsynthesis the adsorption of bilesalts by apotentiallipotropiceffect. In (Sakakibara et al., 1975). This (Sakakibara etal.,1975).This ls offattylivertheeffect synthesis asshownwith operties, notably at the operties, notablyatthe d rats, but effect was was effect but d rats, l contentinrats(Ross

(Figure 1) 57 γ - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 17 16 15 14 13 12 11 10 18 9 8 7 2 1 6 5 4 3 δ unrefined vegetableoils,andbelongtothev Tocotrienols ( activity inrespectivelyhypercholes reduce hepaticcholesterolcontentby19%butfa hexacosanol; otheralcohols -tetracosanol, from sugarcanewax. Itismainly composed Policosanol isamixture ofhigh-molecular-mass a Policosanol effect oftocotrieneols. 0.002% level(Supplemental Table2)(Qureshietal receptor protein levelinHepG2ce processing (SongandDebose-Boyd,2006).Intheend, HMG-CoA reductase,andonly both cholesterol biosynthesisasshown cockerels (Qureshi etal.,1986)a main reportedeffect onlipid metabolism isitsabilitytoinhibit HMG-CoA reductaseasshown in (Cicero andGaddi,2001;Minhajuddin Tocotrienols oryzanol. 1997). Furtherstudieswouldbenecessarytodefi Chandrasekhara, 1988,1993).Inthetwootherstudies, was significantlyincreasedby Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), ). Tocotrienolsarerecognizedashypocholeste δ - and

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] γ

-tocotrienols havebeenshown α , For Peer Review Only Review Peer β For , 535-590. DOI :10.1080/10408398.2010.549596 γ and δ ) aremainly foundinwhole-graincerea Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition around 40%incockerelsuponto nd guineapigs(Khoretal.,1995),a δ lls (Parkeretal.,1993).However, in human cells(Parkeret HepG2 -tocotrienols hasbeenshown terolemic rats(Suhetal.,2005)

et al.,2005;Qureshi in vitro itamin Efamily togetherwithtocopherols( heptacosanol, nonacosanol, dodriacontanoland rolemic compoundsinbothhumans andanimals ofoctacosanolfollowed bytriacontanoland iled tosignificantly inhibit HMG-CoAreductase ., 1986).Suchresultsdo liphated alcoholsinitially nitively concludeon thelipotrope statusof tostimulate ubiquitina γ γ -tocotrienol importantly increases LDL -oryzanol wasreportedtosignficantly et al.,1997).Atth ls (especiallyin to completelyblock SREBP-2 cotrienol supplementation ata nd toreducesubsequentrateof al.,1993).Morespecifically, in thesame time,FASactivity andhamsters (Rongetal., tion anddegradationof not supportalipotropic isolatedandpurified e hepaticlevel,its wheatgerm) and α , β , γ and Page 58of267 58 γ - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 59of267 21 20 19 18 17 16 15 14 13 12 26 25 24 23 22 11 10 9 8 7 6 5 4 3 2 1 lowering propertiesofphytosterols 2001), similarly towhatoccurswithfiberor turn stimulates cholesterol synthesistocompen by theincreasedcholesterolreleas reductase, CYP7A1andsterol27-hy cholesterol content(Supplementa In animal models,phytosterolshavenosignifican there isnostudiesleadinhumans patients withhypothyroidism byaround20%(Best As earlyas1956,itwasshownthat hepatic TGand/orlipidcontents toc enzymes aredirectly involved in FAsynthesis, we and G6PDHactivitiesinhigh-cholesterolfedrats (Brufau etal.,2008).Besides,phyto Phytosterols lipotropic effect (Supplemental Table2).Astocotrienols,policosanol (Menendez etal.,1994).But,to synthesis (Menendezetal.,1997).Similar results also beenshowninhypercholet LDL-binding activity(Menendezetal.,1996,Menendez activity (Mccarty, 2002) andincrease McCarty, 2002;Varadyetal.,2003).And,asto lowering agentabletoprotect tetratriacontanol -areminor comp Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

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For Peer Review Only Review sensu stricto Peer For 535-590. DOI :10.1080/10408398.2010.549596 Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition . from cardiovasculardiseases(G our knowledge,noeffectonhepatic l Table4).Yet,phytosterolswe e withinsmall intestineunderth erolemic rabbits tosignificantly to investigatetheeffectofphyt onents. Astocotrienols,itisfi β havebeenotherwisethoroughl onclude thatphytostero droxylase activities:su sterols wereshowntoimportan -sitosterol (20to25gdaily)c LDL receptorprotein levelasshown

saponins.Mechanisms underlyingthecholesterol- (Figure 2D) (Laraki et al., 1993). Although these (Figure2D)(Larakietal.,1993).Althoughthese sate such intestinal losses (Moghadasian etal., lackstudiesdemonstrat cotrienols, itmay inhibitHMG-CoAreductase t effectsonhepaticTGcontentcontraryto were obtainedinculturedhumanfibroblasts and Duncan, 1956).But,toourknowledge, cannotbethereforec et al.,1997).Studiesar ch enhancedactivitiesmay beexplained ls arelipotropic. ouni-Berthold and Berthold, 2002; ouni-Berthold andBerthold,2002; e actionofphytosterols,whichin re showntoincreaseHMG-CoA osterol consumption onsteatosis. rst recognizedasaserum lipid- ould reduceserumcholesterolin tly decreasehe decreasehepatic y describedbyBrufauetal TG contenthasbeenreported ing asignifi via onsidered as having a onsidered ashavinga anincreased hepatic e scarcebutithas patic ACC, ME patic ACC,ME cant reduced cholesterol cholesterol 59 .

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 alcohol administration) wasmore efficient than Otherwise, itwasshown with cholesterol followingcassavaleavesflourconsump hepatic functionsassugg 2010). Someantinutrientsfrom leaf and TGcontentsthantheco polyphenols from associated lipidmetabolism parameters than Table 5). cereal products,vegetableoils,fruits,seeds,vege al., 2010).Literaturesurveyalso standard diet,lycopenealonein 2009b); andwhiletomato powdersignificantlyredu 44%) thancrudesaponins(-17%,NS) from thefood synthesis. Forexemple, plantextractfrom enzymes involved inFAoxidation,d isolated compounds, note thatcomplexfoodsorfoodextractsmay leadto Studies arenumerous andal study ofisolatedcompounds, oftenusedatdoses extracts onsteatosisisparticularly Plant-based foods may containaw Plant orplant-basedfoodextracts Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), However, thewhole Thus, some authorsfocusedonvariousplant

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Hibiscus sabdariffa Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 i.e. ested bydeMeloetal mainly decreased hepaticTGandTC Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition l couldnothavebeencitedinSupplem food package rresponding plant-extrac Ziziphus Mauritania the same amount than in tomato pow unravels thatfoodstestedcover extracts liketanninsandsaponins relevant tostudyandcloserthe hole setoflipotropes.Thus,the ecreased activitiesofenzymes (74%content)hadmore marked

isnotalways more efficient towards liver steatosis or Platycodi radix . whoobservedinratliver higher thanthatreallyconsumed byhumans. the isolatedcompound. Forexample, purified tables, beveragesorleafextracts(Supplemental co- orpost-administration inreducing hepatic tion comparedtocontrol(DeMeloetal.,2008). leafextract that pre-treatment (30min before similar orenhanced li extracts ratherthan extract (Supplemental Table5)(Kwonetal., ced by22%hepaticTGcontentinratsfed t containing2%polyphe wasmore efficientinreducingTG(- contents,increasedactivitiesof ental Table5.Itisinterestingto involved inFAandcholesterol a largerangeofPBFthatare der hadnoeffect der may beinvolvedinimpaired effectonhepaticcholesterol effect of foods or of their effect offoodsortheir nutritional reality on aparticularcompound. higher levelsoflipidsand potrope-like effectsthan nols (Yangetal., (Alshatwi et thanthe Page 60of267 60 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 61of267 22 21 26 25 24 23 20 19 18 17 16 15 14 13 12 11 10 5 4 3 2 1 9 8 7 6 chemicals ordrugslikeCCl We thereforechosetoselectonlysteatogenicdi hyperlipidemia, inhuman areobserved obesity (Kurtz since many of itsmetabolic abnormalities, including leptin and insuline resistance and Zucker ratswerealsoselected sincetheserats involving excessfat,sucrose,glucoseandfructose diet supplemented withphytochemicals havebeen supplemental Tables1-4.Toallowrelevantcompar The lipotropic potentialofeachplantcompound ha Study selection RAT STUDIES DIFFERENT CLASSESOFPLANTCO COMPARISON OFTHEPOTENTIAL cholesterol reductions accordi hypercholesterolemic hamsters (Kahlonetal.,1 bran oilswithorwithoutgumandwaxon PBF iswellillustratedbyastudy Finally, theimportance ofinterac cholesterol andTGcontentsof (Kahlon etal.,1992). (non significant)fordefattedricebran+ Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition 4 orDDTwerenotconsidered. ng tobranfractiontested, chronicalcoholadministered tions thatexistbetw investigating theeffectofrice

developedfattyliver(D 992). ResultsshowedvariousrangesofTGand ets ofnutritionalorigin;fattyliverprovokedby MPOUNDS ASUNRAVELLEDFROM percentages, alcoholand considered. Selected steatogen diets are those considered. Selectedsteatogendietsarethose isons, onlystudieslead ve beenevaluatedbyselecting studiesfrom oil to-33%(significant)forwholericebran een phytochemicals and LIPOTROPIC EFFECTOFTHE etal.,1989;Marchesini etal.,1999;Sharabi hepatic cholesterolandTGcontentsin e.g. ranking from -14% hepatic TG content rankingfrom-14%hepaticTGcontent Finally, 3studiesusingobese rats (DahiruandObidoa,2009). bran,defattedri aubioul etal.,2002)and lipotrope deficiencies. in ratsfedsteatogen micronutrients within ce branandrice fa / fa 61

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 13 12 11 10 16 15 14 26 25 24 23 22 21 20 19 18 17 9 8 4 3 2 1 7 6 5 respectively phenolicacids,flavonoids,li soluble/insoluble fiber,phytic melaHCA, organosulfurcompounds,MUFA/PUFAand methionine, niacin,pantothenicacid 10, 7,3,2and3studieshavebeenselect and SREBPup-regulatingsynthesisof the orderfiber>choline studies reportedinSupp polyphenol-rich plantextracts, metabolism chosenwere thosethemost the percentagesforphytochemical supplementati However, inordertoobtainasufficientnumber of (Sullivan etal.,1977)andtwow and Eldad,2000;Shimizu etal.,2007;Silverman et steatogen dietconsumption byrats Influence of phytochemicals onhepatictotal fiber (Tables2and3). days whilesupplementation percentagescovera presented inFigures4A-E.Consideringallco are presentedinFigure3A-Cwhilepercenta within Tables2and3.Percentagechangesforhepa PPAR andATPCL/CCE),mRNAle G6PDH, ACC/CBX total lipid/fat,TGandcholesterolcontents Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), α andSREBP;PPAR

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For lemental Tables.Thehighestnumbers Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition myo α up-regulatingperoxisome pr i.e. acid andoligosaccharides;2,4,8,3studiesfor -inositol >carnitine =lignans. Th ith oligofructose (Daubioul etal.,2002; Daubiouletal.,2000). atotalof115studieswhic and folates;8,3,2,32studies

enzymes involved insterolbi common toamaximum ofphytochemicals, gnans, curcumin, saponins,phytosterols, , activityofmain lipoge ed forrespectivelybetaine,choline, mpounds, feedingperiodscoverarangeof1to182 range from around1ppm fo ge changesforlipogenicenzyme activityare lipid, TGandcholesterolcontents following data, allthedurationsforfeedingperiodsand tic totallipids/fat, TGandcholesterol contents al.,1989).OnestudyisconcernedwithHCA on havebeenselected.Markersoflipid tonin; 14,5and7studiesforrespectively vels of 2transcription factors that are oliferation involvedinFA of studieswere h correspondstoaround30%of e collecteddataare synthesized osynthesis. Asaresult,4,12, for respectively carnitine, nic enzymes (FAS,ME, r folatesto30%for therefore foundin γ -oryzanol and myo β i.e. -oxidation -inositol, hepatic hepatic Page 62of267 62 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 63of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 have leadtotheabsence ofTGreductioneffect safflower (n-6PUFA-rich) oils. rely on the fact thatfish oilis (USDA, 2005e).Anotherexplanationforthehigh 78%) and18:1n-9( 16:0 ( coconut oil)withlargelylessHUF 22:6n-3) thatisfishoil,oilsusedinotherst that thesoleincreasewasobtai all excretion (Ideetal.,2004).Concerningotherstudies change expressionofgenesinvolvedinVLDL 2004). Asanexplanation,authorssuggestedthatthe not withpalmandsaffloweroils(res lignans isverysurprising.However,theeffecthas hepatic cholesterol turnover consequently toan in on TGcontent(+136%).(Table3). effects reachedonlyforfiberand for cholesterolcontentwithphenol 83%) (Goheenetal.,1983).Conversely,increasesin study concerned)may alsoleadto Although onlyonestudycouldhaveb total lipidandTGcontents First, concerninghepaticlipidcont Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), ≤ 0 withinthe range [ ≈ 45%)and18:1n-9( If increased cholesterol contentsarenotune

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For ≈ 13%)(Ideetal.,2004)andcoconutoi ≈ Comment citer cedocument: 0/-68%](Figure3BandSupplementalTa Critical ReviewsinFoodScienceandNutrition ≈ with choline,methionine, a n-3PUFA-richoilcontrary to 39%)(Ideetal.,2004),safflower ned withtheonlyoil Indeed, PUFAareknown tobeli lignans oncholesterolcontent(res importantreductionintotallipid ic acidsand+136%forTGconten A contents:indeed,palm oilisch ents, themost strikingreductions, p. -68 and -23% TG content reduction, p. -68and-23%TGcontent

een selected,unsaturatedFA( udies beingallvegetableo assembly andproduction, bysesamin:otherwise, inthisstudy,palm and crease faecalexcretion, th increased TG contentof+136%might therefore been reported for fish oil only (at a level of 8%) been reportedforfishoilonly(atalevelof8%) hepaticlipidpercenta rich inHUFA(10%of20:5n-3and32.6% withlignans,TGcontentmodifications were xpected withfiber since theymay stimulate interaction ofsesamin w myo l byahighlevelof -inositol, fiber(ligni palm (saturated andMUFA-rich) oil byahighlevelof18:2n-6( potropic (seeabove)which may /fat (-63%)andTGcontents(- p. +17 and +21%), and lignans p. +17and+21%),lignans ble 4).Itisinterestingtonote t with lignans with significant t withlignanssignificant aracterized byahighlevelof i.e. i.e. ges rangedbetween+1% > 80%, are reached for >80%,arereachedfor ils (safflower,palm and arachidonic acidinthe at ofTGcontentwith impairing hepaticTG saturatedFA( ith fishoilmay have p <0.05)(Ideetal., n) andphyticacid. ≈ 87%) 63 ≈

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 these compounds may beallefficientdepressors often testedfortheirability to Myo consumption byrats Influence ofphytochemicalsonhepaticlipogeni 60%), fiber(-75%),saponins(-52%)a cholesterol contentreduction reachedarequitehi opposite tendencymay beobservedwithphytoster content reduction with choline, whatever the leveloffiber. may behypothesizedthatatooim increase inproteinlevelfrom in thestudy byStewartetal generally 20%ofthedietforgrow protein dietmay besteatogen(B to 9.31%)(Supplemental Table3)(Stewartetal., (from wheatbran)ofthedietfr TG contenthasbeenfoundinrats the 10%-fishoildietwasnotsteatogen. oil for which level of hepatic TGis quite low(14 safflower oilsaloneleadtorespectively5.8-an Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), -inositol, unsaturatedFA,phyticacid,oligofru Concerning hepaticcholestero Besides, althoughnolevelofsignificancewasgi

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition . , ataconstantfiberandfatleve 21.93 to35.93%lead+82%TGcontent(Stewartetal.,1987).It om 2.83to11.17%attheexpenseof reduce lipogenic enzyme activitiesin est etal.,1955)andth ing rats and14% foradultrats (R myo (Table3)whenincreasingthe portant distancefrom standard nd phytosterols(-76%)(Tables2and3). l contentreduction,ittendsto

-inositol, carnitine,phyticacid d 3.2-foldmorehepaticTG gh forcholine(-56%),folates(-51%), carnitine (- 1987). Oneexplanationmay ctose andlignanswerethecompounds themost μ of them(Figures4A-E). Themostimportant ols (Tables2and3).Fi c enzyme activities following steatogen diet c enzymeactivitiesfollowing steatogendiet mol/g liver)(Ideetal.,2004).This means that at normal proteinle ven, asurprising+47%increaseinhepatic ls ofrespectively7and17.5%,the theproteincontent(from 19.01 protein levelremainssteatogen eeves etal.,1993).Inaddition, neutral detergent fiber content neutral detergentfibercontent rats, andresults showedthat be lessimportant thanTG and oligofructose, while andoligofructose,while accumulation thanfish nally, maximal hepatic vels recommended are vels recommendedare be foundinthatlow- Page 64of267 64 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 65of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 i.e. lignan importantly reducethatof are scarce,buttheyindicatethat Concerning changesinthelevels steatogen dietconsumptionbyrats Influence ofphytochemicals on hepaticPP (Castelein etal.,1994). dual roleplayedbythetranscriptionfactor PPARthatbothfavourFA increased PPARmRNAexpressionmay increasein other lipogenicenzymes likeFASorG6PDH(Caste explanation may bebasedonthePPAR-dependent confirmed ratswithquitethesame in conditio increasing mRNAlevelsfortheenzyme (Asha increased by25and125%atrespec i.e. lignans toincreaseMEac 1997a). Oneunexpectedresultasregardswitheff 65%-decrease hasbeenalsoobtainedwithphytic natural formfoundinPBF(Supplem FA testedherewerealleithermethylated oret ACC/CBX and/orATPCL/CCEactivities(Tables 2 reductions ( Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), byAshakumary etal a reductionofhepaticlipid

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

≥ 50%)areobtainedwithunsaturated 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For tivity (upto+125%,Table 3).However, . Comment citer cedocument: , MEactivitywasfirstreducedby50%at0.1%sesamin levelthen Critical ReviewsinFoodScienceandNutrition content (Tables2and3). SREBP, bothresultsbeinginagre flavonoids importantly increasePPAR of bothtranscriptionfactorsPPAR

tively 0.2and0.5%levelofthedi ental Table2)(Clarkeetal.,1977;Toussant1981).A

hylated, andthereforethey ns (Supplemental Table4)(Ideetal.,2001).One AR and SREBP mRNA expression following AR andSREBPmRNAexpression ect onotherlipogenicenzymes isthetendencyof kumary etal.,1999).Thes acid onFAS(Figures4A regulation ofMEgeneexpressionunlikeother lein etal.,1994).Thus, the sametime MEactivity and 3;Figures4A-E). FA andlignansonFAS,ME,G6PDH, inthestudyrepor ement withalipotropiceffect, α et, andthiswas β andSREBP,datacollected -oxidation andMEactivity α didnotcorrespondtothe mRNAlevels,andthat lipotropes, byinducing However, unsaturated ) activity (Katayama, e resultswerelater : thisunderlinedthe ting thisresult, paralleled by 65 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 21 20 19 18 17 16 15 14 13 12 11 10 26 25 24 23 22 9 8 7 6 5 4 3 2 1 acid protect betteragainstH demonstrated withvariouscombinations ofantioxidants, oxidized vitamin Eandglutathion regenerate theotherafterbeing 2004). Thesynergybetweenantioxidantsappearsth foods, assuchdietarypatternsare Stanner etal underlines thathighdoseofonlyon carotene (The Alpha-Tocopherol, BetaCarote cancer registered in the group of male smokerscancer registeredinthegroupof Cancer) study hasdramatically showedit,witha (Murakami etal.,2003,Stanner2004),as that itispreferabletoconsume severalantioxidantsinalimited amount onlyoneathighdose than decreased fattyliveroraoxidativest different physiologicalmodesofac capacity ofPBF.Indeed,lipot The lipotropic potential of PBFhasquiteinteresti The antioxidant“package” THE WHOLELIPOTROPEVS rats receiving H (Parker etal.,2010),and tomato powder ismore pr have beenshown 2005), combinationsofvariousantioxidants( Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] . , “Themost prudentpublich

2 O Only Review Peer For in vitro 2 535-590. DOI :10.1080/10408398.2010.549596 thanisolatedlycopene(Alshatwi et tohaveahigherantioxi Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition 2 O ropes andantioxidantsbothincl 2 -induced cellulardamages than oxidized. Thisiswellillustrated byvitamin Cthatregenerates associated withreducedriskof e thatregeneratesoxidizedvitamin C.Thishasalso been tion dedicatedtoreachasame e substancemay bepro-oxidative

ANTIXODANT “PACKAGE” ealth advice remains toincrea i.e. consuming asupplemented doseof20mg/day ne CancerPreventionStudyGroup,1994).This ress. Indeed,itistodaymoreandassumed ascorbic acid,caffeicaci 8% increased mortality and18% increase in lung dant potentialthanthe theATBC(Alpha-Tocopherol,Beta-Carotene ng similarities with the concept of antioxidant otective againstelevated serum MDA levelsin erefore essentialsinceoneantioxidantmay al.,2010).Thus,atleast 30phytochemicals e.g. greentea extract, quercetin andfolic ude severalphytochemicals with compound alone(Jeongetal., chronic diseases”(Stanneretal., physiological effect:eithera se theconsumption ofplant andharmful. Asstatedby sum oftheircomponents d, quercetinandurate) Page 66of267 β 66 - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 67of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 choline andfolates(Laird etal., 1965), with was shownwithpantothenic acidand effect inratsofonecompoundreinforcedandim Mercier etal.,1967;WelshandEd with absenceofthesideeffectsobservedwhenni inositol hexanicotinate(orhexanicite)thatproduces folates (Mccarty,2000),methi accompanied withotherlipotropessuchasbetain a therapeuticcontext(McKenney hepatotoxic andproduceothe of synergism forlipotropesmight bewellillust mode ofactiontowardslipidmetabolism inliver containing severallipotropesthanonlyonelipotrope We believe thatthesame istruefor lipotropes, The lipotropic“package” fruits andvegetables(Gey,1998). combined actionsofvitamins E,CandA,of reviewed that optimal health -notablyasrega of enzymesinvolvedintheanti detoxifying potentiallyoxidative differently bytrapping reactiveoxygen specie vivo or groupofcompounds inwhole-grai Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), , directorindirect(Fardet,

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition r harmful side-effects ( onine (Aronovetal.,1999)or 2009);andtheirphysio oxidant defense(Fardetetal., compounds,regulatingglutathione

et al.,1994),butmay bebene e, 1961).Thereareseveralothe n cerealshavebeenreportedtoanantioxidanteffect

myo -inositol (CatollaCavalcanti andLevis,1950),with choline andcarnitine (Ball, 1964)and withcholine rds withCVDandcancer carotenoidsandother“c that cancomplete betweeneachothers. Theissue e (McCarty,2000),choline (Wenru etal.,1994), acin isadministeredalon proved bytheadditionofanotherlipotropeasit s (ROS),breakingoxidativechainreactions, i.e. rated by theexample of asustained-release of nicotinic acidtogether e.g. athighdose,notably itispreferabletoconsume complex PBF flushingandnausea)at logical mode ofactionmay expressvery 2008). Moregenerally,ithasbeen myo -inositol in the form of synthesis or being co-factors synthesis orbeingco-factors r examples ofthelipotropic ficial atlowerdoseand/or prevention -requiresthe onutrients” containedin e (El-Eneinetal.,1983; niacinthatmay be due totheirdifferent highdoseswithin myo in 67 - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 compounds wereantagonistic athighdoses(50 μ Accordingly, same authorspreviouslyshowedsyne mechanisms thanonlyoneagentathighdosewithside-effect (OhigashiandMurakami, 2004). mechanisms andthatmight bebestprevented byco carcinogenic processthatinvolv physiological mechanisms ofaction.Suchan that would bemasked bycombining several agents at lowerdoses withcomplementary (Thor etal.,1982). hydroxyquinone) inculturedHepG2cells(Rushmore may havepro-oxidativeeffectathigherdo niacin whenusedatclinicaldo potentiate and/or tocatalize the lip interferences thatmay existbetween lipotropes, some Bvitamins beingfor exemple ableto acid imbalance (Arvidson andAsp,1982).Theseexam supplementation leadtoincreasedtotalhepaticlipi Stewart, 1954).Itwasalsoshowninratsfe consumption ofBvitamin inthislatterstudy cobalamine (Drill,1954)andthecons optimum whencombining respectivelythe consum lipotropic effectinratsfedeither in rats,theuseofbothcompounds almost completely the studyofKotakietal and Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), M) andgenistein(2 myo This raisestheissuethatasingleagentat

-inositol (AndersenandHolub,1980;Engel, 1942

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For . μ , whiletheuseofonlycholineor M) atlowdosestowards suppre Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition ses, some phenoliccompounds that ahigh-fatorBvitamin-deficient otrope actionofotherlipotropes es severalstageswithdiffe

umption ofBvitamins, cholineand ses asshownwithquinones(menadione and unexpectedly aggravatingfattyliver(Shilsand d choline-deficientdietthat0.5%-methionine highdosemay havephys d content,probablyasa issue hasbeennotablyemphasized forthe mbining multipleagents withdistinct molecular rgistic effects of epigallocatechin gallate (0.04 μ curedrats(Kotakiet M) andhadnoeffect when testedalone ption ofcholine,folicacid,inositoland ples illustrated welltheinteractionsor et al.,1991)andisol myo ; Kotakietal.,1968).Forexemple, in ssion ofNO generationwhileboth -inositol only partly cures fatty liver diet hasbeenshowntobeatits rent impaired physiological areantioxidantatlowdoses such as choline. Similarly to al., 1968).Similarly, the result ofdietaryamino myo iological side-effects ated rathepatocytes -inositol, the only Page 68of267 68 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 69of267 10 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 9 8 7 6 5 4 3 2 1 such asthedown-orup only oneortwocompounds; andforwhichphysiologi lipotropic phytomicronutrients for for antioxidantphytomicronutrients, itwoul decreased lipogenicenzyme activities)(SeeSupplementa and/or lipid/fatcontents) phytochemicals may beconsideredas magnesium andBvitamins, we haveshowedthat immunomodulatory actions,thatm dihydroxyphenylethanol), oleicacid compounds (hydroxytyrosol,oleuropein,caffeic ac proptective role of oliveoiltowa physiological functionsassociated compounds withcomplementary propertiesthat illustrated by theunrefined/virgin olive oil phytochemical lipotropes andantioxidantsmay synerg In addition, sinceincrea Several phytochemical properties toimprovefattyliver VLDL/LDL exportationfrom liver,and/ stimulation ofFAoxidationenzymes, methyl should be“aprerequisite”totestsy (Murakami etal.,2003).Inaddi Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Finally, besidesthe4main lipotro

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For -regulation ofgeneexpression,thei sed oxidative stressisalso generally Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition rds NAFLDmaybeattributedto asindirectlycontributingto tion, choiceofcompounds withdifferentmechanisms ofaction odulate transductionpathways, that nergicity (OhigashiandMurakami, 2004). which thesynergicactionwould with fattyliver:thus,Assyet and squalenethatexert anti-inflammatory,antioxidantand

istically contribute to alleviate he having adirectlipotropiceffect( or actionofenzyme co-factors. pes thatarecholine, betaine, d alsoexistwithinPBFawholefood donation for the synthesis of PL involved in donation forthesynthesisofPLinvolvedin atleast14otherphyt all may contributeto id, o-coumaric acid, cal modes ofactionappearverydiversified l Tables1-4).Itseems, therefore,thatas nhibition oflipogenicenzymes andthe package associatedwithfattyliver,both the overalllipotropeeffect( the combinedactionsofphenolic al.proposedthatthepotential thatiscomposed ofseveral be betterthantheactionof regulategeneexpression in myo patic steatosis. Thisiswell i.e. ochemicals orgroupsof -inositol andmetionine, protect from impaired vanillic acidand3,4- decreased hepaticTG package e.g. of 69 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 literature. Despitetheabsence ofstudy,magnesium contributing totheoverall lipotropi Tables clearlyshowedthatniaci of actiondifferfrom onecompound toanother myo cysteine-containing compounds. Studiesinratshave inositol, magnesium, Bvitamins andpolyphenolswh potential lipotropesforhuman nut Araya etal.,2004).Onsuchabasis,most of TG contentsincearemain constituent ofexce DefiningthelipotropiccapacityofPBFi considered asalipotrope. databases remain insufficient, especially for free that theinterestinbetaine, choline and studies havedefinedthelipotropecontentandlipotr If thelipotropiceffectofso What compoundshouldbeconsideredaslipotropes? CONCLUSIONS AND al., 2009). transduction pathways) activation, all of them bei fluidity and/orthatdecreaseRAS(belongsto liver regeneration,thatinhibi Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), -inositol, methionine andcarnitinehavelipotr

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Sensu stricto Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition PERSPECTIVES PERSPECTIVES me phytonutrientshasbeenwellst t HMG-CoAreductaseandlipooxige n, pantothenicacid,folatesmay be rition, some beingubiquitousin c effect.Allthesecompounds have

, itisacompoundthatdecreasedhepaticfatcontent,mainly myo -inositol contentsofPBFseems ratherrecentand compounds citedinSupplementalcompounds Tables1-4are GTPases,involvedinreceptor-mediated signal myo (Figure 1A-D).Then,resultsofSupplemental ng involvedinfattyliverdevelopment (Assyet opic effectsandthatphysiological mechanisms ss fatdeposits insteatosis (Adams etal.,2005; nvolves definingwhatcompoundsshouldbe ope densityofPBF,rawor can be reasonably alsoconsideredashavinga can bereasonably -inositol.

clearlydemonstrated thatbetaine,choline, ile otherbeingspecific PBFlikebetaine,choline, udied inrats,paradoxicallyno nase, thatchangemembrane considered assignificantly beencitedaslipotrope in ofplant processed. It is true processed.Itistrue species like species like myo Page 70of267 70 - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 71of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 positively affect some metabolicbiomarkers, there Although numerous studies-mainly interventiona The lackofhumanstudies symptom toseveralchronicdiseases,especially in thedevelopment ofnumerous metabolic and/or similarly toincreasedoxidativest investigated, thelipotropiccapac Whiletheantioxidantandhypolipidemic ca metabolism andtheirabilitytoreduce itshepati remains tobedemonstrated inbothratsa tocotrienols, theirabilitytosignificantly reduce are phenolicacids, these firstresults,inanimal models,then However, exceptforphytic acid and lignans, furt lignans, stilbenes,curcumin andsaponinsmay be oleic acid),aceticacid,melatonin, deoxynojirimyci compounds, unsaturated FA (probabl based onsignificanthepaticTGcontentreduc lipotropes inliterature.From st compound befoundexclusivelyinanimal-based to foods. CoA. Otherwise,cobalamine (vitamin B12),cite lipotropic actionsinceindispensa Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Concerning theotherphytochemi

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For γ -oryzanol, propionicacid,phytosterols Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition udies reportedinSupplemental ress and/orhyperlipidemia that ble asCoAcofactorallowing tr ity ofPBFwouldthereforede y mainly n-3 PUFAsuchas

cals, toourknowledge,they nd humans. Theireffectonhepaticcholesterol c synthesisare more relevant thanwithTG. inthefirststageof in humans. Fortheremaining phytochemicals that steatosis, hepatic TG and/or total lipid contents steatosis, hepaticTGand/ortotallipidcontents her studies areundoubtedly necessary toconfim chronicdiseases,fatty is undoubtedly alackofstudiesin humans that n, phyticacid,fiber,oligofructose, flavonoids, d aslipotropeinsome tion, onehasconsideredthatorganosulfur l -haveunderlinedth consideredashavingalipotropiceffect. pacities of PBFhavebeenextensively , alkylresorcinol,policosanoland α Tables and23 have beenshowntobeinvolved -linolenic and/or n-9 MUFA like -linolenic and/orn-9MUFAlike pathologydevelopment. ansformation ofFAintoacyl- serve more attention.Indeed, have neverbeencitedas liver is alsoacommon studies,istheonly e abilityofPBFto 71 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 neglected orunder-estimated toth intervention studies,orsimply Spadaro etal.,2008)thatallows dimensional X-rayimages) (Buchman etal., resonance imaging scanning,computerized tomography (densitymeasurements obtained when more serious liver diseases standard sufficiently specifictodi determine whichformofliverdisease ispresen compared tothoseof used inroutinefor evaluating liver injuryin humans the natureoftechnicsthathastobeused class ofphytochemicals withNAFLDriskorprevalence. studies andtosearchforassociationsbetween the prevention of fatty liverdevelopment inhumans there isnointervention studiesdirectly investig (Abdelmalek etal.,2001)orPUFA(Capanni parenteral nutrition(Buchman2001),in etal., in choline-deficientsubjects(Fischer etal.,2007,Z al., 1954;Navarranne etal.,1964;Warembourg a patients that wereadministered compounds. Thus,apartthefewmedical/clinical have investigatedthelipotropi Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Other explanationsforthelackofhuman The reasonsfortherarityofhuman studies

to bestcharacterizingsteatosis

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For alkaline phosphatase(ALP) and agnose fattyliver.Themostreliablete Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition on thefactthatlipotropicpr lipotropic formula ortablets(Col estimating hepaticfatstorage. c effectofcomplexPBFor arediagnosed.Alternatively,non- e benefitoftheirantioxidant a

, butitisinvasive.Itth diagnose hepaticstetaosis. consumption ofsome food 1995) orultrasonography(C al., 2006;Spadaro etal.,2008),toourknowledge, ating theeffectofcomplex PBFconsumption on nd Bertrand, 1964) and the few reported studies nd Bertrand,1964)andthefewreportedstudies reports publishedin NAFLD patientsadminist eisel etal.,1991)-notablyasaresultoftotal are unclear.Oneexplanat t, notably for hepatitis. Butthis test isnot . The first step might be to lead observational . Thefirststepmight betoleadobservational istheserum levelof ALT.Thislevel isthen studies may bebasedonthecostlinessof aspartate aminotransferase (AST)tohelp st isbiopsy,consideredasthe operty ofphytochemicalshasbeen nd/or anticarcinogen son and Gallay, 1964; Nadeau et son andGallay,1964;Nadeauet erefore generally invasive technicslikemagnetic their phytonutrients as free theirphytonutrientsasfree 1954 and1964concerning Generally,thebiomarker s, phytochemicals and/or ion may belinkedto apanni etal.,2006; ered either betaine ered eitherbetaine performed only ic properties. via two- gold gold Page 72of267 72 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 73of267 26 25 24 23 22 21 20 19 18 17 13 12 11 10 16 15 14 9 8 7 6 5 4 3 2 1 patients may beseparatedfrom controlsby helpful for futurehuman intervention studies.Subr liver, andbynotablyfocusingonthelipidome, oneha it hastheadvantageofnon-i prevention remainsas, possible diseases (Brindleetal.,2002) development ofchronicdiseasessuchasdiab nutritional interventions other signallingmolecules, thatcanbe molecules (<1500Da)suchasmetabolicinterm soluble, likefrom liverhomogenates. Themeta biological fluidslikeurine,plasma Metabolomics isaquiterecent setoftechnicsth The contributionofmetabolomics essentially leadbyprivateindustry. have beenperformed inhumans butthattheirre manufacturers. Onemay thereforereasonablysupposeth market targeted forpeopleaiming atloosingweight spectrometry or metabolites ( or organism (Wishart etal.,2007).Byallowing Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), From thefewstudiescarried out Yet, thelipotrope supplements or complexes

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] i.e. For Peer Review Only ametabolic fingerprint), Review Peer For 1 H NMR,bringsnewinformation onthem 535-590. DOI :10.1080/10408398.2010.549596 (Fardet etal.,2007;Stellaal Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition nvasiveness, notablybysimply andcancer(Yangetal.,2004),espe e.g. interms ofnutritionalchoices orsaliva,butalso foundwithinabiologicalsamples,

inbothhumans withsteatosis this high-troughputtechnic, a significant increase inthe levelofserum etes (GriffinandVidal-Puig, 2008),cardiovascular at enablecharacterizingthemetabolome ofvarious sults have not been published, since being perhaps sults havenotbeenpublished,sincebeingperhaps characterizing simultaneously severalhundredsof bolome correspondstothewholesetofsmall amanian etal.havenotablyshownthat NAFLD ediates, secondarymetabolites,hormones and ve collectedpromising resultsthatwouldbe apparently constitute a largeandlucrative at itisverylikely of tissue extracts, either lipid-or water- collecting urine orsaliva. odified metabolic pathways following ., 2006;Walsh etal.,2007)orthe via “fatburning”as . Inaddition,forhuman studies, cially intheini and animal models offatty generally based on mass generallybasedonmass i.e. that interventionstudies a specific cell, organ tial stageswhen indicatedby β -anomer 73 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Databases forthelipotrope contentsofplant-basedfoods biomarkers. more human studiesbasedonthesimple meas phytochemical consumption andrisk/prevalenceor Metabolomics appearsthereforeasasuitabl phytochemicals onhepaticsteatosisdevelopment the phosphatidylethanolamine- et al.showedthatalcoholicsteatosisislikelyto such oddTG beingrarecompounds steatosis wasalsoobserved;and importantly reducedafter24hour (Zivkovic etal.,2009).Forexample, inmice, respectively mice (Ginnekenetal., been provockedbystarvation,high-f Griffin etal.,2007;Pilvi and howlipidome orlipidprofiles hepatic lipidmetabolic pathways effective, easyandrapid todiagnose he unravelling newbiomarkersinserum orurine patients ascontrolorNAFLDsubjects(Subram (Subramanian etal.,2008). Based on thesetwoma glucose level andthatserum lactatelevelte Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Otherwise, thefewstudiesleadinanimal

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition N -methyltransferase pathway(Fi 2008; Zivkovicetal.,2009).Inth it wasidentifiedasa49:4-TGw are involvedinsteatosis,which 2007;Pilvietal.,2008 s starvation,theappearanceof aremodified compared tocont at diet,1%oroticacidsupplem (Ginneken etal.,2007).Inthe

patic steatosiswitha100%-reliability. notablyresultfrom alc nded tobeloweratthelimit ofsignificance anian et al., 2008).Onemayanian etal., understandthatby urement ofnewserum and/orurinaryNAFLD while hepaticphosphatidyl models haveallowed degreeofNAFLD.That e complementary technicforstudyingeffectof through metabolomics, itwillbecome quite rkers, theyhaveaccurately classified118/120 or findingassociationsbetweenlevelsof ), rats(Griffinet gure 2A)(Zivkovicetal.,2009). ith anoddnumber ofCatoms, anewputativebiomarker of one areactivatedordepressed entation andalcoholexcessin study withminipigs, Zivkovic ese four studies, steatosis has ese fourstudies,steatosishas rols (Ginnekenetal.,2007; ohol suppressiveefefcton better understandinghow al., 2007)andminipigs shouldallowleading choline contentwas Page 74of267 74 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 75of267 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 corresponds to make theapproximation thattheTPCcontentofPB give suchinformation fornumerous PBF.Inthe flavonoid (USDA,2007),proanthocyanidin(US now,the recentfood. However, Phenol-Explorer (N acid). Thismeans that,ideally,oneshoulddeterm sesamin (alignan)whilenosignifica Supplemental Table4,moststrikingeffectshave polyphenols isthatallar and accessible(Neveuetal., food group. available USDA releasedin2008(USDA,2008). Zeisel etal.,2003),the recently between2002and2008(De Zwartetal.,2003; the lipotropiceffecthasnotb myo myo they exist!Concerning acetic acid,oligofructose, curcumin andsaponins.Da compounds foundPBF,notablyfree Last butnotleast issueistheabsence ofoffici Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), -inositol-derived compounds,notablyphyticacid( -inositol (Clements andDarn Concerning polyphenols,databasesandliteratu Data forthemethionine, magnesium, andBv Concerning cholineandbetain via

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] notablytheSoucietal.(Soucial

one compound 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For myo most exhaustiveandinvolvingfoodsof Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition -inositol, the sole database is that of Clements andDarnellfortotal -inositol, thesoledatabaseisthatofClements 2010;USDA,2004,2007,2008;Wu et een demonstratedinhumans. withapotentiallipotropic effect. ell, 1980);however,itincludes nt lipotropiceffecthasbeenre myo e probablynotlipotropic:forex

e contentsoffoods,database -inositol, carnitine, melatonin, organosulfur compounds, DA, 2004) and isoflavone (USDA, 2008) contents andisoflavone(USDA,2008) contents DA, 2004) ., 2008) and USDA (USDA, 2005a) databasesby ., 2008)andUSDA(USDA,2005a) al databaseavailablefo end, aswediscussedpr been obtainedwithcatechins(aflavonoid)and ine thecontentinspeci eveu etal.2010)and USDAdatabasesforthe F -thatisgenerally measured inliterature- itamin contentsofPB ta hastobefoundar myo re databecome moreand numerous Sakamoto etal.,2002;Slow etal.,2005; -inositol hexakisphosphates)forwhich differentcountriesbeingthatof ported for ferulic acid (phenolic myo al.,2004b).Theproblem for s havebeenreleasedonly ample, ascanbeseenfrom -inositol moieties from all r some of thelipotropic eviously, onemay also fic polyphenolfoodby ticle by article - when ticle byarticle-when F areobviouslyeasily 75 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 5 4 3 2 1 acknowledged foritshelpfulassistance Ferrand, France ;CRNH Auvergne,F-63000Cler France ;ClermontUFRMédecine Université, Jean-François Martin(INRA,UMR1019Nutrit ACKNOWLEDGMENTS Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

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in theelaborationofscattergrams. , UMR1019NutritionHumaine, F-63000,Clermont- ion Humaine, F-63122SaintGenèsChampanelle, mont-Ferrand, France) isgratefully Page 76of267 76 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 77of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 ME: MalicEnzyme LDL: LowDensityLipoprotein i.p.: intraperitoneally HighlyUnsaturatedFattyAcid HUFA: HDL: High-DensityLipoprotein G6PDH: Glucose-6-Phos FFA: FreeFattyAcid FAS: FattyAcidSynthase/Synthetase FA: FattyAcid Acid DNA: Deoxyribonucleic Acyltransferase DGAT: Diacylglycerol CYP7A1: CYtochrome P450,family 7,subfam CYP2E1: Cytochrome P4502E1 CVD: CardiovascularDiseases CPT: CarnitinePalmitoyltransferase CoA: Coenzyme A CETP: Cholesteryl EsterTransferProtein BHMT: BetaineHomocysteine S-Methyltransferase ATPCL/CCE: ATP-CitrateLyaseor CitrateCleavageEnzyme ATP: AdenosineTriphosphate ApoA/ApoB: ApolipoproteinAorB ALT: Alaninaminotransferase ACO: Acyl-CoAOxidase ACC: Acetyl-CoACarboxylase ABCA: ATP-BindingCassettetransporter ABBREVIATIONS Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For phate Dehydrogenase Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition

ily A,polypeptide1orcholesterol7 α -hydroxylase 77 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Lipoprotein LowDensity VLDL: Very USDA: UnitedStatesDepartment ofAgriculture TG: Triglyceride Regulator SREBP: Sterol PUFA: Poly-Unsaturated FattyAcid PPAR: Peroxisome ProliferatorActivatedReceptor PL: Phospholipid PBF: PlantBasedFoods PABA: Para-Aminobenzoic Acid NAFLD: Non-AlcoholicFattyLiverDisease NAFL: Non-AlcoholicFatty Liver MTP: Microsomal triglyceride Transfert Protein mtGPAT: mitochondrial Glycerol mRNA: MessengerRibonucleicAcid Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For y Element BindingProtein Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition -3-Phosphate Acyltransferase

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138 : 1677-1683. m inman andinanimal models. eases ketosisduringfastingand

268 : 442-452. y lipotropeandprotein American Journalof ities inintestinal Page 84of267 84 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 85of267 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 M.(2008) Brufau, G.,Canela,M.A.andRafecas, Brouwers, M.,Bilderbeek-Beckers,M.A.L.,Geor M.,West,C.E., Brouwer, I.A.,vanDusseldorp, Broun, G.O.andMeuther,R.(1942).Thetreatme Broun, G.O.(1948).Treatment cirrhosis. ofhepatic Brindle, J.T.,Antti,H.,Holmes, E.,Tranter,G., Briggs, G.M.andDaft,F.S. Brandt, K.,Langhans,W.,Geary,N. Brandsch, C.,Shukla,A.,Hirche,F.,Stangl,G.I. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), related tocholestero Supplements subjects withfamilial combined hyperlipidemia: Importance of visceral fat. Greevenbroek, M.J.anddeBruin,T.W. controlled trial. vegetables andcitrusfruitdecreas K. H.V.,Eskes,T.,Hautvast, and adietlowinfatcholesterol. based metabonomics. noninvasive diagnosisofthepresenceandsever Schofield, P.M.,McKilligin, E., Mosedale, D. and para-aminobenzoicacid. of hydroxycitrateinrats Nutrition pork andturkeymeat onplasma

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6 : 30-30. Only Review Peer For Journal ofNutrition 535-590. DOI :10.1080/10408398.2010.549596 l-lowering properties. Nature Medicine fed ahigh-fructosediet. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition Annual Review (1955). Water-soluble vitamins. I. J. andSteegers-Theunissen,R.P. and liver lipids of ratscompared es plasma homocysteineconcentr andLeonhardt,M.(2006).Bene

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Atherosclerosis 118 : 1403. 85 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 20 19 18 17 16 15 14 13 12 11 10 24 23 22 21 9 8 7 6 5 4 3 2 1 Burton, L.E.andWells, W. W.(1977).Characteriza Buijsse, B.,Feskens,E.J.M.,Schulze,M.Fo Buchman, A.L.,Dubin,M.D.,Moukarzel,A., Busserolles, J.,Gueux,E.,Rock,Demigne, C.,Mazur,A.andRayssiguier,Y.(2003). Buchman, A. L.,Ament, M.,Dubin, M.E.,Sohel, Brunt, E.M.,Janney,C.G.,DiBisceglie,A. Bruno, R.S.,Dugan,C.E.,Smyth, A.,DiNatale, J. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), myo (diogenes). in bodyweighteuropeanpopula Boeing,H.(2009).Fru D., Sorensen,T.I.A.and Tognon, G.,Halkjaer,J.,Tjonneland, 1403. nutrition thatcanbereversedwith J. andAment, M.E.(1995).Cholinedeficiency: fructose dietinrats. Oligofructose protectsagains controlled trial. patients receivingparenteral W., Awal,M.andAhn,C.(2001).Cholinedeficien American CollegeofGastroenterology (1999). Nonalcoholicsteatohepatitis Nutrition protects leptin-deficient,spontaneouslyobe -inositol deficientrats.

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tions: Resultsfrom theprojec

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133 : 2467-2474. se micefrom steatosisandinjury. hepatic : 1903-1908. M., Neuschwander-Tetri,B.A.andBacon,R.

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A causeofhepaticsteat D. A.andKoo,S.I. 90 : 1871-1883. cy causes reversible hepatic abnormalities in tion ofthelactation-de : 202-209.

25 : 260-268. choline requirement: Aplacebo- aging thehistologicallesions. t ondiet,obesityandgenes , vanderA,D.L.,Du,H. (2008). Green tea extract (2008). Greenteaextract J.,Sharp,S.,Palli,D., Hepatology osis duringparenteral pendent fattyliverin

Journal of 22 : 1399- Page 86of267 86 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 87of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Castelao, J.E.andGago-Domingu P.J.R. (1951). Carter, C.W.andPhizackerley, T.D.(1962). Liverlip Carter, C.W.andHockaday, Carroll, C.andWilliams, L.(1982).Choline deficien Carlson, L.A.(1963).Studiesoneffectofnicotin Capanni, M.,Calella,F.,Biagini,M.R.,Genise Cantoni, G.L.(1951).Methylationofnicotinamide Calhoun, W.K.,Hepburn,F.N.and Calhoun, W. K.,Bechtel,W. G.andBradley,W. B. Caldas, T.,Demont-Caulet, N.,Ghazi,A.and Caballero, F.,Fernandez,A.,Fernandez-Checa, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Relationship tolipid peroxi the rat. in pantothenate. sources. adipose tissue 1151. alcoholic fattyliver polyunsaturated fattyacidsupplementationamelio G., Sofi,F.,Milani,S.,Abbate,R.,Surren Journal ofBiological Chemistry wheat incommercial mill products. bread. betaine andcholine. steatohepatitis. deficiency accountsfortheliverdamage obs

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(1958).Thevitamin contentofwheat,flourand 173 ids andketone-bodyforma with asolubleenzyme systemfrom ratliver. rates hepaticsteatosis

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71 in patientswithnon- timulated lipolysisin tion inratsdeficient : 39-44. ase inwomen:

23 : 1143- 87 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Channon, H.J.,Mills,G. T.andPlatt,A.P. Channon, H.J.,Loach,J.V.,Loizides,P.A.,Mani Chan, M.Y.andHeng,C.K.(2008 Chan, J.M.,Wang, Holly,E. F.and Chahl, J.S.andKratzing,C.(1966b).Envir Chahl, J.S.andKratzing,C. Causi, N.,Romano, A.andGalfano,G.(1958).Coen Catolla Cavalcanti,A.andLevis,F.(1950).Stea Catala, A.,Zvara,Puskas,L.G.andKitajka, Castelein, H.,Gulick,T.,Declercq, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), liver-fat deposition. of proteinsinthepreventi the expressionlevelsofhepa Epidemiology population-based case-controlstudyinthe 22-26. rats .2.Cholineandmethionine re .I. Cholinedeficiency inra 163-164. pantothenic acidandnicotinamide. Mediche (Torino) action ofpantothenicacidand of PinealResearch changes and its preventive effectson adriam of BiologicalChemistry The peroxisome proliferator

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269 Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition on ofdietaryfattylivers. ts atvarioustemperatures. : 26754-26758. tic genesandplasma lipids. activated receptor regulatesmalic enzyme geneexpression. (1966a).Environmental temperature and cholinerequirement inrats ). Sequentialeffectsofahigh-fi quirements forlipotropicactivity. A. (2007).Wholegrainsandriskof P. E., Mannaerts, G. P., Moore, D. D. and Baes, M.I.(1994). P. E.,Mannaerts,G.P.,Moore,D.andBaes, Bollettino-Societa Italiana its combination withmeso-inositol.

37 san franciscobayarea,california. : 483-492. ycin-induced lipidperoxi (1943). Theactionofamino-acids and proteinson onmental temperature andcholinerequirements in tosis oftheliverduetophosphorus.I.Lipotropic K.(2007).Melatonin-i fold, M.C.andSoliman, G.(1938).Theeffect Biochemical Journal zyme ainratliverdur Journal ofLipidResearch Nutrition Biologia Sperimentale(Napoli)

ber dietwithpsyllium huskson 24 Journal ofLipidResearch : 57-66. pancreaticcancerinalarge dation in rat liver.

32 nduced geneexpression Archivio per leScienze : 976-985. ing administration of American Journalof

7 : 17-21. Journal Journal Page 88of267

88 7 : : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 89of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Clarke, S.D.,Romsos, D. Clarke, S.D.(2001).Nonalcoholic Cicero, A.F.G.andGaddi, Christman, J.K.,Chen,M.-L.,Sheikhnejad,G.,Di Choi, J.S.,Koh,I.U.,Jung,M.H.andSong, Cho, Y.Y.,Kwon,E.Kim, H.J.,Park,Y.B., Chen, Q.(2004).Determination ofphyticacida Chatenoud, L.,Tavani,A.,LaVecchia,C.,Jacobs, D. Chapman, M. J.,LeGoff,W., Guerin,M.and Channon, H.J.andWilkinson, H.(1935).Protei Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Journal ofNutrition of long-chainsaturatedand polyuns Gastrointestinal andLiverPhysiology polyunsaturated fattyacidregu hyperlipoproteinaemias andotherconditions. lipotrope-deficient diet. Methyl deficiency,DNAmethylati fed ahigh-fatdiet. linoleic acidpreparationsoninsulinsignalling, mice. trans structured fatfrom flaxseedoil improves performance ionchromatography. (1998). Whole grainfoodin cholesteryl ester transf protein: Attheheartof theac Biochemical Journal Food andChemicalToxicology

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29 er proteininhibitors. : 350-356. Journal ofNutritional Biochemistry : 1170-1181. R. andLeveille,G.A.(1977).Differen Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition take andcancerrisk. tion oflipid-modulating therapywith (2001). Ricebranoilandgamma-o lation ofgenetranscription. Journal ofAgriculturalandFoodChemistry on andcancer:Studiesthereve steatosisandsteatohepatitis.: aturated fattyacidsonrat liver

47 281 : 1550-1555. : G865-869. European HeartJournal Phytotherapy Research

98 nd inositolpentakisphos Lee, K.T.,Park,T.andChoi,M.S.(2009).Low plasma andhepaticlipid International JournalofCancer fat oxidationandmitochondrial functioninrats : 264-275. Kontush, A.(2010).Choles (2007).Effectsofthreedifferentconjugated n andthedietaryproduc zik, M.,Abileah,S.andWainfan, E.(1993). R., Jr.,Negri,E.,Levi,F.and Franceschi, S.

4 : 672-680. American JournalofPhysiology- tial effectsofdiet andadiposetissuelipogenesis. I.Molecularmechanismfor 31

statins,fibrates,niacinand 15 ryzanol inthetreatment of rsibility ofth : 149-164. : 277-289. phates infoodsbyhigh- metabolism inapo e-/- tion offattylivers. teryl ester transfer teryl estertransfer

ary methyl esters 77 : 4604-4613. : 24-28. e effectsofa 89 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 10 18 17 16 15 14 13 12 11 9 8 7 6 5 4 3 2 1 Daubioul, C., Rousseau,N.,Demeure, R.,Gallez, Dalton, T.A.andBerry,R.S.( Cortez-Pinto, H.,Jesus,L.,Barros,Lopes, Cortez-Pinto, H.,Camilo, M.E.,Baptista,A.,De Colson, J.A.andGallay,C.(1964).Trialtreatmen Clements, R.andReynertson,(1977).Myoinositol Clements, R.,JrandDarnell,B.(1980). Dahiru, D.andObidoa,O.(2009) da Costa,K.-A.,Garner,S.C.,Chang,J.andZeis Craig, S.A.(2004).Betaine inhuman nutrition. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), zucker fa/farats. (2002). Dietaryfructans, butnotce American JournalofMedicine Journal ofNutrition cholesterol andtriglyceride levelsinseru 358. Non-alcoholic fattyliver:Another Toulouse Med formula containing mainly ornithine combined insulin treatment. high- protein kinasecinratliver. choline deficiencyandsubsequentre-feedingof 549. 816-823. different isthedietarypatternin

myo

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8 : 1884-1888. American JournalofClinicalNutrition Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition

26 Carcinogenesis : 215-221.

93 1992). Hepatotoxicityassociated : 102-104. llulose, decreasetriglyceride a feature ofthemetabolicsyndrome? . Effectofaqueousextract non-alcoholic steatohepatitis patients?

132 Myo : 967-973.

-inositol contentofcommonfoods:Development ofa m andliverof ratsadministered alcohol. 16 C., Moura,M.C.andCa : 327-334. choline on1,2-sn-diradylglycerol,fattyacidsand Oliveira,A.G.andDeMoura,M.C.(1999). American JournalofClinical Nutrition el, S. H. (1995). Effects el, S.H.(1995).Effects t ofhepaticmetabolic disordersbyanoriginal B., Taper,H.,Declerc with variousclassical metabolism indiabetes mellitus. Effectof

33 ccumulation intheliverofobese : 1954-1967. ziziphusmauritiana leafon with sustained-releaseniacin. Clinical Nutrition milo, M.E.(2006).How k, B.andDelzenne,N. Clinical Nutrition lipotropic substances. of prolonged (1 year) of prolonged(1year)

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25 90 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 91of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Delzenne, N.M.andKok, N.(1999).Biochemi Delzenne, N. M.andDaubioul,C.(2000).Dietaryfr Degrace, P.,Demizieux,L.,Du,Z.Y.,Gresti,J.,Ca Decombaz, J.,Gmuender, B.,Sierro,G.andCerret de Zwart,F.J.,Slow,S.,Payne,R.Lever,M., de Munter,J.S.,Hu,F.B.,Spiegelman, D.,Fran de Melo,D.S.,Correa,A.D.,Ma Day, C.P.andJames, O. Day, C.P.andJames, O.F.W. (1998a).Hepatic Daubioul, C.A.,Taper,H.S., Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), in animal models. from thecolontoliver. Chemistry adipose tissue during transient hepatic st Guilland, J.C.,Hocquette, F.andClouet,P. endurance exercise. 197-204. (2003). Glycinebetaineandglycine review. bran andgerm intakeandriskoftype2diab hepatic lipidsofwistarrats. Santos, C.D.(2008).Effectsof 114 Hepatology rats. oligofructose lessenshepaticsteat : 842-845. Journal ofNutrition

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129 eatosis incarnitine-depleted rats. : 1467-. (2007). Regulation oflipi George, P.M.,Gerrard,J.A.andChambers, S.T. etes: Aprospectivecoho z, M.andvanDam, R.M.(2007).Whole grain, cal basisofoligofruct elli, P.(1992).Musclecar verot, L.,Djaouti,Jourdan,T.,Moindrot,B., steatosis: Innocent bystander orguiltyparty?

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28 V., de Abreu, C. M. P. and dos V., deAbreu,C.M.P.anddos lzenne, N.M.(2000).Dietary : 32-37. glyceridemia inobesezucker lt, alpenzyme ose-induced hypolipidemia ose-induced hypolipidemia 3 : 227-238. d fluxbetweenliver and rt studyandsystematic lism: Buildingabridge Journal of Biological Journal ofBiological nitine afterstrenuous Food Chemistry Gastroenterology s activityand

83 91 :

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 26 25 9 8 7 6 5 4 3 2 1 Dumas, M.E.,Barton,R.H.,Toye Dulloo, A.G.,Duret,C.,Rohrer,D.,Girardier, du Vigneaud,V.,Cohn,M.,Chandler,J.P.,Sc du Vigneaud,V.,Chandler,J.P.,Cohn,M.andBrow Drill, V.A.(1954).Lipotropic effect Doherty, J.F.,Adam, E.J.,Griffin,G.a Di Nunzio,M.,vanDeursen,D Demigné, C.,Morand,Levrat,M.-A.,Besson, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), microbiota tofatty liver phenotype ininsulin-resistant mice. Gauguier, D.andNicholson,J. Tatoud, R.,Blanc,V.,Lindon,J.C Nutrition in increasing24-henergyexpenditu Vandermander, J. (1999). Efficacyof agreen tea Journal ofBiological Chemistry utilization ofthemethyl groupof group from methionine tocholineandcreatine. Academy ofSciences 1348-1352. Academy ofSciencesth of theextenthepaticsteat 167. increase flowofnon-esterified polyunsaturated fattyacidssuppresssterolre hepatocytes. of propionateonfattyacidandcholesterolsynthe

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57 : 654-663. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition e UnitedStatesofAmerica osis inseveremalnutrition. cholesterolinHepG2cells. ., Verhoeven,A.J.M.andBo

140 K. (2006).Metabolic profiling re methionine inthebiologicals , A.,Cloarec,O.,Blancher,C.,Rothwell, Fearnside, J., re andfatoxidationinhumans. s ofvitamin-b12andotherfactors. : 625-641.

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67 92 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 93of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Esfandiari, F.,You,M.,Villanueva, J.A.,Wong, D. Esfandiari, F.,Villanueva,J.A Engel, R.W.(1942).Therelationof b-vitamins a El-Enein, A. M.A.,Hafez,Y.S.,Salem, H. Eikelboom, J.W., Lonn,E.,Gene Eckstein, H.C.(1952).Dietary Eastwood, M.A.andHamilton, D. Eastwood, M.A.andGirdwood,R.H.(1968). Eastwood, M.A.(1999).Interact Eastwood, M.A.(1975).Vegetabl Eastwood, M.andMowbray,L.(1976).Thebindingof Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), deficient diet. adenosylmethionine attenuateshepatic lipidsynt micropigs. ethanol feedingandfolatedeficiencyactivate Journal ofNutrition International inositol hexa nicotinateasanticholesterolemic andantilipemic agents. Medicine cardiovascular disease:Acriticalrevi rats. components ofdiet. 1170-1172. prevent disease? 188-190. fiber. Journal ofBiologicalChemistry American journalofClinicalNutrition

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29 and Abdel,M.(1983).Role and Lignin -abile-salt : 1461-1467. hepatic endoplasmic reticulum stresspathwayin nd dietaryfattothelipot H.,French,S.W. andHalsted,C. H.(2007). hesis inmicropigs fedethanolwith afolate-

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128 rmation ofmethioninemethyl groups. (1986). Involvement of (1994). Phytaseactivityinthehuman andratsmall-(1994). : 310-312. R. (2007).Whole-grain cons

29 d Fushiki,T.(2000).Chronic(-)-hydroxycitrate late, vitaminB12,pantothenicacid,biotinand ., Yan,M.,Biller,S.A., Gregg,R.E.,Wetterau, of magnesium inenzyme-catalyzed syntheses : 495-501. osomal triglyceridetran promotes lipidoxidationduring exercise in y plant-proteins.

30 : 85-96. . Whole-grain intakeandcancer: (nash):Adiseaseofemerging to inflammatory diseases in toinflammatorydiseasesin post-digestion hydrophobic

85 Dietary reference intakes : 1606-1614. sfer protein islimiting umption isassociated Agricultural and Journal of Lipid Lipid of Journal Federation 103 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 24 23 22 21 20 19 18 17 16 13 12 11 10 15 14 9 8 7 6 5 4 3 2 1 Karanth, J.andJeevaratnam, K. Kaplan, N.O.andLipmann, Kang, D.H.,Jung,E.Y., Chang,U.J.,Bae,S.H. Johnston, P. V.,Kopaczyk,K.C.andKummerow, F. Jin, F.-Y.,Kamanna, V.S.andKashyap,M.L.( Jin, F.-Y.,Kamanna, V.S.a Jin, F.Y.,Kamanna, V.S.andKashyap,M. Jeong, Y.,Choi,Kim, D.,Park,S.,Yoon, Kahlon, T.S.,Saunders,R.M.,Sayre,N.,Chow,F. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), profile inratblood,liverandmuscle. Biological Chemistry Research with hydroxycitratereduces hamsters. fatty acidcompositionofcarcass cholesterol transport. lipoprotein apolipoprotein human hepatoblastoma (hepg2)cells. translational apolipoproteinbtran Arteriosclerosis ThrombosisandVascularBiology degradation byinhibitingtriacylglycerolsynthe oxidative stress. Cytoprotective effectofgreen Cholesterol-lowering effect

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Circulation Thrombosis, and L. (1999). Niacin acceleratesintracellularapob 1997). Niacindecreasesremo andSuh,H.J.(2007).Psyllium huskcombined

28 J., Kwon,S.,Park,E.andK.(2005). sis inhuman hepatoblastoma (HepG2)cells. 94

19 A. (1961).Effectofpyr : 1251-1256. : I149. I.,Chiu,M.andBe : 1051-1059. rcetin againsthydr

Vascular Biology perimental Biology Journal ofNutrition il fractionsinhypercholesterolemic in diet-inducedobeserats. G2 cells:Implication forreverse carnitine andexerciseonlipid ng triacylglycerolsynthesisin

17 ogen peroxide-induced idoxine deficiencyon : 2020-2028. tschart, A.(1992).

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74 : 748-753. : 96-102. Journal of Journal of Nutrition Page 104of267 104 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 105of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Khairallah, E.A.andWolf, G. Peters,J.M., Gonzalez, F. Kersten, S.,Seydoux,J., Kelley, B.,Totter,J.R.andDay,P.L.(1950). The Keim, N.L.andMares-Perlman, J. Keaney, J.F.,Larson,M.G.,Vasan,R.S.,Wilson, Katayama, T. (1997b).Effectsofdietary Katayama, T. (1997a).Dietaryphyt Katayama, T. (1995).Effectofdi Kashyap, M.L.,Jin,F.Y.andKamanna, V.S. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), fed dietslimitedinprotein andmethionine. Clinical Investigation Peroxisome proliferator-activatedreceptor various purifieddiets. 1807-1815. acid deficiencyinratswithhyperc 467-467. oxidative stress:Clinicalcorrelatesof M., Sutherland,P.,Vita,J.A.andBenjamin, E. Research lipids andhepatic activities of lipogenic enzyme Agricultural andBiologicalChemistry dietary Biotechnology andBiochemistry on thehepaticactivitiesofnadph-generatingenzymesratsfedsucrose. in Atherosclerosis synthesis andtriacylglycerolformation, augm myo

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87 tabolism ina similar manner as : 469-476. and serum levelsoflipidsand c steatosisand c effectofcarnitineinrats Journal ofNutrition and Wahli, W. (1999). acidonratsreceiving ting bothfattyacid Circulation essential fatty Bioscience Journal of Nutrition

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6 29 odon grandiflorumagainstfattyli P., Chung, Y. C. and Jeong, H. P.,Chung,Y.C.andJeong, : 355-360. whole-grain, branandcerealfibe : 615-623.

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34 : 409-414. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition Phytochemistry

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4 : 619-625. hepatic lipid levels indiabetic KKmice. Cho, S.M.,Y.andLillehoj,H.(2005). Phosphatidylcholine homeostasis andliverfailure. Jung,H.-J.,Cho,S.-M.,Kim, D.-Y.,Kang,M.-S. s ofgarlicextractand yo, J.C.,Tan,D.-X.andReiter,R.(2004). B., Fisch,C.,Degott,Benhamou,J.P.and

75 te haslong-termeffect itric acid-theprincipal : 765-790.

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167 eral nutritioninrats. cysteine-containing : 869-870. Kwon, T.(2002).

Nelumbo Nelumbo 257 Journal Journal : 3401- : 59- 111 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Madani, S.,Lopez,Blond,J.P.,Prost, Luo, Q.-F.,Sun,L.,Si,J.-Y.andChen,D.-H. ( Lowenstein, J.M.(1971).Effectof(-)-hydr Lott, J.N.A.,Ockenden,I.,Raboy,V.andBatte Lotito, S.B.andFrei,(2006).Consumption Lopez, H.W.,Vallery,F.,Levrat-Verny,M.A., Lopez, H.W.,Leenhardt,F.,Coudray,C.an Lombardi, B.,Pani,P.andSchlunk, Lombardi, B. (1971). Effectsofcho B.(1986) Locker, J.,Reddy,T.V.andLombardi, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), reduces polyunsaturated protein isnothypocholesterolemic inratsbutstim Phytomedicine containing extract-fractionfrom Journal ofBiological Chemistry crop seedsandfruits:aglobal estimate. and Medicine antioxidant capacityinhumans: Caus Journal ofNutrition Dietary phyticacidandwheatbranenhancemu Technology interactions: isitareal problem for human nutrition? hepatic triglycerides. 139-142. rats fedacholine-devoiddiet.

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L.ondiet-inducedhyperc : 1309-1312. 9 Journal ofNutrition . DNAmethylation andhepatocarcinogenesisin n, G.D.(2000).Phyticacidandphosphorusin : 437-446. 2008). Hypocholesterolemic effectofstilbenes of flavonoid-rich foods and increased plasma of flavonoid-richfoodsandincreasedplasma ulates cholesterolsynt cosal phytaseactivityinratsmallintestine. International JournalofFoodScienceand

10 : 11-33. fatty liver:impaired releaseof

128 Federation Proceedings : 1084-1091. hesis andexcretion holesterolemi Free RadicalBiology rals andphyticacid a inmice. invivo Page 112of267

112 30 : . 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 113of267 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 25 9 8 7 6 5 4 3 2 1 Masuda, T.,Kawano,A.,Kitahara,K.,Nagash Martinez, L.O.,Jacquet,S.,Esteve,J.-P.,Ro Marchesini, G.,Brizi,M.,Morselli-Labate,A. Mantovani, M.S.,Bellini,F.,Angeli,J.P. Mannarino, M.R.,Pirro,M.,Helou,Covelli, Mamone, F.,Riggio,S.,Mandraffino, Maiese, K.,Morhan,S.D.andChong,Z.(2007) Mahboob, S. andEstes,L.W. (1978).Effectofpa Mahboob, S.(1975).Effectofpantothenic-aciddefi Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Quantitative determination of sugars and Nature [beta]-chain ofATPsynthaseisanapolipopr Georgeaud, V.,Walker, J.E.,Terce,F.,Collet, insulin resistance. Forlani, G.andMelchionda,N.(1999).Associat Research-Reviews inMutationResearch (2008). Beta-glucansinpromoting health:Preventionagainstmutation andcancer. Nutrition, MetabolismandCardiovascularDiseases (2009). Liversteatosis:anindependentpredictor Cardiovascular Diseases hyperlipidemia withdifferentdegreeofhepaticsteatosis. (2009). Assessment combined ofliverstiffnessvaluesinsubjectsaffectedbyfamilial type 1and2diabetesMellitus. Annals ofNutrition andMetabolism of NutritionandMetabolism

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19 : 91-95.

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658 myo : 154-161. otein A-Ireceptor inhepaticHDLendocytosis. lland, C.,Cabezon,E.,Champagne, E.,Pineau,T., M., Bianchi,G.,Bugianesi,E.,McCullough,A.J., -inositol incitrus fruits

107 X., Perret,B.andBarbaras,R.(2003).Ectopic D., Pucci,G.,Schillaci,G.andMannarino,E. . Oxidativestressbiology ciency onmicrosomal Oliveira, R.J.,Silva,A.F.andRibeiro,L. ima, Y.andArai,S.(2003). K.,Aikawa, ntothenic-acid deficien ion ofnonalcoholicfattyliverdiseasewith of arterialstiffnessindyslipidemic patients.

19 : 450-455. : S15-S16. Nutrition, Metabolismand

4 Sardo, M.A.andSaitta, grown inJapanusinghigh- : 63-71. lipidsofrat-liver. cy onrathepatocytes. and cellinjuryduring Mutation Annals 421 113 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Menendez, R.,Arruzazabala,L.,Mas, Menendez, R.,Amor,A.M.,Gonzalez,R.Fraga, Mellen, P.B.,Walsh, T.F.andHerrington,D. M. McKenney, J.M.,Proctor,D.,Harris,S.a McHenry, E.W. andPatterson,J. McHenry, E. W. G.(1941).TheBvitami andGavin, McCarty, M.F.(2002).Policosanolsafelydown McCarty, M.F.(2000).Co-administration of McCarty, M.F.(1994).Promotion ofhepaticlipid McCance, R. A. andWiddowson, E.M.(1935). Phytinin human nutrition. Mayor, F.,Veloso,D.andWilliams.Dh (1967).E Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Fraga, V.,Molina,V.and Illnait,J.(1997).Chol 253-257. on thehepaticcholestero disease: Ameta-analysis. patients. efficacy andtoxiceffectsofsustained- from protein. component oftheEsselstynregimen. hepatotoxic riskassociatedwithniacintherapy. appetite control. 2694-2699. hydroxybutyrate concentrations 49 performance anion-exchangechromatography. : 64-68. Journal oftheAmeric URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

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nd Chinchili,V.M.(1994).Acomparisonofthe 138 Medical Hypotheses Journal ofNutritional equimolar dosesofbetainemay alleviatethe -regulates HMG-CoA reducta -regulates HMG-CoA esterol-lowering effectof policosanolonrabbits (2008).Whole graininta oxidation andgluconeoge : 471-475. ffects ofnicotinic aci ns andfatmetabolism. IV.Thesynthesisoffat V. and Mas, R. (1996). Effect of policosanol V.andMas,R.(1996).Effectofpolicosanol

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55 : 189-194. Science andVitaminology inhypercholesterolemic d onacetoacetate and3- Biological Research Biochemical Journal

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60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 115of267 25 24 23 22 21 11 10 20 19 18 17 16 15 14 13 12 9 8 7 6 5 4 3 2 1 Moat, S.J.,Hill,M.H.,McDowell,I.F.W., Pulli Miglio, F., Rovati,L.C.,Santoro, A.andSetnikar J.(1957).Effect Merrill, J.M.andLemley-Stone, Mercier, J.,Lumbroso, A.,Vovan,L.andDessai Menendez, R.,Fernandez,S.I.,DelRio,A.,Gonzal Mizrahi, A.,Knekt,P.,Montonen,J.,Laaksonen, M. Minhajuddin, M.,Beg,Z.H.andIqbal,J.(2005) Miller, O.N.,Hamilton, J.G.andGoldsmith, G. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), total homocysteine through increasing Whiting, J.M.,Newcombe,R.G.,Lewis,M. British Journal ofNutrition placebo-controlled prospective clinicalstudy. glucuronate innon-alcoholic in rabbits. proprieties ofhexanicit. processing inculturedhuman fibroblasts. M. (1994).Policosanolinhibitscholesterolbi 923-932. with hypercholesterolaemia induced Plant foodsandtherisk Food andChemicalToxicology tocotrienol richfractionisolated 8 Action ofNicotinicAcidon 727. : 480-490.

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102 Serum LipidLevelsinMan.

: 1075-1083.

43 steatohepatitis -A 5 from ricebranoilinexperiment

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27 . ally inducedhyperlipidemic rats. British JournalofNutrition duals isnotassociatedwith xidant propertiesof d, parallel-group,

50 : 722-

115 77 :

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Morin, R.J.(1967).Theinfluenceof Morgan, A.F.andLewis,E.M.(1953).Them Moon, Y.S.,Latasa,M.J.,Griffi Moon, Y.S.,Keller,W.L.andPark,C.S. Mookerjea, S.,Park,C.andKuksis Mookerjea, S.(1971).Actionofc Mongeau, R. andBrassard,R.(1982). Moiseenok, A.G.,Sheibak,V.M.andGurinovi Moghadasian, M.H.,Nguyen,L.B.,Shefer,S.,Sale Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Biophysica Acta phosphatidyl cholineandetha pantothenic aciddeficiency. promoter bypolyunsaturatedfattyacids. carcinogenesis infemale rats. fed normalandcholine-deficientrats. 143-150. salt binding andwater-holding capacity inrelation toparticle size. pantothenic-acid deficiency. biosynthetic precursorsofthecoenzyme and treatment. and fecalsterollevelsinmice: Hepatic cholesterol andbileacid synthesis, lo Nutrition changes inmeasures ofantioxida

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10 nolamine Mitochondria. ofrat-liver w-density lipoprotein receptor function, and plasma w-density lipoproteinreceptorfunction,andplasma : 374-382. odification ofcholinedeficiencybysimultaneous (1998).Dietarylipotrope-mediated mammary

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116 30 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 117of267 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 26 25 9 8 7 6 5 4 3 2 1 Nagiel-Ostaszewski, I.andLau-Cam,C.A.(199 Nageswara Rao,R.andSakariah, Nagata, Y.,Ishiwaki,N.andSugano,M. Nadler, J.,Buchanan,T.,Natara Nadeau, G.,Rouleau,Y.andDelage,J.(1954).Th B.,Steffen, Murtaugh, M.A.,Jacobs,D.R.,Jacob, Murakami, A.,Takahashi,D.,Koshimizu, K.and Moskaug, J.O.,Carlsen,H.,Myhrstad,M. Nagura, J.,Iso,H.,Watanabe, Y.,Maruyama, Morise, A.,Thomas, C.,Landrier,J.-F.,Besnar Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Communications inChemicalPathologyandPharmacology cystamine againstcarbonte )hydroxycitric acid. relation tothe casein counterparts inrats. antihypercholesterolemic actionof soyprotein Hypertension Magnesium deficiencyproducesinsulinresist lipotropic factorsinthetreat 62 support fortheprotectionofw Mutation Research-FundamentalandMo superoxide andnitricoxidegenerationfrom glutathione synthesisregulation. mice. Kikuchi, S.,Koizumi, A.,Kondo,T., Wada, Y., Inab metabolismresponse todietaryfattyaci : 143-149. European JournalofNutrition URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

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60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Newberne, P.M.andRogers, A.E.(1986).Lab Neveu, V.,Perez-Jimenez, J.,Vos,F.,Crespy, Neuschwander-Tetri, B.A.andCaldwell,S.H. Nehra, V.,Angulo,P.,Buchman, A.L.andLi Navarranne, Fritz,Tanguy,Meriauxa Nauss, K.M.,Connor,A.Kavanaugh,andNe Naruta, E.andBuko,V.(2001).Hypolipidemic effect Nakamura, Y.andTonogai,(2002).Effects Nakamura, Y.,Kaihara,A.,Yoshii,K.,Tsumura, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Annual ReviewofNutrition database onpolyphenol R., Cruz,J.,Wishart, D.andScalbert,A.(2 an AASLDSingleTopicConference. 2347-2352. considerations intheetiology formula. 2333-2341. function inratscausedbydietarylipot 393-398. hypothalamic obesityinducedbyaurothioglucose. Health Science lipid contents andfecalsteroid excretion contents and fecalsteroidexcretioninrats. of theoraladministration ofgr Japanese men andwomen: theJACCStudy. (2009). Fruit, vegetable andbean intake and

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118 46 53 : : : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 119of267 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Noethlings, U.,Schulze,M.B.,Weikert,C., Nieminen, P.,Mustonen,A.M.,Karja,V.,Asikai Nieminen, P.,Kakela,R.,Mustonen,A.M.,Hyvari Nichols, M. R.andMorimoto, B.H.(2000) Nichols, M.R.andMorimoto,B. Newby, P.(2009).Plant foodsandplant-based Newberne, P.M.,Wilson, R.andRogers,A.E.( Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), of Nutrition risk forall-cause,cardiovascular, and cance Trichopoulo, A.(2008).In Johansson, I.,Lund,E.and Boffetta, P.,Bueno-de-Mesquita,H.B.,vander A, M.-J.,Bingham, S.,Khaw,K.-T., Key, C. A.,Tormo, C., Vercambre,M.-N.,Kaaks,R.,Linseisen,J., Ov A., Tumino, R.,Panico,S.,Masa Benetou, V.,Lagiou,P.,Krogh,Beul Animal model forliver steatosis. composition anddevelopment ofhe Biochemistry andPhysiology melatonin affects lipids andenzyme activities inmink ( 745. phosphodiesterase isozymes by 224-230. phosphodiesterase bygenisteinandtyrphostin51. American JournalofClinicalNutrition Pharmacology of youngmale ratstopyrrolizid

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128 Lauzon, B.,Boutron-Ruault,M.- ndent inhibition of cyclic-AMP ndent inhibitionofcyclic-AMP : 203-211. ation-mustelids asapotential

234 Toxicology and Applied Toxicology andApplied : 278-286. nst childhood obesity? nst childhoodobesity? ) liver. Comparative

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366 119 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 23 26 25 24 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Okazaki, Y.,Setoguchi, T.andKataya Okazaki, Y.,Kayashima,T.andKatayama, T.( Okazaki, Y.andKatayama, T.(2008).Di Okada, M.andSuzuki,K.(1974) Okada, M.andOchi,A.(1971).Theeffectofdiet Ohigashi, H.andMurakami, A.(2004).Cancer Oakenfull, D.G.,Fenwick,E.,Hood,R.L.,T Nunn, S.L.,Tauxe,W. N.andJuergens,J.L.( Novelli, G.D.,Kaplan,N.O.an Nolte, K.D.,Hanson,A.D.andGage, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), inositol and Biochemistry rats fedon1,1,1-trichloro-2,2- chlorophenyl) ethane(DDT). activities of lipogenicanddrug-metabolizing en trichloro-2,2-bis (p clearly improves hypercholesterolemia inrats pyridoxine. deposition invitamin B6-depletedratliver. combination. 42 (1979). Effectsofsaponinsonbile-aci biosynthesis. coenzyme A. American SocietyforHorticultural science proline betaine in citrus: Implications fo : 209-216.

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Circulation Biofactors 70 Journal ofBiologicalChemistry - chiro Only Review Peer For : 2766-2770. 535-590. DOI :10.1080/10408398.2010.549596 -chlorophenyl) ethane. -inositol onhepatic lipids withreference tothe hepatic

22 Comment citer cedocument:

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2003). Effect of dietary phytic acid on hepatic 2003). Effectofdietaryphyticacidonhepatic 23 opping, D.L.,Illman, R. : 97-107. zymes inratsfed1,1,1-trichloro-2,2-bis(P- prevention withfoodf : 1089-1096.

28 : 714-721. Bioscience, Biotechnology, and fed ahighprotei tion ofpantothenicacidfrom

70 British Journal ofNutrition : 581-585. minase activitiesandfat on andmethylation to myo actors: aloneandin myo L. andStorer,G.B. -inositol, -inositol statusin n dietwithout myo Journal of Journal of -inositol, D - chiro Page 120of267 120 -

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 121of267 23 22 26 25 24 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Osumi, Y.,Nagasaka,Y.andShimamot.K (1969).Li Ournac, A.(1970).Vitamins ofwine. Ortega, M.F.(1989).Effect ofdi Orbetsova, V.T.,Polyakova,E.D Orbetsova, V.T.,Kiprov,D.I.andVucheva,N. Orbetsova, V.T.(1977).Changesinlevelsofse Onomi, S.,Okazaki,Y.andKatayama, T.(2004).E Onning, G.andAsp,N.(1995).Effectofoat Olthof, M.R.andVerhoef,P.(2005).Effect Olson, R.E.,Vester,J.W.,Gursey,D.,Davis, Olson, R.E.,Jablonski,J.a Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), by lowproteindietandeffect calcium pantothenateuponit. levels inthe liver Akademiya NaNaukite acid onthesynthesisofcholesteroland Bolgarskata AkademiyaNaNaukite serum andliverlipidsinspontaneouslyhype nicotinic-acid. 68 and serum statusinratsfedahigh-sucrosediet. lipid ( concentrations andconsequencesforhealth. protein dietsuponserum Nutrition Choline upontheSerum Lipids Meriones unguiculatus : 1379-1381.

6 URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] : 111-118. For Peer Review Only Dokladi NaBolgarskataAkademiyaNaukite Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 of pregnantrats.

29 ) andrats. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition cholesterol inman. : 137-140. Japanese JournalofPharmacology s oforaladministration of nd Taylor,E.(1958a).TheEffect etary lysinelevelandproteinrest ., Klimova, T.A.andDizhe,E. British Journal ofNutrition Annals ofNutritionandMetabolism and LipoproteinsoftheRat.

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30 : 275-286. B. (1976).Influenceofnicotinic- riction onthelipid

: 613-616. 19 American JournalofClinical ofDietaryProtein,Fat,and : 74-88.

33 6 L : 15-22. -cysteine pantethineand Dokladi NaBolgarskata : 162-169. tinic-acid onlevelof a singleinjectionof th fattylivercaused

24 : B333-B365. s andcarnitine

6 : 310-324. Dokladi Na 121

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Parsons, W. B.J.(1961b).Reductioninhe Parsons, W. B.,Jr.andFlinn,J.H.(1959).Re Parsons, W. B.(1961a).Studiesofnicotinicacid Parker, T.L., Miller,S.A.,Myer Parker, R.A.,Pearce,B.C.,Clark,W., Gor Pardue, W. O.(1961).Severeliverdys Pan, M.,Song,Y.-L.,Xu,J.-M.andGan,H.-Z.( Pagano, G.,Pacini,Musso,Gambino, R.,M Owens (1942).Thecomparativeeffectsofinos Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), hypercholesterolemic patientsbynicotinicacid. lipoprotein cholesterolle 85-99. function, carbohydratetolerance, Chemistry (ORAC) andelectronparamagnetic resonance(EPR). misynergistic antioxidantpotentialofcomplex 11238. hydroxy-3-methylglutaryl-coenzyme Areductase. regulate cholesterolproductioninmammalian ce American Medical Association liver inducedbyhigh-fatdietinrats. metabolic syndrome: Further eviden Cavallo-Perin, P.andRizzetto,M.(2002).Nonalc Proceedings

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1 : 209-217. For Peer Review Only Review Peer For : 65. 535-590. DOI :10.1080/10408398.2010.549596 Comment citer cedocument: vels bynicotinicacid. Critical ReviewsinFoodScienceandNutrition

175 s, L.E.,Miguez,F.E.andEnge anduricacidmetabolism. : 137-138. ce foranetiologicassociation.

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Internal Medicine

24 Journal ofAgricu Archives ofInternal Medicine : 1099-1100.

41 seth, N.J.(2010).Evaluationof cholesterol from C Hepatology : 79-84.

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35 ltural andFood : 123-130. : 367-372. Journal ofthe

268 14 Federation -acetate in : 11230- Page 122of267

107 122 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 123of267 19 18 26 25 24 23 22 21 20 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Perry, W. F.(1960).Effectofnicotinicacida Pettinelli, P., delPozo, T.,Araya,J., Rodrigo,R Perrault, M.andDormard, Y.(1966) Perlzweig, W.A.,Bernheim, M.L.C.andBer Perlman, I.andChaikoff,L.(1939).Radioa Peluso, M.R.(2006).Flavonoidsattenuatecardi Pellegrini, N.,Serafini, M.,Colomb Pavia, M.,Pileggi,C.,Nobile,C.G.A.andAn Patrick, L.(2002).Nonalcoholicfattyliverdisease: Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), cholesterol, fattyacidsandCO fatty aciddepletion. steatosis inobesepatien Poniachik, J.andVidela,L.A.(2009).Enhanc L., Rojas,J.,Korn,O.,Maluenda,F.,Diaz, J. 689. steatosis. Study usingtriolein-C by ratliver metabolism. 1287-1299. modulate lipidhomeostasis inadiposetissueandliver. by threedifferent (2003). Totalantioxidantcapacityofplantfoods,be Journal ofClinical Nutrition vegetable consumption andoralcancer:a Review stress. Treatment approaches using

7 : 276-291.

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in vitro Journal ofBiologicalChemistry 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For invitro . Journal ofBiologicalChemistry Biochimica etBiophysica Acta ts: correlationswithinsu Comment citer cedocument: assays. Critical ReviewsinFoodScienceandNutrition

83 2 14 : 1126-1134. byratliver slices. . Journal ofNutrition Thérapie i, B.,DelRio,D.,Salvatore,S., . Lipotropic effect of betaine as . Lipotropiceffectofbetaine

vitamin E,magnesium, andbetaine.

130 nheim, F.(1943).Themethylationofnicotinamide meta-analysis ofobservationalstudies. : 719-731. gelillo, I.F.(2006).Asso ctive phosphorusasanindicatorofphospholipid ., Araya,A.V.,Smok, G.,Csendes,A.,Gutierrez, nd nicotinamide of onincorporation acetateinto ovascular disease,inhi ement inliver SREBP-1c/PPAR-alpharatio and lin resistanceandn-3long-chain polyunsaturated : 593-600. C., Rencoret, G.,Bra C.,Rencoret, relationship toin -Molecular BasisofDisease Metabolism-Clinical andExperimental

150 verages andoilsconsumed inItalyassessed

133 Experimental Biology andMedicine : 401-406. : 2812-2819. partate onexperimental hepatic sulin sensitivity Bianchi, M.andBrighenti,F. bit phosphodiesterase,and ciation between fruitand ghetto, I.,Castillo,J., Alternative Medicine Medicine Alternative

1792 andoxidative : 1080-1086. American

9 : 686-

231 123 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 7 6 5 8 4 3 2 1 9 Poirier, L.A.andWhitehead, Pfiffner, J.andBird,O.D.( Popper, H.andSchaffner,F.( Pilvi, T.K.,Seppanen-Laakso,T.,Simolin, H., Quan, P.C.andLeBreton,E.(1973). Study of Prior, R.L.(2003).Fruitsandvegetablesin Preuss, H.G.,Bagchi,D.,Bagchi Preuss, H.G.,Bagchi,D.,M.,Rao,C.V. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Naturelles Comptes-Rendus Hebdomadaires desSéancesdel'Ac different oils.Effectsoffas excretion duringchronicdiethylnit Gastroenterology modified bydietarypr Korpela, R.,Oresic,M.andMervaala,E.(2 25 phospholipid intheliver,ratshavingeaten,afte Journal ofClinical Nutrition human volunteers:Apilotstudy. HCA-SX, niacin-boundchromium and Efficacy ofanovel,naturalex and Metabolism plus niacin-boundchromium and naturalextractof Effects ofa 1367-1372. histological andbioc : 397-434.

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: 171-180. 14 : 4462-4472. hemical observations. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition otein andcalcium duri 1956). Water-soluble vitamins, PartI.

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Gymnema sylvestre thepreventionofcellu Journal oftheAmeric 008). Metabolomic changesinfattylivercanbe r weaning,during3or45days,dietscontaining Finckenberg, P.,Huotari,A.,Herzig,K.H., S., Dey,D.K.andSaty fatty acidcomposition of3mainclasses

ng energyrestriction. 24 extract onweight loss. : 45-58. adémie desSciences. extractinweightmanagement in lar oxidativedamage. and acombination ofHCA-SX CA-SX) andacombination of Annual ReviewofBiochemistry Cancer Research andformiminoglutamic acid a, S.andDey,D.K.(2004b). an MedicalAssociation disease:coordinateduseof anarayana, S.(2004a). World Journalof Série D:Sciences Diabetes, Obesity

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60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 125of267 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Rhew, T.H.andSachan,D.S.(1986).Dose-depe Rejman, J.andKozubek,A.(2003).).Inhibito Reimund, E.andRamos, A.(1994) Reid, A.E.(2001).Nonalcoholicsteatohepatitis. Reeves, P.G.,Nielsen,F.H.andFahey,G.C Reddy, N.R.,Sathe,S.K.a Recknagel, R.O.(1967).Carbon Rahman, I.,Biswas,S.K.andKirkham, P. Rader, J.I.,Calvert,R.andHathcock, D.M. Qureshi, A.A.,Burger,W. C.,Peterson, Qureshi, A.A.,Bradlow,B.Salser,W. A. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), alcoholic rats. Agricultural andFoodChemistry dependent dehydrogenasesandontriglycerideacc of niacinuse. reformulation ofthe rodents: finalreportoftheAm in FoodResearch 208. signaling bydietarypolyphenols. release preparationsofniacin. 10544-10550. inhibitor ofcholeste Nutritional Biochemistry bran modulatecardiovasculardiseaserisk

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28 rol biosynthesisisol AIN-76A rodentdiet. : 1-92. Comment citer cedocument:

Critical ReviewsinFoodScienceandNutrition 8 : 290-298. nd Salunkhe,D.K.(1982).Phytat American JournalofMedicine tetrachloride hepatotoxicity. erican Institute ofNutrition

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18 : 270-271. Journal ofBiologicalChemistry

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92 72 Pharmacological Reviews

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261 125 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 2 1 3 9 8 7 6 5 4 Ross, A.B.,Kamal-Eldin, A.andAman, P. Rikans, L.L., Arata,D.andCede Rikans, L.L., Arata,D.andCede Ross, A.B.,Chen,Y.,Frank, J.,Swanson,J.E., Rosolova, H.,Mayer,O.,Jr.andReaven,G.(1997) Rosenfeld, B.(1973).Regulationby Rong, N.,Ausman, Nicolosi,R.(1997).Oryza L.and Rogers, A.E.andNewberne,P.M.(1969).Aflatoxi Rogers, A.E.(1975).Variableeffectsofa Rissanen, T. H.,Voutilainen,S.,Virtanen,J.K., Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Reviews bioactivities, andpossible useasbiomarkers 40% fatdietswith0.1%ofniacin. niacin inhigh fat diets: I. Alterations inen in ratsandinhibitgamm Aman, P.andKamal-Eldin, A.(2004a).Cereal of ClinicalEndocrinology andMetabolism concentration onresistancetoinsulin-mediate Journal ofLipid Research fatty streaksinhamsters. Cancer Research carcinogenesis inrats. 199-204. men: theKuopio Ischaemic HeartDi J. T.(2003).Lowintake offruits,berriesand vege niacin inhighfatdiets.II.E

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29 : 1965-1972. Cancer Research a-tocopherol metabolism Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition Lipids

14 ffect of choline supplements.ffect ofcholine : 557-562.

rquist, D.C.(1964).Fa rquist, D.C.(1965).Fa 32 Journal ofNutrition : 303-309.

dietary cholineofhepaticfatty sease RiskFactor(KIHD)Study.

35 zyme andcoenzyme systems induced bysupplementing

: 2469-2474. 82 ofwhole-grainwheat : 3783-3785. d glucosedisposalinnondiabeticsubjects. Venho, B.,Vanharanta,M.,Mursu,J.andSalonen, Parker, R.S.,Kozubek,A.,Lundh,T.,Vessby,B., alkylresorcinols elevate lipotrope-deficient, high-fatdietonchemical (2004b). Dietaryalkylres in vitro n B1carcinogenesisinlipotrope-deficientrats. nol decreasescholesterolabsorptionandaortic . Effect ofvariationsinplasma magnesium. Effect tables is associated withexcess mortality in

tty liversproducedin tty liversproducedin 82 . Journal ofNutrition : 83-87. Journal ofNutrition - andrye-richfoods. acidsynthetaseintherat. Journal ofNutrition gamma-tocopherol levels orcinols: absorption, albino rats by excess albino ratsbyexcess albino rats by excess albino ratsbyexcess

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60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 127of267 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Sakakibara, K.,Shibata,Y.,Higash Sahyoun, N.R.,Jacques,P.F.,Zhang,X.L.,Ju Saheb, J.L.andDemers, J.M.(1972).Effectof Sachan, D.S.andHongu,N.(2000).Increasesin Ryu, M.H.andCha,Y.S.(2003).Theeffectsof Russakoff, A.H.andBlumberg, H.(1944).Cholin Rushmore, T.H.,Morton,M.R.andPickett,C. Rumpler, W.,Seale,J.,Clevidence,B.,Judd, Rubis, B.,Paszel,A.,Kaczmarek, M.,Rudzinsk Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), with ginsenosides. on cholesterol-metabolism .1.Levelandsynthesisof American JournalofClinicalNutrition intake isinverselyassociatedwiththemeta Duckling. 11 by caffeine,carnitine, andcholine supplementation inrats. carboxylase mRNAlevelsinrats. profiles, hepatic acyl-CoA synthetase, carnitine palmitoyltransferase-I, andtheacetyl-CoA cirrhosis oftheliver. functional activity. Activation byoxidativestressan Journal ofNutrition Ishikura, Y.andHosoda,K.(2001).Oolongteaincr 1183-1191. Beneficial orharmfulinfluence : 521-526.

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131 Annals ofInternalMedicine : 2848-2852. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition of phytosterols i, T.,Sanada,S.andShoji,J. Journal ofBiochemistry d identificationoftheDNAconsensussequencerequiredfor

83 : 124-131. Wiley, E.,Yamamoto, S.,Komatsu, T.,Sawaki, an, W. andMcKeown,N. onhuman cells? LipotropicFactorsonC bolic syndrome andmortal VO2max andmetabolic markers offatoxidation

B. (1991).Theantioxidantresponsiveelement. a, M.,Jelen, H.and Rybczynska, M.(2008). 21 a high-fatorhigh-sucrosedietonserum lipid

266 eases metabolic ratea : 848-862. e asanadjuvantto serumandlivercholesterolinratstreated : 11632-11639.

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12 British Journal ofNutrition : 149. holesterol Metabolism in M. (2006).Whole-grain nd fatoxidationinmen. the dietarytherapyof ity inolderadults. ional Biochemistry

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60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 12 11 10 25 24 23 22 21 20 19 18 17 16 15 14 13 9 8 7 6 5 4 3 2 1 Sanchez-Lozada, L.,Mu,W., Roncal,C.,Sau Samman, S.,Sivarajah,G.,Man,J.,Ahmad, Z.,Peto Salama, R. H.M.,Nassar,A.Y.A.,Nafady, Schade, H.andSaltman, P.(1959). Sanz, M.L., Villamiel, M.andMa Sanders, L.M.andZeisel,S.H.(2007).Choline. Sandberg, A.S.andAndlid,T.(2002).Phytogeni Sandberg, A.-S.,Andersson,H.,Carlsson,N.-G.a Sandberg, A.S.andAndersson,H.(1988).Effectof Sakamoto, K.,Vucenik,I.a Sakamoto, Y.,Ono,H.andSa A.,Nishimura, Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), to sucrose in theabilitytocausefatty liver. Nakagawa, T.,Lan,H.,Yu,X.andJohnson,R.( plasma homocysteine inmen. with amixed fruitandvegetable 27 therapeutic drug(copperni is absorbedanddistributed rabbits. fresh fruit juices. International Journalof on digestibility. of branphytateformed duringdige the stomach andsmall intestineofhumans. concentrations infoods. : 454-464.

Proceedings of theSocietyfor Experimental Biology andMedicine URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] For Peer Review Only Journal ofNutrition Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 Food Chemistry FoodScienceandTechnology Pediatrics International Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition nd Shamsuddin, A.M.(1993).[ cotinic acidcomplex) fo to various tissues inrats. FASEB Journal rtinez-Castro, I.(2004). Inositolsand carbohydratesindifferent

87 concentrate increases plasma an Influence ofnicotinicacidonhe stion inthehuman small intestin

: 325-328.

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16 tin, Y.,Abdelmalek, M.,Reungjui,S.,Le, Nutrition Today A. M. and Mohamed, H. H. T. (2007). A novel A.M.andMohamed, H.T.(2007).Anovel

: A238-A238. 44 nd Sandstrom, B.(1987). 2010). Comparisonoffreefructoseandglucose kura, N.(2002).Betaineandhomocysteine cz, P.andCaterson,I.(2002).Supplementation c andmicrobial phytases dietaryphytaseonthe : 409-413. r non-alcoholicfattyliver. Journal ofNutrition

37 : 823-833. 3 H]Phytic acid(ino

118 42 : 181-186. tioxidant vitamins andlowers : 469-473. e: effectofextrusioncooking patic cholesterolsynthesisin

123

49 102 digestion ofphytatein Degradation products inhuman nutrition. : 713-720. : 1-9. sitol hexaphosphate) sitol hexaphosphate) Liver International : 265-267. Page 128of267 128

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 129of267 24 23 22 11 10 21 20 19 18 17 16 15 14 13 12 9 8 7 6 5 4 3 2 1 Scriban, R.(1970).Vitamins ofbarley,malt andbeer. Schwarz, J.M.,Chen,T. W. andLinfoot, Schön, H.(1958).Effectofnicotinicacidon Schneeman, B.O.andRichter,D.(1993).Changes Schatzkin, A.,Park,Y.,Leitzmann, M.F.,Hollenbec Scharrer, E.andLanghans,W. (1986).Cont Schaefer, A.E.,McKibbin,J.M.andElvehjem, C. Schwenk, T.L.andFisher,M.(1994). Hepatitis I.andWürsch,P. Schweizer, T.F.,Horman, Schweikart, J.,Reimann, J.andSchön,C.(2009). Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), 24 Journal Nutrition histology andpancreatic-enzyme activitydue 1163-1167. study ofdietaryfiber, Journal ofPhysiology -Regulatory, dogs. Agriculture leguminous seeds;anewdisa dosages. metabolism inaphysiologicdose:randomized, double- Circulation lipogenesis, gluconeogenesisan : B377-B399. Journal ofBiologicalChemistry

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29 100 : 1328-1337. : 148-154. Only Review Peer For

(Suppl. I) 535-590. DOI :10.1080/10408398.2010.549596 whole grainfoods,andsmall intestinalcancer. Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition : 196-197(abstractn°1015). of ccharide: Galactopinitol. Food SciencesandNutrition d glucoseproductioninobese Family Practice Integrative andCom

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7 in plasma and hepaticlip : 242-244. k, A.R.andCross,J.(2008).Prospective Annales delaNutrition etdel'Alimentation Investigation ofniacinonparameters of parative Physiology parative blind clinicaltrial Journal of the Science of Food and Journal oftheScienceFoodand

60 ts ofrat-livers. : 192-202. hyperinsulinemic subjects. Gastroenterology

250 deficiency studiesin with threedifferent ids, small-intestinal Nature : R1003-1006.

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9 R.,Trakht,I.andCardinali,D.P.(2007). : 129-134. Journal ofNutritionalBiochemistry Journal ofAgriculturalandFood jury inratsfedahigh-fatand rough alterationofhepatic

34 pid content in brain and liver pid contentinbrainandliver (-)-hydroxycitrateuponthe : 1677-1687. Lipids ceride andapolipoprotein

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t database forstandardrefere 4 p/Data/SR18/reports/sr18fg04.pdf>. p/Data/SR18/reports/sr18fg04.pdf>. p/Data/SR18/reports/sr18fg12.pdf>. p/Data/SR18/reports/sr18fg16.pdf>. : 149-155. database forstandardreference,release18:fatsandoils. ace/12354500/Data/isoflav/Isoflav_R2.pdf>. ace/12354500/Data/isoflav/Isoflav_R2.pdf>. d Yoshida,T.(1956).Studiesonthemetabolism of ontent of common foods, re ontent ofcommonfoods, Agriculture(USDA). nt ofAgriculture(USDA).< of Agriculture (USDA). < of Agriculture(USDA).< content ofselectedfoods,release2.1.United ji, K. and Yoshida, T. (1958). Studies on the ji, K.andYoshida,T.(1958).Studiesonthe ontent ofselectedf Journal ofVitaminology ment of Agriculture (USDA). < ment < of Agriculture(USDA). Agriculture (USDA).< rence, release18:legumes and nce, release18:nutsandseed c acidinpatientswithvarious id treatment inpatients with oods, release2.0.United lease 2.UnitedStates

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29 E.,Lamont, J.,Sheard,N.andBeiser,A.(1991). (1994). Down-regulationof andHalsted,C.H.(2009).Quantitativelipid role ofcholineinthe lden, J.M.(2003).Concentrationsofcholine- : 365-379. FASEB Journal Best, C.H.(1965).Li shyap, M.L.(2008).Niacininhibitssurface Journal ofNutrition liverdisease.

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133 potropic dose-response Canadian Journalof liver diseaseandlow- hepaticperoxisomal : 1302-1307. Annual Review Journal of Nutrition Page 146of267

146 10 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 147of267 12 26 25 24 23 22 21 20 19 18 17 16 15 14 13 11 10 9 8 7 6 5 4 1 3 2 the phospholipids precursorsfortrigly folate (vitamin B9)asmethyl donor deposits intheliver: A-Thelipotr Figures 2A-D. ABBREVIATIONS Figure 1 Figure captions CCE activityinhibition, ofmela on thespecificactions of fiber transcription factors involved respectively inFA which ismainly basedontheup-anddown-regul lipoproteins outsideliversareal favour andreduceeffluxofrespectivelyApoA lipolysis inadiposetissue;mechanisms bywhic 4°) reducingthereleaseofFFAinplasma through syntheses ( precursors lysineandmethionine, 2°)inhibiti factorial lipotropic action while carnitineallowsacyl-CoAto is cofactor oftheenzymatic reac lipogenesis; B-Thelipotropicactio participating incellvolume regulation, cellshrink studies. significant hepatic total lipids/fat or triglycerid Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), β -oxidation pathway:pantothenic acidisprecur

Gamma (

Molecular structureofmain i.e.

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] ACC and DGAT), 3°) up-regulatingexpre andDGAT),3°) ACC For Peer Review Only Review Peer The For γ : SCFA,Short-ChainFattyAcid;PUFA:Poly-UnsaturatedAcid. 535-590. DOI :10.1080/10408398.2010.549596 )-oryzanol isamixtureoffe

different potentialmechanismsdifferent bywhichlipotropesmay preventexcessfat of niacinthatmay exertby1°)favour Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition tonin ondecreasedoxida on incorporation ofacetateinto so presented.D-Thelipotropic tion thatallows transformation of be transferredintomitochondria for n ofpantothenicacid ceride-rich lipoproteinformation andasosmolytes possibly s inthetransmethylation pathway opic actionofcholine,betaine,

lipotropes andofphytochemi rulic acid estersoftriterpe ng activityofenzymes involvedinFAandTG e contentreductionhasb (HDL)- andApoB(LDLVLDL)-containing oxidation andsynthesis,butwhichisalsobased h niacinmayinhibitcholesterolsynthesisand age beingacatabolic signal likelytodecreased sor and constitutive of coenzyme A,magnesium inhibition ofcatecholamine stimulationofTG ation ofgeneexpressionforenzymes and/or (vitamin B5),magnesi ssion of genes that codeforPPAR ssion ofgenesthat tive stressandinsulino-resistance andof ing carnitinesynthesisfrom itstwo cholesterol andFA,ofHCAon effects ofotherphytochemicals free fatty free acids intoacyl-CoA myo for methionine synthesis,as cals for which atleast one β -oxidation; C -Themulti- -inositol, methionine and ne alcoholsandsterols. een reportedin animal um andcarnitinein

α ; and 147 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 12 25 24 23 22 21 20 19 18 17 16 15 14 13 11 10 7 6 5 4 3 2 1 9 8 PhosphatidylEthanolamine- ABBREVIATIONS triglyceride levelshavebeenobtainedwith indicate the means andthemedian. Concerninguns supplementation arepresentedin (control group).Rangesfordurationofthe feed and C-cholesterolcontentfollowinglipotrope Figures 3A-C TetraHydroFolate; VLDL,Ve Regulatory Element BindingProt Proliferator Activated Recepto AcylTransferase; FA,FattyAcid;FAS, Protein; CoA,Coenzyme Carnitine A;CPT, Homocysteine MethylTransferase; CE,Choleste Lyase/ ATP-Citrate TriPhosphate; ATPCL/CCE, MonoPhosphate; ApoA,ApolipoproteinA;A Carboxylase; Transporter; ACC,Acetyl-CoA results presentedinSupplemental Tables1-4. oligofructose onFAre-esterifica Mono-Unsaturated FattyAcid;NF- Density Lipoprotein;ME,MalicEnzyme; Mg, GSH, reducedglutathione;HCA,HydroxyCitric Fatty Acid;Glycerol3-P,3-Phospha Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

. Percentagechangesfor:A- : HCA,HydroxycitricAcid;PUFA, Only Review Peer For 535-590. DOI :10.1080/10408398.2010.549596 Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition N -MethylTransferase; PP,PyroPhosphate;PPAR ry LowDensityLipoprotein. r alpha;PUFA,PolyUnsaturated tion inhibition.Figures1A-Dhave Tables 2and3.Redcrosses ein; TC,TotalCholesterol; TG,triglyceride; THF,

hepatic total lipids/fat conten κ B, NuclearFactorKappaB;PEMT, te; G6PDH, Glucose-6-Ph te; G6PDH, arachidonicacidonly(Supplemental Table2). Palmitoyl Transferase; ABBREVIATIONS Acid Synthase;FC,Free Magnesium; MS,MethionineSynthetase;MUFA, Acid; HDL,HighDensityLipoprotein;LDL,Low consumption byratsiniti ACO, Acyl-CoA Oxidase; AMP, Adenosine Oxidase;AMP,Adenosine ACO, Acyl-CoA ryl Ester;CETP,Choles po B,ApolipoproteinB;ATP,Adenosine Citrate CleavageEnzyme; BHMT,Betaine ing periodsandpercen Poly-Unsaturated FattyAcid aturated FA,reductions of total/lipid and : ABCA,ATP-BindingCassette beenmainly elaborated from fatty Acid;SREBP,Sterol horizontal barsrespectively DGAT, DiacylGlycerolO- osphate-DesHydrogenase; t, B–triglyceridecontent Cholesterol; FFA,Free ally fedsteatogendiet teryl Ester Transfer teryl EsterTransfer tages oflipotrope α , Peroxisome Page 148of267 148

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 149of267 11 10 9 8 7 6 5 4 3 2 1 2). and ethyllinoleate;reductionofACCactivity and G6PDHactivitieshavebeenobtainedwithmet (Glucose-6-Phosphaphate DeHydrogenase). yielding NADPH,H Carboxylase) andATP-CL/CCE(A are thosedirectlyinvolvedinFAsynthesis, Carboxylase (ACC),E–ATP-Citr – MalicEnzyme (ME);C–Glucose-6-Phosph consumption byratsinitiallyfed Figures 4 A-E. Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), ABBREVIATIONS

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] For Peer Review Only Review Peer For Percentagechangesforlipogenicen 535-590. DOI :10.1080/10408398.2010.549596 + directlyusedforFAsynthesis, : PUFA,Poly-UnsaturatedFattyAcid Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition steatogen diet(controlgroup):A ate Lyase/CitrateCleavageEn TP-Citrate LyaseorCitrate

Concerning unsaturatedFA, i.e. ate dehydrogenase(G6PDH);D–Acetyl-CoA FAS (FattyAcidSynthase),ACC(Acetyl-CoA withethyllinoleate hyl linolenate,methyl li i.e. zyme activities followinglipotrope ME (Malic Enzyme) andG6PDH zyme (ATP-CL/CCE). Enzymes – FattyAcidSynthase(FAS);B Cleavage Enzyme) and those Cleavage Enzyme)andthose only (Supplemental Table reductions of FAS, ME reductions ofFAS,ME noleate, methyl oleate 149 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 include resultsofinterventionstudies ris&Vgtbe + 1 Fruits &Vegetables Vegetables juices) (not Fruits Legumes + Cereals All-cause (whole-grain) + Table 1ProtectiveeffectofPBFagainstchro significant positiveeffectandno effect;resultsar Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman + indicatesconvincingprotectiveeffect; Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For mortality mortality Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition ± ± ±

indicatesthat results are notsufficiently convi control/obesity control/obesity

Weight + + ± ± e onlytendenciesdeducedfrom

nic diseaseand all-causemortalityrisks acr V Type Cancers CVD 2 + ± ± ±

ncing or inconclusive, withstudiesshowing both positive ornoassociationand + + ± ±

Diabetes they donot ± ± ±

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Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Table 2Lipotropiceffectsofma fde - 01055 - - - . 3 - 3 0.5 - - 3-5 - -63/0 ------0.1-0.515 - - - - 0.5 ppm 0.1-1.6 - - - - - 0.1-0.5 -31/-29 - - - - %ofdiet 0.2-0.5 0.01 0.4 0.1-0.515 -21 - - %) (range, Change %ofdiet Duration - 0.2 ME - 1-7 - - - 5 ------1 0.1-0.515 1 - - Duration - - - activity 0.5 - -3-14.5 (days) %ofdiet n 2 (days) 0.001-0.005 - 0.4-0.5 0.2-4 - 0.15-0.68 Duration 0.1-0.515 %ofdiet 13-16.5 - 7-56 45 - 7-56 - 42 - 14-45 21 - 0.16-0.64 (days) 30-84 0.16-0.64 - - %ofdiet Duration - - - (days) n Duration - 2-3 TL/fat content 45 14-21 7 (days) - 3-16.5 14-65 - 21 - 13-21 4-21 14-65 - - 10-21 7-56 16-18 - 64 30 10-26 84 7-56 14 30 - Change(range, %) Cholesterol 1- 9 1 - - 1 content - 5 2 - 1 n hne(ag,% -6-2 -70 -12 -37/0 - -56/-52 Change(range, %) -62/-51 FAS -84/-60 Change(range, %) TG - 8 - 1 2 1 - 2 8 - - 1 content n 4 - -3 1 ------2 - activity n 535-590. DOI :10.1080/10408398.2010.549596 a 92 6 3 1 1 3 7 1 1 -

Comment citercedocument : For Peer Review Only Review Peer e For -4-9 7/6 -00 -87/-10 -46/-9 -50/0 -79/-64 -84/-39 in plantlipotropes,micronutrien Choline Betaine URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

anlptoe Vtmn Other phytochemicals Vitamins B Main lipotropes

Critical ReviewsinFoodScienceandNutrition Myo 8/1 --9-3- 6/4- -83 - - -64/-4 - -79/-23 -81/-17 -17/-9 - - ioio Methionine Niacin Pantothenic -inositol ts and othercompoundsonmainmarkers of lipid metabolism in - - -51/-6 - -60/+16 -21/-10 - -28/-7 6/5 4/1 - 5/7 1/1 6 - -63 -11/-1 -55/-7 - -62/-51 -48/+11 acid ≈ 1-25 ppm Folates HCA Carnitine Organosulfurs MUFA/PUFA Melatonin d c,d - .-. . - 0.5 0.1-1.6 - 9+70116 0.5 -9/+67 0.1-1.6 rats ≈ ≈ 0.1 01 - 0.1 c

151 ≈ ≈ 0.003-0.014 0.003-0.014 b

c c

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Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), b a MUFA, Mono-Unsaturated Fatty Acid;PUFA,Poly-Unsaturat e d c ABBREVIATIONS corresponding Supplemental Tables) generallyconsume around 20 gchow dietdaily Number ofreferences extracted Max-min-values and for reduced and/or increased percentages The sign “ No datafound ppm =10 fde - 0105 ------5 - - -57/-11 ------3 - - -69/0 ------57/+3 - - -10 - - - - 0.1-0.5 - - -31/-20 ------0.1-0.5 - -31/-20 - - - - %) (range, Change - - - - diet %of - 0.1-0.515 - -43/-24 - - - Duration - %) (range, Change ------diet %of - - -3-13 - - (days) - -42/-12 ATPCL - - 1 - - - - Duration - - - - %) (range, Change - - 1-4 - - - activity - - - %ofdiet - - -3-13 - n (days) - ACC - - 1 ------1 - %) (range, Change Duration activity n - - (days) G6PDH 13-16.5 - - - - - 5 - - - - 7 ------1 - activity n -6 ≈ , ” indicates thatfor some references, thecompound percentage of i.e. 1 mg/kg 1 : ACC, Acetyl-CoA Carboxylase; ATPCL, ATP-Citrate Lyase or Citr 535-590. DOI :10.1080/10408398.2010.549596

from Supplemental

Comment citercedocument : For Peer Review Only Review Peer For Tables 1and2 URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

ed Fatty Acid;TG,TriGlyceride; Total Lipids TL, are given:they includeboth significant and unsignificant results Critical ReviewsinFoodScienceandNutrition the diet has been calculatedfrommg/kg thedosegiven in b.w. ate Cleavage Enzyme; FAS,ate Synthase; Fatty G6PDH,Glucose-6 Acid

(notably 0 change)dese effect since anabsenceof or from thedosegiven daily, assuming –when data was not given in article - thatrats -Phosphate Dehydrogenase; HCA, HydroxyCitric Acid;ME, Enzyme; Malic rves to be mentionedrves tobe (for significanceof results, see Page 152of267 152 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 153of267

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Tableau 3Lipotropiceffectsoffibercomp hne(ag,% - 6/2 -10 0 6/2 ------63/-21 0 - -41/0 -65/-26 - Change(range, %) ME ------2 - 5 - 2 activity n TG 6 5 6 1 4 4 3 1 2 2 content n hne(ag,% -5+7 8/4 -7- -9 - -19 -57/-1 -84/-42 -85/+47 Change(range, %) Cholesterol 14 4 3 2 4 5 3 2 34 3 content n fde - .-. 1 - 0105 ------0.1-0.5 - - 10 0.1-2.5 - - - 0.15-0.2 10 - 0.06-0.5 0.1-2.5 0.1-1 %ofdiet 0.15 - - 0.075-0.4 0.06-0.5 0.001-0.07 5-10 0.1-1 0.2 Duration %ofdiet 0.5-1.02 0.002-0.2 0.075 0.6-30 (days) - - 5-10 12-13 Duration 42-70 - 15 - - - - 0.1-2.5 - %ofdiet - 0.4 - - 12-13 (days) - 182 21-70 - 10-15 - 3-10 10 Duration 13-3028-49 19-5635-63 28-42 19-84 28-49 10-2828-49 13-35 9-63 %ofdiet 0.1-2.5 (days) 6.5-16 Duration 35-63 49 Change(range, %) 21-84 31-35 49 28-42 10-15 49 %ofdiet 28-56 12-30 19-70 (days) Duration n (days) TL/fat content 19-63 12-30 42 28 - 28 Fiber 28 - 14-84 - - hne(ag,% -5+3 1/ - -13/0 -75/+23 Change(range, %) FAS 5 - - - -2 - - 1 4 - 6 activity n 535-590. DOI :10.1080/10408398.2010.549596 a 5 5 1 1 -

Comment citercedocument : For Peer Review Only Review Peer For c -0+2 5/2 -3 9 -4+ - -5+ - - - - -45/+8 -4 -24/+7 - -9 -43 -52/-29 -60/+12 URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

ie-yecmons Polyphenol-type compounds Fiber-type compounds ounds, polyphenolsandderivedcompoundson htcai Oligo- Phytic acid Critical ReviewsinFoodScienceandNutrition fructose 14/-3 -3/+1 -28/+14 -39/+21 -37/- hnlcaisFaood Lignans Flavonoids Phenolic acids ≈ 0.0018 3+ 6/16 2 -40/-35 -22 23/+3 -68/+136 b 213 - - - - 3 1 2 d 0.06-0.5 - - - main markersoflipidmetabolisminrats Curcumin Saponins Phytosterols 6-2+4-6-8-6-4 -19/-7 -26/-14 16 -52/+14 -76/-18 ≈ ≈ 0.005-1 0.005-1 d d 015 0.01-1.2 0.1-5 0.2-1.2 0.1-2

-12/+16 -33/-7-27/+35 γ -oryzanol -oryzanol *

153 plant extract ≈ ≈ Mixture or 0.15-0.61 0.15-2.5 d,e d

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Change SREBP (range, mRNA %) - - 2 - - - - level - - - - +160 ------n Change Change ATPCL ------5 - 1 - 2 (range, activity n %) - -16 - 0 -57/-36 - - - fde - . 1 - 00-. ------0.06-0.4 -70/-30 ------10 - Change -26/0 - % - 0.5 Duration -37 (range, diet %of - of - - - (days) %) ------14-28 ------0.5 diet 0.002-0.4 %) (range, Change -55/-9 Duration ------%ofdiet -50/+125 - (days) PPAR - - - - - 182 ------Duration - - - %ofdiet - - - 10-15 13 - 42-70 - (days) -16/0 Duration -44/-2 Change - (days) ACC - 13 - - % 182 - 1 - 1 2 - - - - Change(range, %) 15-28 Duration - - -- - (range, activity n of (days) G6PDH %) - - 12-13 - - - - 0.1-2.5 - - diet - - - - 5 - 10-15 - - 5 -47/+5 ------0.06-0.4 activity -77/-3 ------n α mRNA - - - 1 - - - level n 535-590. DOI :10.1080/10408398.2010.549596

from Supplemental

Comment citercedocument : For Peer Review Only Review Peer For Tables 3and4 URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Critical ReviewsinFoodScienceandNutrition ≈ ≈ 0.0018 0.0018 0.1-0.4 - - -- - d - - - - Page 154of267 154 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 155of267

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), e d c corresponding Supplemental Tables) RiboNucleic Acid;PPAR ABBREVIATIONS mLaround 20 water daily generallyconsume around 20gchow dietdaily Range ofthecompound percentage isthatof2references among Max-min-values and for reduced and/or increased percentages The sign“ The ≈ ” indicates thatfor some references, thecompound percentage of : ACC,ATPCL, Carboxylase; Acetyl-CoA ATP-Citrate Lyase orCitr

535-590. DOI :10.1080/10408398.2010.549596 α , Peroxisone Proliferator Activated Receptor Activated PeroxisoneProliferator ,

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are given:they includeboth significantand unsignificant results the three selectedsinceonereference didnotgivethepercenta alpha Critical ReviewsinFoodScienceandNutrition ; SREBP, SterolRegulatory Element-Binding Pr the diet has been calculatedfrommg/kg thedosegiven in b.w. ate CleavageEnzyme;Fatty FAS, Ac oteins; TG, TriGlyceride; TL, Total Lipids Total Lipids TL, TriGlyceride; oteins; TG, id Synthase;Glucose-6 G6PDH, ge; theupper limitwas evaluatedfrom percentage in (notably0change)dese effect since anabsenceof or from thedosegiven daily, assuming –when -Phosphate Dehydrogenase; ME, Malic Enzyme;mRNA, messenger rves to be mentionedrves tobe (for significance of results, see drinking water assumingan adultrat consumes that datawas not given in article - thatrats 155 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Betaine Choline Carnitine Magnesium Niacin Pa Figure 1

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

535-590. DOI :10.1080/10408398.2010.549596 s

allcsen ognslu opud Acide -allyl cysteine (organosulfurcompound)

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Critical ReviewsinFoodScienceandNutrition Myo ttei cd Folates ntothenic acid -inositol Methionine

α -linolenic (PUFA) Acetic acid (SCFA)

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vncsd spnn Avenacoside A(saponin) Epigallocatechin gallate(flavonoid) Melatonin Pectin (soluble fiber)

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

535-590. DOI :10.1080/10408398.2010.549596

Comment citercedocument : For Peer Review Only Review Peer For

Sesamin (lignan) Cajanin (stilbene) Curcumin γ URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] -oryzanol 1-Deoxynojirimycin

Critical ReviewsinFoodScienceandNutrition

Phytic acid Fructans (oligofructose)

157 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 B) A) Figure 2A-D Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

Grc iorti secretion lipoprotein TG-rich Cell volume signalling volume Cell

1 2 Mg ↓ elshrinkage Cell reftyacid Free fatty ioeei ? Lipogenesis

aaoi signal Catabolic URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] attei acid Pantothenic ATP + Coenzyme A

Coenzyme A Intermitochondrial membrane space membrane Acylcarnitine For Peer Review Only Review Peer TG For (LDL, VLDL) Lipoproteins 535-590. DOI :10.1080/10408398.2010.549596 Carnitine palmitoyl Carnitine rnfrs II transferase ↓ ↑ Synthetase Acyl-CoA ? elvolume Cell Osmolarity Water β (CTP II)(CTP Sphingomyelin Acetylcholine Phospholipids -oxidation Myo Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition Acyl-CoA -Inositol AMP + AMP PP Cysteine Carnitine Acyl-CoA Acyl-CoA Phosphatidylinositol i Carnitine Choline Choline (lecithin) Phosphatidylcholine

Dimethyl-glycine Phosphatidylethanolamine Betaine Mitochondrial matrix Mitochondrial Carnitine palmitoyl Carnitine Acetyl-CoA Betaine PEMT rnfrs I transferase acylcarnitine translocase Carnitine/ (CTP I) (CTP Myo pathway Transsulfuration Myo S-Adenosylmethionine -Inositol -Inositol Cytoplasm Homocysteine S-Adenosylhomocysteine Methionine BHMT GSH MS iai B12 Vitamin Acylcarnitine Acylcarnitine THF Methyl-THF xdtv phopshorylation Oxidative Folate Folate Ethanolamine Hepatocyte Hepatocyte Bloodstream Bloodstream membrane mitochondrial Outer membrane mitochondrial Inner Methionine Methionine Mg

Page 158of267 158 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 Version37 36 35 34 preprint33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 159of267 D) C) Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6), Bloodstream cholesterol Bile acids Bile Bloodstream Hepatocyte methionine ↑ Aminoacids & ↑ aeo cholesterol of Rate Lysine iesl hlseo efflux &cholesterol bile salt synthesis + Fe, vit B6, B1 & C - ↑

hlseo & FA cholesterol FA FA (soluble) trapping (insoluble) or adsorption Fiber Carnitine iorti (HDL lipoprotein URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] β

Niacin Niacin -oxidation ↑ ↑ ↓ Apo A-I-containing - HDL half-life HDL Apo catabolism A-I For Peer Review Only Review Peer For + opud and compounds Acetate Bile salts Bile Organosulfur 535-590. DOI :10.1080/10408398.2010.549596 ↑ ( propionate ↓ β PPAR -ATP synthase)? HDL-catabolism 2 ) secretion FA receptor Up-regulation ↓ α, lipogenesis & insulinoresistance activity ↓ β ↓ P n ACO and CPT ACC ACC -oxidation xdtv stress oxidative Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition antn,oioacaie,fbe htcac Carnitine, oligosaccharides, fibre, phytic Melatonin lipoprotein (VLDL, LDL) (VLDL, lipoprotein ↓ ↑ ↑ Apo B-containing ↓ Apo B degradationApo B esterification TG synthesis secretion ↓ Niacin Niacin DGAT-2 ↓ FA eeexpression Gene hlseo and/or FFA cholesterol Adipose tissue Original compounds Original raoufrcmons UA&PF n acetate and & PUFA compounds, MUFA organosulfur

and/or metabolites ↓ Glycerol 3-P Glycerol Total lipid,Total TG, Glycerol Glycerol contents ↓ ag Grc VLDL Large TG-rich ↓ - 3 Acyl-CoA Small denseLDL Small T,F n CE) (TC, FC and → ↓ Acetate Cholesterol aehlmn-iuae TG hydrolysiscatecholamine-simulated G6PDH, FAS, ME, ACC, ATPCL/CCE, ACC, ME, ATPCL/CCE, FAS, G6PDH, - id, flavonoids, lignans, saponins, phytosterols,id, flavonoids,saponins, lignans, FA re-esterification FA - GTadSREBP-1/2 and DGAT FA FFA FFA 1 ↓ Oligofructose Lipogenesis noTG into Down-regulation - Peroxysome β proliferation -oxidation? ↑ ↑ PPAR ApoA-1-containing HDL FA Regulation ↑ α Efflux transport Efflux ↑ Transfer to Transfer usd cell outside Cholesterol ABCA-1 efflux eeexpression Gene sensitivity ↓ ↑ Niacin Niacin Citrate Insulin apoB-lipoproteins + NF- Hepatocyte Bloodstream ↓ Bloodstream rmHDL to from transfer of CE CE of transfer ↓ κ CETP ↓ B lipogenesis acetyl-CoA + ↓ HCA uptake/endocytose rate of synthase - activity CCE ↓ ↓ HDL HDL ATP β chain

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A) Figure 3A-C

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Niacin Pantothenic acid Critical ReviewsinFoodScienceandNutrition Folic acid Carnitine Hydroxycitric acid Organosulfur compounds PUFA Fiber Phytic acid Phytic Oligofructose Phenolic acids Lignans Curcumin Saponins Page 160of267 160

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Myo

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Carnitine Organosulfur compounds Critical ReviewsinFoodScienceandNutrition UAMelatonin PUFA Fiber Phytic acid Oligofructose Phenolic acids Phenolic Flavonoids Lignans Curcumin Saponins

Phytosterols γ -oryzanol extract/mixture Polyphenol 161

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Myo

Comment citercedocument : -inositol For Peer Review Only Review Peer For Folates URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Carnitine Organosulfur compounds Critical ReviewsinFoodScienceandNutrition eaoi ie Phytic acid Fiber Melatonin Oligofructose Phenolic acids Flavonoids Lignans Curcumin Saponins

Phytosterols γ -oryzanol extract/mixture Polyphenol Page 162of267 162

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A) Figure 4A-E

Comment citercedocument : Myo Only Review Peer For -inositol URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

MUFA/PUFA Critical ReviewsinFoodScienceandNutrition Phytic acid Phytic Oligofructose lvnisLignans Flavonoids

163 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1

-inositol

Comment citercedocument : For Peer Review Only Review Peer For Organosulfur compounds URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

PUFA Critical ReviewsinFoodScienceandNutrition Phytic acid Oligofructose Lignans

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Myo Comment citercedocument : ioio UAPF htcai Lignans acid Phytic MUFA/PUFA -inositol Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Critical ReviewsinFoodScienceandNutrition

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ioio UAPyi cdFaood Lignans Flavonoids acid Phytic PUFA -inositol Comment citercedocument : For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Critical ReviewsinFoodScienceandNutrition

Page 166of267 166 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 167of267 E)

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

-70 -60 -50 -40 -30 -20 -10 10 0 535-590. DOI :10.1080/10408398.2010.549596 Myo

Comment citercedocument : -inositol For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Phytic acid Phytic Critical ReviewsinFoodScienceandNutrition Oligofructose Lignans

167 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Supplemental Table 1 1 Table Supplemental Supplemental Tables 1-Btie Betaine Betaine Betaine Betaine (crystalline Betaine Betaine anhydrous Anhydrous betaine Anhydrous betaine Betaine aspartate Betaine Betaine Betaine Betaine Betaine A1 - Betaine lipotropes -Main A compounds Lipotropic Choline chloride Choline chloride Choline Choline Choline A2 - Choline white granule)white solution hydrochloride hydrochloride hydrochloride

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

Mice fed high-fat (20% energy) diet Isolated hepatocytesfrom ethanol-fedrats for 4 Ethanol-treated guinea pigs for thelast 10 days Intragastric alcohol-fed mice In vivo Rats fedRats balanced diet ( Rats fed low-protein (14.7%)/low-fat ( (14.7%)/low-fat low-protein fed Rats Humans with NASH Rats fed ethanol diet Rats fed semiliquid ethanol diet Rats fed high-fat (40%) diet Rats fed high-sucrose (45.8%) and betaine- Rats fed high-fat (30%) and methionine- Rats fed fat-free and methionine-restricted diet Rats fed high-fat (20%) and high-sucrose Rats fed high-fat (20%) and high-sucrose Rats fed high-fat (40%) diet Rats fed high-fat (40%) diet Patients (n = 10) with decompensated portal Rats fed high-fat (20%) and high-sucrose Rats fed high-fat (20%) and high-sucrose diet (40%) fedhigh-fat Rats Rats fed high-fat (40%) diet Rats fed high-fat (40%) diet (BIBRA diet) (BIBRA weeks protein; BrandeisUniversity diet) same diet without betaine for 28 days lysine and threonine deficient diet supplemented with histidine, diet restricted In vivo (48.9%) dietadded with 0.3%cystine (48.9%) diet (48.9%) dietadded with 0.3%cystine (48.9%) diet or 535-590. DOI :10.1080/10408398.2010.549596 in vitro in , ex vivo ± betaine for 28 days then the models Comment citercedocument : and ≈

8% fat and 23.5%

in vitroin

studies reporting effects on hepatic lipid metabolism following following metabolism lipid hepatic effects on reporting studies ≈

3%) diet 1.5%diet of 1 mM 0.5%diet of 0.5%diet of 250 mg free From 100 to 200 100 mg 120 mg daily dose Supplemented 70 mg 70 mg 75 mg 2% ofdiet 0.5 or 1.5% of 0.5, 0.75, 1.0 or 1, 2or 5% 20 g solution From to 0.08 0.32% free 0.16% free From 50 to 200 From 10 to 117 to117 From 10 0.5thrice g From to75 15 From to40 20 betaine /kg bw bw /kg betaine diet 5.0%diet of daily 0.64% betaine betaine mg mg mg mg mg mg mg

8 months 4 hrs 30 days 28 days 28 days 28 days 1 year 21 days 14 days 30 days 21 days 21 days 21 days 8 days 8 days 21 days 21 days exposition exposition lipotrope Duration of 18 months 8 days 8 days 21 days 21 days 21 days 21 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↓

Hepatic effect(s) Liver histology Improvement in degree of steatosis, necroinflammatory grade and

Case 2

↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↓ ↓ ↓

TG content (resp. -11%, NS, -20%, NS, -13%, NS, and -39%) NS,and NS,-13%, -11%, NS, -20%, (resp. content TG TLpercentage ( fat percentage (-60%) (-60%) fatpercentage (-37%) fatpercentage FA percentage (-66%) FA percentage (-68%) FA percentage (from -40 to -69%) FA percentage (-64%) histologic liver injury (0.7 content TG ( TGlevel (-43%) cholesterol (-18 and -47%) and TG(-29 and -67%) levels, TGcontent (-51%), TGcontent (-62%), C TLpercentage (from 0to-79%): sharp decrease begins at a level TLpercentage ( (-54%) fatpercentage (-51%) fatpercentage FA percentage (-82%) FA percentage (-59%) stage of fibrosis,stage of activity (+92%) of 0.16% betaine HCl supplementation (-42%) SREBP-1 relative mRNA expression ( mRNA expression relative SREBP-1 concentrations and betaine treatment (resp. +45, +90 and +125%), then -62, -59 and -71%) microvacuolisation upon the last 28 datys without betaine (resp. 14 -trioleine catabolism (-44% trioleine retention rate) : complete disappearance of ascites and smaller liver ≈

: -20%) ↑

≈ Critical ReviewsinFoodScienceandNutrition lipid droplet and microvacuolisation upon ≈ -64%) -64%) ↓ ALT and AST concentrations (-69%) ↑ ↑ ↑ BHMT activity (+46%)

SAM concentrations (+722%)and SAM(+305%) and betaine (+354%) b

deficiency orsupplementation of betaine, choline,methionine, vs 3.5, p < 0.01) ≈

-50 and ≈ - 70%) ↓

↑

BHMT ↓

(Russakoff and Blumberg, 1944) 1944) Blumberg, and (Russakoff (Griffithand Mulford, 1941) (Best and Huntsman, 1935) 1934) (Best, (Best and Huntsman, 1932) (Borgschulte et al., 2008) (Kharbanda et al., 2005) etal., 2004) (Balkan (Ji and Kaplowitz, 2003) 2003) al., et (Hayes (Abdelmalek etal., 2001) (Barak et al.,1997) (Barak et al.,1996) (PerraultDormard, and 1966) etal., 1965) (Young (Best et al., 1950) (Griffithand Mulford, 1941) 1934) (Best, (Best and Huntsman, 1932) References

myo -inositol, magnesium, niacin , pantothenic acid and folate 1 s Commentaire [A.F. Page 168of267 1 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 169of267 Choline chloride Choline Choline chloride Choline Choline chloride Choline Cl Choline chloride Choline Choline chloride Choline chloride Choline chloride (dessicated)

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Rats fedRats choline-deficient diet Rats fed high-peanut meal (30%) andcasein fedRats high-sucrose (69%) and casein diet at Rats fed hypolipotropic and high-sucrose (62%) Rats fed high-fat (40%) and 0.1% niacin diet Rats fed choline-deficient diet for 10 days then choline- and basal fed hypolipotropic Rats Rats fed high-sucrose (45.8%) and choline- Mice fed high-fat (28%), low-protein and Rats fed high-fat (corn oil: 39.9%) and casein Rats fed high-fat (butter fat: 39.9%) and casein Rats fed high-fat (corn oil: 39.9%) and soy Rats fed high-fat (butter fat: 39.9%) and soy Rats fed high-fat (lard: 39.9%) and casein Rats fed high-fat (lard: 39.9%) and soy protein fedRats high-sucrose (69%) and casein Rats fed high-sucrose (69%) and soy protein Rats fed 20% protein choline-deficient diet Rats fed steatogen diet (76% bolted white corn Rats fed high-fat (30%) and methionine- Rats fed fat-free and methionine-restricted diet diet at 21°C 21°C diet at 21°C injectedsubcutaneously with cholinechloride deficient diet lysine and threonine deficient diet supplemented with histidine, hypolipotropic diet liver (adequate methionine) diet liver (adequate methionine) diet protein (low methionine) diet protein (low methionine) diet (adequate methionine) diet (low methionine) diet liver (adequate methionine) diet (low methionine) diet meal and3%casein) diet restricted high carbohydrate and lowfatdiet and carbohydrate high the liver) and treated with a high protein, associated with extensivefatty infiltration of cirrhosis of the liver (cirrhosis is frequently 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : → → → less drastic fatty less drastic fatty fatty moderate

0.6%diet of 0.025, 0.05, 0.1 0.05, 0.10.2% or 0.2% free 1.00%diet of 0.75or 1.00% of 0.30or 0.50% of 8, 20mg40 or 0.6%diet of From 0.01 to 0.002% of diet 0.3%diet of 0.3%diet of 0.3%diet of 0.3%diet of 0.3%diet of 0.3%diet of 0.3%diet of 0.3%diet of 0.26%diet of 0.25%diet of 0.32% free 0.16% free 6 g 1.5thrice g 4-6 g 6 g then 4.5 g 4.5 g 0.5times g4 or 0.2% of diet of diet choline diet diet injected 0.64%diet of choline choline

45 days 3 weeks ≥ ≥ ≈ ≈ 15-18 hours 21 days 21 days 14 days 14 days 14 days 1 day - 21 days 4 weeks 14 days 14 days 14 days 14 days 14 days 14 days 14 days 14 days 3 weeks 65 days 21 days 21 days 6months 9months

c then 6 monthsthen 6 10 days 4 weeks

For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Case 5

Case 8 [Casesand 1,4 6

↓ ↓ ↑ Case 7 Case 10 Case 9

Case 3 ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓

TG content (-60 (-60 content TG lipid percentage (-66 lipid percentage (respectively -36, -71, -73 or -73%) lipid percentage (respectively -70, -74 or -75%) and PL(-14%) neutral fat (-22%) percentages, fat(-19%), total fat percentage for 1% choline only (-36%) compared to 0.50% choline to compared 0.15% -49%) and -39 (resp. fatpercentage total esterified FAcontent (-89%) TLpercentage (from -10 to -84%; -82% at 0.16%): sharp (histological droplets fat of size and quantity importantly lipid percentage (-67%) lipid percentage (-70%) lipid percentage (-66%) lipid percentage (-71%) lipid percentage (-75%) lipid percentage (-83%) lipid percentage (-51%) lipid percentage (-80%) lipid percentage (-68%) (-78%) fatpercentage TLpercentage ( TLpercentage ( plasma PLFAlevel for 40 mg only (+30%) tests, feeling of well-being and good health choline + 0.1% niacin (-60%) decrease begins at a level of 0.06% choline Cl supplementation observations) PL in fat of 2.2% compared to 0.25% choline +0.1% niacin PL infat choline of 2.2%compared to0.25% : continued improvement ( : steadily improvement ( : improvements ( : marked improvement ( : complete disappearance of ascites, improved liver function : considerable improvements ( : deathor no improvement] Critical ReviewsinFoodScienceandNutrition ≈ ≈ ± -73%) -75%), 5%, n = 4 experiments), ± e.g. 12%, n = 4 experiments)12%,= 4 n ↓ less abdominal paracenteses required) CE( e.g. e.g. e.g. ≈ e.g. -69%) ↓ ascites disappeared) ascites) ascites) ↓ e.g. ascites and

↓ ascites) ↑

PL(+21%, n = 1) ↓ icterus index) ↓

(Lombardi etal., 1968) (Chahland Kratzing, 1966b) (Chahland Kratzing, 1966a) (Rikans et al., 1965) Mookerjea, 1965) and (Haines etal., 1965) (Young 1964) (Ball, (Olson et al., 1958) (Fritz andDupont, 1957) (Shils and Stewart, 1954) (Best et al., 1950) 2 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 dl Methionine l d dl Choline Choline chloride Choline chloride Choline Choline Choline Choline chloride Choline dihydrogen Choline chloride Choline Choline chloride dl Methionine A3 - Methionine -Methionine -Methionine -Methionine -Methionine -Methionine citrate

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Rats fed high-fat (20%) and high-sucrose Mice fed high-fat (40%), high-glucose (40%) Rats fed high-fat (40%) diet Rats fed high-fat (40%) diet Rats fed high-fat (40%) diet and (46%) high-glucose (40%), high-fat fed Rats Rats fed high-fat (40%) diet 129S6 mice (susceptible to IR and NAFLD) fed Totalparenteral nutrition patients with hepatic Long-term total parenteral nutrition patients with fedRats choline-defient then refedwith choline- fedRats choline-deficient diet Healthy humans fed choline-deficient diet Rats fed low-choline, 38% sucrose and 20% Rats fed low-choline, 38% sucrose and 20% Rats fed high-glucose (60%) diet not fedRats choline-deficient diet Rats fed hypolipotropic and high-sucrose (60%) fedRats choline-deficient diet

supplemented diet hightallow beef orhigh safflower blend diet beef tallow or safflower oil diet supplementedcholine with diet and low-methionine (5% arachin) 5% gliadindiet high-fat (40%) diet steatosis low plasma freecholine and hepatic steatosis 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

0.58%diet of 0.5%diet of No 2 g in TPN to4gin TPN 1 0.48%diet of 0.69%diet of 500 mg 0.2%diet of 0.2%diet of 0.01, 0.02or 0.5%diet of 0.4%diet of 0.5%diet of From 75 to 300 to300 From 75 0.64% ofdiet 0.06, 0.15or 0.06, 0.15, 0.25 0.06, 0.125, 0.25%diet of or 0.5% of diet diet 1.0 or 2.0% of 0.15, 0.25, 0.5, solution solution choline 0.06% free

8 days 15-17 days 21 days 21 days 21 days 17-18 days 18-19 days 4 months 6 weeks 16 weeks weeks1, 2or 4 21 days 21 days 21 days 7 days > 3 days 2 days 2 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↑ ↓

Mice strainmimic that choline-deficient diet:microbiota-related Hepatic steatosis resoved completely (baseline liver-spleen HU No significant effect onproteine kinase C activity ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↓ ↓ ↓ ↓ ↓ ↓ ↓

TG(-60%) and PE (-28%) content, fat percentage (resp. -23% [n = 2 experiments], -16, -26, and-

fat percentage (-64%) (-64%) fatpercentage TLpercentage (-49 -20%) and -21 [n = -30% experiments], (resp. 2 fatpercentage = -10, -24 [n -24, [n = -26% experiments], (resp. 2 fatpercentage (-78%) percentage TL (-87%) TL andcompletely resolved hepatic steatosis (significant FFA(-87%), phospholipase A (-34%) plasma and PC(-32%), serum activity ALT PLcontent (-21%/beef tallow or -16%/safflower oil) cholesterol content (-56%/beef tallow or -52%/safflower oil) lipid content (-71%/beef tallow or -53%/safflower oil) lipid content (-69%/beef tallow or -61%/safflower oil) TGcontent (respectively -27, -29 or -73%) TG(-84%), PE (-15%), CDP-E (-64%) and ethanolamine (-76%) floating lipid fraction(-71%), TG content in plasma VLDL (+85%) % cholesterol of total lipid (+47%/beef tallow or no %PL of total lipid (+143%/beef tallow or +72%/safflower oil) phospholipase(resp. C incorporation of ethanolamine in of ethanolamine incorporation density byan average 20 patients patients (+18%); signs of incipient liver dysfunction in choline-deficient 2], -40 and content, ↑ 58%) reduced choline bioavailability between serum TG concentration and liver HU and serum TG concentrations, significant negative correlation TG/HDL/LDL concentrations and between plasmafree choline choline concentration andtotal serum cholesterol/total serum significant positive correlation between plasma PL-bound change/safflower oil) higher: 1.5 liver and liver-spleen HU, patients, significant correlation between plasma free choline and placebo) with more seriousadverse events in choline-deficient

liver TG TG liver ± 7 [n = 3], -28 [n = 2] and -20%) ± 10.8 in choline-supplemented group group choline-supplemented in 10.8 ↑ ↑

PC content (+27%) content PC DRG (+915%) Critical ReviewsinFoodScienceandNutrition 2 (resp. ± 10%, n = 6 experiments) n=6experiments) 10%, ≈ ≈ -20, -35, -35, ± 16.5 HU) HU) 16.5 ↓ serum alkaline phosphatase; ≈ ↓ ≈ -31 and FAS specific activity (-21%) -43 and → to CDP-E/choline-deficientrats impaired VLDL assembly and ↑

PC content (+21%), lower (+21%), lower PC content ≈ ≈ -48%)activities -69%) and

vs -11.6 ↑

serum TC ↑

liver ± 7.9 in (Griffithand Mulford, 1941) 1941) Eckstein, and (Singal 1940) Ridout, and (Best (Tucker and Eckstein, 1938) (Tucker and Eckstein, 1937) (Dumas et al., 2006) (Buchman et al., 2001) (Buchman et al., 1995) (Da Costa etal., 1995) etal.,1990) (Singh (Zeisel etal., 1991) Williams, 1982) and (Carroll (Andersenand Holub, 1980b) 1979) Haines, and (Tokmakjian 1973) (Rosenfeld, (Haines and Rose, 1970) 3 Page 170of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 171of267 Methionine Inositol Inositol Myo Myoinositol Inositol Inositol Inositol Inositol Inositol Inositol Inositol A4 - L L L DL DL DL Methionine Methionine -Methionine -Methionine -Methionine -Methionine -Methionine -Methionine (free) (free) -inositol -inositol Myo

-Inositol -Inositol Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Rats fed high-fat (51%) diet and administered 3 Rats fed high-fat (51%) diet Rats fed high-cholesterol (1%) diet rats injectedYoung large dose of Rats fed high-sucrose (84%) diet Rats fed high-fat (51%) diet Humans with hepatic dysfunctions Rats fed high-fat (30%) and methionine- diet methionine-restricted and 12%-fat fed Rats Rats fed fat-free and methionine-restricted diet Rats fed fat-free diet, thiamine, riboflavin, Rats fed high-fat and cholesterol diet Depancreatized dogs Rats fed high-sucrose (78%) diet Rats injected daily biotin subcutaneously in

Mice fed methionine-deficient diet fedRatsa 9%casein-based diet Rats fed low-protein diet (5% casein) fedRats low-protein (5% casein)diet Rats fed high-sucrose (69%), casein and Rats fed high-sucrose (45.8%) and methionine- Rats fed high-sucrose (45.8%) and methionine- Rats fed steatogen diet (76% bolted white corn Rats fed choline-deficient, high-sucrose and casein(5%) low and (35%) high-fat fed Rats Rats fed high-fat (40%) and 35% gelatin diet restricted diet restricted cholesterol pyridoxine and pantothenic acid and/or pyridoxine and pantothenic acid in the diet conjunction with thiamine, riboflavin, deficient diet supplemented with 0.2% cystine deficient diet 20% casein diet diet (48.9%) diet choline-deficient diet at 21°C meal and 3% casein) 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : myo

-inositol -inositol

0.32%diet of 0.32%diet of 0.16%diet of - - 40 and 20 10, 5, - week) 2.0 mg (3 1.02%diet of 0.774% of diet No 0.68 % of diet 0.34 % of diet From 0.08 to From 0.08 to 1.0%diet of 0.5%diet of 3 x 2 mgper3 x2 mgper3 x4 mgper3 x2 0.5% ofdiet 40 mg/rat 30 mg 1 gdissolvedin 4.0 mg (3 0.6 and 1.0% and of 0.6 2.5% ofdiet 0.5% ofdiet 0.02, 0.2and week week week) mg mg 100 mL mg mg 0.48%diet of 0.48%diet of diet 0.5%diet of x x

71 days 33 days 33 days 128 or weeks 1 hour 7 days 64 days 64 days - 21 days 21 days 21 days - - 21 days - 1-15 days 3 or 7 days 3 weeks 6 weeks 21 days 21 days 21 days 65 days 65 days 27-37 days 14 days 21 days 21 days

For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↓ ↓ ↓ ↓ ↓ ↓ Prevents acutely “biotin” type offatty liver development and

No effect on TL percentage No effect on TL percentage No significant change Moderate lipotropic action Moderate lipotropic action Small lipotropic activity but no somarked than a preparation of After 3days ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↑ ↑ ↓ ↓ ↓ ↓ ↓ ↓ ↓ After 7days

lipid percentage (mean decrease of -65%) -33%) and (resp.-29 fatpercentage (-63%) percentage TL crude FA content (-69%) cholesterolemia

fat percentage (-24%) (-24%) fatpercentage NS) (-17%, fatpercentage content TC (respectively -37and-56%) PI/PC ratio in liver (+45%) and mitochondrial (+8%) microsomes TL(-67%) and total cholesterol (-35%) contents, TL ( ) -22% and -34 -28, -30, (respectively fatpercentage cholesterol content (respectively lipid percentage (-68%) lipid percentage (-67%) TLpercentage (from 0to-73%): sharp decrease begins at a level TLpercentage (from 0to-65%): sharp decrease begins at a level fat percentage (mean decrease of-64%) fat percentage (mean decrease of-59%) fat content (-24%) (-24%) fat content (-17%) fat content liver injury but lipid (mainly TG and FFA) accumulation was total-coenzyme (+17%) A and acyl-coenzyme (+6%) A activities cholesterol accumulation PL (+20% for 200 mg/kg and no change for other doses) after 1 hour injection lipocaic of 0.16% methionine supplementation (-39%) of 0.24% methionine supplementation (-51%) less than with choline- and choline+methionine-deficient diets cholesterol acetate incorporation inrespectively liver andadipose ≈ -34%) ( and CE : :

↑ ↓

incorporation ofsodium acetate into lipids (-26%) incorporation ofsodium Critical ReviewsinFoodScienceandNutrition ≈ -45%) percentages ≈ -17, acetate into lipids (+118%) ≈ -12 and ≈ -12%, NS), ↓ and and ↑ 1- 14 C- ↑

(Laird andDrill, 1971) (Chakrabartiand Banerjee, 1969) 1969) Kotaki, and (Yagi (Kotaki et al., 1968) (Drill, 1954) (Gargini, 1951) (Best et al., 1950) (Mchenry and Patterson, 1944) 1942) (Owens, 1942) (Engel, (Gavin and Mchenry, 1941) (Caballero etal., 2008) (Yokota etal., 1974) (Osumi et al.,1969) (Chahland Kratzing, 1966b) etal., 1965) (Young (Shils and Stewart, 1954) (Harper et al., 1954) (Eckstein, 1952) (Beveridgeal., et 1945)

4 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Myo Myo Myo Myo Myo -inositol -inositol -inositol -inositol -inositol -inositol

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

Young rats fed high-glucose (60%) and and (60%) ratsfed high-glucose Young Lactating rat dams fed Lactating rat dams fed Rats fed a high-sucrose (65.5%) and Rats fed a high-sucrose (65.5%) and Rats fed a high-sucrose (65.5%) and Rats fed high-glucose (60%) and Rats fed high-glucose (60%) diet not (60%) and ratsfedhigh-glucose Old Rats fed a high-sucrose (65.5%), 10%-fat Rats fed a high-sucrose (65.5%), 10%-fat Rats fed a high-sucrose (65.5%), 10%-fat Rats fed a high-sucrose (65.5%), 10%-fat Rats fed a high-sucrose (65.5%), 10%-fat phthalylsulfathiozole (62.1%) diet +0.5% high-sucrose and inositol-deficient diet inositol-deficient diet inositol-deficient diet μ (coconut oil) and and oil) (coconut deficient diet (hydrogenated soybean oil)and deficient diet (natural cottonseed oil) and inositol-deficient diet (hydrogenated cottonseed oil) and inositol-deficient diet (hydrogenated cottonseed oil) and x 2 mg choline, 1 g folic acid perweek phthalylsulfathiozole (62.1%) diet+0.5% high-sucrose and and choline-deficient diet supplemented with inositol-deficient diet inositol-deficient diet 535-590. DOI :10.1080/10408398.2010.549596

myo μ Comment citercedocument : g cobalamin (B12) and 2.5 myo myo myo -inositol-deficient diet -inositol -inositol-deficient -inositol-deficient myo myo -inositol- myo

myo myo myo myo myo myo -inositol- -inositol- myo ------

0.5% ofdiet No No No 0.5% ofdiet 0.5% ofdiet 0.5% ofdiet 0.5% ofdiet 0.5% ofdiet 0.5 % myo- 0.5 % of diet ≈ ≈ 0.075 and 0.5% 0.5% ofdiet 0.5% ofdiet 0.01, 0.05and 0.072 %myo- 0.072 %ofdiet 0.072 week inositol % + inositol % + choline 0.015% of diet 0.5%diet of ≈

7 days 7 days 7 days 7 days 7 days 14 days 7-14 days lactation 14 days hr+ 241 week hr+ 241 week 1 week 1 week 1 week 2 weeks 1 week lactation 21 days 2 weeks For Peer Review Only Review vein tail in injection palmitate Peer after fat pads epididymal of For incubation palmitate after URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↓ ↓ ↓ ↓ ↓

↓ ↓ ↓ ↓ ↑ ↑ ↓ ↓ ↓ ↓

Natural

TGlevel (-92%) TGlevel (-74%) TGlevel (-77%) TGlevel (-71%) level TG (respectively -48 and -76%) TGlevel (-6%, NS)

TGlevel (-70%, n = 2 experiments, NS) TL(respectively -75, -75 and -82%), TG (respectively -75, -83 ( TG TG(-36%) and cholesterol (-12%, NS) contents (-79%) TG and cholesterol (-17%) contents (-81%), TG cholesterol (-28%) andnon-esterified fatty acid (no PL (-13%),and (-61%), FA(-16%) cholesterol TG non-esterified 2.7 times the rate of[1- 2.5 times the level of [1- L +46%) concentrations, no change in plasma CEconcentration +210%), free cholesterol ( concentration, droplets in change in free cholesterol content; numerous large intracellular and -96%) and CE (respectively -70, -91 and -96%) contents, significant change) contents, (no significant change) contents lipids FA from liver the lipids from labelled epididymal fat pads from adipose tissues to the liver change for serum concentration LDL IDL (+168%) and HDL (+107%) concentrations, no significant for LPC, Sph,forLPC, percentages; PCand PS phospholipids: +4.0% PI, -4.3% PEand no significant change (respectively +28, +29 and +91%) contents; distribution of PL and +29%) and +7 +13, (respectively cholesterol cholesterol contents -glycerol -glycerol 3-phosphate (direct pr ≈ -96%)and( CE vs → hydrogenated cottonseed oil: no effect onTG and

↓ disappearance (by transport and degradation) rate of myo ↑ Critical ReviewsinFoodScienceandNutrition -inositol defcientdams; plasma TG( ≈ -95%) contents, 14 14 C]palmitate incorporation into liver C]palmitate incorporation into liver liver into incorporation C]palmitate ≈ +31%) and lipoprotein lipid ( ≈ ↑ +203%), PL( PLcontent (+14%) ecursor of TG)content (-62%) ↑ ↑ ↓ serum (+159%), VLDL PL( plasma FFA( →

↑ ≈

+38%), PI ( FA mobilization ≈ +93%) content, no ≈ -21%) ≈ ≈

↑

(Andersenand Holub, 1980b) (Andersenand Holub, 1980a) Wells,1977) and (Burton (Hayashi et al., 1974b) (Hayashi et al.,1974a) 5 Page 172of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 173of267 Myo Myo Myo Myo Myo Inositol Myo Myo -inositol -inositol -inositol -inositol -inositol -inositol -inositol -inositol

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Rat damfed

Rat damfed Rats fed Rats fed high-starch/high-sucrose (50.2%) and Rats fed diet with orotic acid (1.5%) Rats fed high-sucrose (65%) diet Rats fed high-starch/high-sucrose (65%) and Rats fed high-starch/high-sucrose (65%) and fedAINformulawith dietsupplemented Rats Mice (germ-free protein (8%) diet myo myo myo 0.1% DDT deficient and high-sucrose (60%) diet diet fructose (40%) and normal-protein (20%) -inositol-deficient diet -inositol-deficient diet -inositol-deficient diet myo 535-590. DOI :10.1080/10408398.2010.549596 myo myo -inositol-deficient and balanced diet -inositol-deficient and low- -inositol-deficient, high- vs conventional) fed inositol- fed conventional) Comment citercedocument :

0.2% +0.07% 0.2% ofdiet 1.03% ofdiet 0.515% of diet 0.1% ofdiet 0.1% ofdiet 0.2% ofdiet No 0.48% ofdiet 0.48% ofdiet 0.5% ofdiet DDT DDT choline 0.056%

14-15 days 14-15 days 8 days 13 days 12-13 days 16-17 days 13-14 days 23 days 14 days 14 days hours 12 3 days 14 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

Degree of fatty liver more evident in conventional mice Sucrose Sucrose ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↑ Starch Starch Starch Sucrose Starch Sucrose ↑ ↓ ↑ ↓ ↓ ↓

MEactivity/ g protein ( neutral lipid content (-78%), no change for PLcontent neutral lipid content (-67%), no change for PLcontent rate of FAS synthesis ( TGlevel ( plasma (+29%, TG NS), FFA (+38%) and total cholesterol

PL content (+8%) (+8%) content PL plasma TG(+42%), FFA (+4%, NS) and total cholesterol (+6%, ACC activity/g protein ( G6PDH activity/g protein ( FAS ( TL (+5%, NS), TG (+14%, NS), cholesterol (+10%, NS) (+14%,cholesterol PL and NS), TG TL (+5%, NS), TL (-34%), TG (-80%), cholesterol (-13%) and PL(-8%, NS) TL (-38%), cholesterol (-34%) and TG (-66%) contents contents; cholesterol, PL andFFA levels; cholesterol and PLcontents; noeffect onplasma TG, contents; cholesterol and PL levels; levels; PL and cholesterol levels; PL and cholesterol NS) levels, cholesterol, PL andFFA levels; cholesterol and PLcontents; noeffect onplasma TG, conventional mice) NS) levels in conventional mice 34%) activities NS) and FAS (-30%, NS) activities (/mg protein) (+15%, NS) levels in germ-free mice activity/mg protein specific activity activity levels; 4%, NS) levels, no change in plasma TG,cholesterol and PL NS) levels, conventional mice) NS) activity/mg protein NS), CC (-29%, FAS NS), 42%, NS) activity/mg protein NS), (-38%, FAS NS), 19%, ME (-13%, NS) activities NS) and FAS (-4%, NS) activities (/mg protein) ( conventional mice) concentrations; ≈ 0) concentrations; : : : :

↓ ↓ ≈ ↓ ↓ : : : : TL (-34%), TG (-44%), cholesterol (-23%, NS) and PL(- and NS) (-23%, (-44%), TG TL(-34%), cholesterol (-5%, cholesterol TG TL(-19%, and NS), (-41%, NS)

TL (-3%, NS) and TG (-20%, NS) contents; no effect on effect TG no NS)and (-20%, on NS) TL(-3%, contents; NS),cholesterol TG(-22%, TL(-2%, (-2%, NS),and NS) -31%: maximumreached) and ACC/CBX ( ↓ ↓ ↓ ↓ ↓ TL (-10%, NS), TG (-29%, NS) and cholesterol (-2%, TL (-50%) and TG (-81%) contents; no effect on total lipid (-33%) (-40%S),(-40%), cholesterol and lipid TG total (-74%) TG and (-47%), (-20%), TL cholesterol ME (-23%, NS), G6PDH (-41%) and FAS (-30%, NS) FAS and G6PDH (-41%) ME(-23%, NS), ≈ ↑ ↑

-70%) -70%) PL content (+6%, NS) ; PL content (+9%, NS); ↑ ↑ PL level (+19%), nochange in plasma TG, PL level (+9%, NS), no changein plasma TG, Critical ReviewsinFoodScienceandNutrition ↓

G6PDH (-36%) and ME (-23%) (-36%) ME activities and G6PDH ↑

≈ G6PD (+58%, NS) and ME(+10%, NS) ≈

-40%: maximumreached)

≈ -50% in germ-free in germ-free -50%

-32% in germ-free ↓ ↓ ≈

ME (-19%, NS), ME(-19%, G6PDH (-24%, and -45% in -45% germ-free CCE (-9%, NS) and CBX(-9%, NS)and (-9%, CCE ↑ ↓ ↓ E (-31%, NS) and CBX (-20%, (-20%, (-31%, NS) and CBX E ME (7%, NS), G6PDH (+5%, G6PDH (-39%, NS), ME (- G6PDH (-27%, NS), ME (-

↓

↓ G6PDH (-26%, NS) and and NS) (-26%, G6PDH G6PDH (-43%) and and ME (- (-43%) G6PDH vs vs ≈

no change in vs -27% in ≈ ≈

-32% in

-31%) -31%) (Okazaki and Katayama, 2003) Katayama,(Onomi 1997) and (Katayama, 1997b) (Katayama, 1994) (Katayama, 1993) (Ikeda et al., 1992) (Leclerc and Miller, 1989) (Beach and Flick, 1982) 6 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Myo 1-Mgeim Nicotinic acid Nicotinic acid Nicotinic acid Nicotinic acid Niacin (vitamin -Niacin B2 Magnesium Magnesium B1 - Magnesium -B Magnesium and Myo B3) vitamins B chiro -, -inositol -inositol D

- -inositol chiro Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

-and -and L -

Rat liverRat slices incubated in2-C Liver slices (of rabbits fed 6 months high- Liver slices (of rabbits fed 6 months standard Rats fed hypolipotropic and free-cholesterol diet Rabbits fed high-cholesterol (2%) diet Pigeon liver extract containing pantothenic acid Heart muscle mitochondria +0.5 mM carnitine Rats fed low protein, high fat (40%) and

Rats fed high-sucrose (50.3%) and Rats fed high-sucrose (50.3%) and Rats fed high-sucrose (50.2%) and or acetylcarnitine deficientdiet with 0.07% DDT C cholesterol diet, 2%)incubated inacetate-1- diet) incubated in acetate-1-C choline-free diet deficient diet +0.07% DDT deficient diet 14

535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : ± 0.5% L -cystine -cystine 14 14 sodium acetate

myo myo myo

-inositol- -inositol- -inositol-

1.13 mM ATP From 0.01 to 5

1 mg/mL 0.5% ofdiet 0.5% ofdiet 1, 2,or3 4% of 0.4% ofdiet 0.375 or 0.15% 0.2% 0.2% 1.13 mM ATP + 0.2% 0.2% 0.2% inositol solution diet of diet inositol inositol 0.67 mM Mg inositol inositol mM myo myo myo L D - - chiro chiro - - - - -

14 days 14 days 14 days 14 days 14 days 21 days 8 weeks 3 weeks 2.5 hours 1 hour 1 hour 30 min 3 hours 3 hours incubation incubation Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↑ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↑

↓ ↓ No cystine: With cystine: cystine: With ↓

TL(+23%), TG (+47%), cholesterol (+2%, NS) andPL (+8%, PL(-6%, levels, and NS) NS) (-2%, cholesterol incorporation level ofacetate into cholesterol (-33%) and FA (- TCcontent (-10%) and relative rate of cholesterol synthesis (- TCcontent (-28%) and relative rate of cholesterol synthesis (- TC percentage (resp. -12, -22, -42 and -46%) CoA content ( CoA synthesis and palmitate oxidation by TL (-45%), TG (-50%) and cholesterol (-18%) levels, levels, (-18%) and cholesterol TG TL(-45%), (-50%) TL(-3%, NS), TG(-17%, NS) an TL(-24%), TG (-62%) and cholesterol (-28%) levels, cholesterol content (-77%) PE, PS, LPC and Sph percentages/total PL and forPI/PC ratio, cholesterol and PLconcentrations; nosignificant change for PI, NS) activities (/mg protein); no significant effect on serumTG, ↑ PE, PS, LPC and Sph percentages/total PL, cholesterol and PLconcentrations serum TGconcentration (-30%), no significant effect on serum (+10%); (+10%); PC percentage (+1.5%) no change in PL level; PL levels; PL (-5%, NS) levels; nochange inplasma TG, cholesterol and percentages/total PLand for PI/PC ratio no significant change for PI, PE, PC, PS, LPC and Sph PS, LPC and Sph percentages/total PL 1.3%) and PI/PC ratio (-10%), no significant change for PC, PE, ME (-13%, NS) and levels; (+5%, NS) levels; no change in plasma TG, cholesterol and PL TG, cholesterol andPLlevels; (+17%, NS) and TG(+29%, NS) levels; no change in plasma ( NS) levels; no change in plasma TG, cholesterol and PL levels; 25%) change for PC, PE, PS, LPC and Sph percentages/total PL PI percentage/total PL(+0.9%) and PI/PC ratio (+10%), no activity/mg protein as compared with ATP alone 36%) 48%) acetylcarnitine ≈ PI percentage (+0.6%)

+1%, NS) activity/mg protein; ↓ ME(-42%) and G6PDH (-47%) activity/mg protein; ↓ ↓ ME (-29%) and G6PDH (-43%) activity/mg protein; ↓ TL (-9% for high high for (-9% TL ME (-37%), G6PDH (-44%) and FAS (-21%, NS) ↓ TL (-16% for for TL(-16% high ≈

+149%) and Critical ReviewsinFoodScienceandNutrition ↓ pantothenic acid content ↑ G6PDH (+6%, NS) activity/mg protein; ≈ ↓

ME (-12%, NS) and G6PDH (-28%, (-28%, NS)andG6PDH ME(-12%, 800% withcarnitine and by ↓ pantothenic acid content ( vs

↓ low niacin percentage) ME(-11%, NS) and vs d cholesterol (-3%, NS) levels, NS)levels, (-3%, cholesterol d ↓ ; nosignificant change for PC, PI percentage/total PL(- low niacin percentage) ↑ PI/PC ratio (+7%), ↑ total lipid lipid total ≈ ↑ ↑ ↑

950% with G6PDH G6PDH PL level PLlevel PL level ≈

-69%) ↑

↓ ↑ ↓

1960) (Perry, (Schade and Saltman, 1959) 1958) (Schön, (Merrilland Lemley-Stone, 1957) (Tyner et al.,1950) (Andrieux-Domontand LeVan,1970) (Fritz, 1959)

(Okazaki and Katayama, 2008) (Okazaki et al.,2006) 7 Page 174of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 175of267 Niacin Nicotinic acid Niacin Niacin Nicotinic acid Nicotinic acid Nicotinic acid Nicotinamide Nicotinic acid Nicotinic acid Nicotinic acid Nicotinic acid

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

HepG2 cells incubated 16 hours with hourswith 16 cellsincubated HepG2 HepG2 cells Hyperlipidemic male patients Healthy patients i.v. infused with [U- with infused i.v. patients Healthy Healthy patients Human hepatoblastoma (Hep G2) cells Partially purified ACC from chicken liver Hepatocytes isolated from rats fed cereal based 45 weeks-old laying hens fed diet without 41 weeks-old laying hens fed diet without 33 weeks-old laying hens fed diet without Rats intragastrically fed with single dose ethanol diet supplemented standardlaboratory fed Rats HepG2 cells incubated with HepG2 cells incubated with 0.4 mmol/L oleic HepG2 cells Rats fed standard laboratory diet and Hypercholesterolemic patients Nondiabetic patientsinjected with C μ incubated stock diet nicotinamide nicotinamide nicotinamide (6 g/kg, 50% solution) 8 hours before killing with 2% orotic acid containing HDL particles and niacin HDL (100 acid (1 acid (inihibits early apoB degradation) 13 13 incubatedwith [1- with 45% CCl intramuscularly injected with 0.25 mL of Ci/mL), C C 4 6 ]palmitate [2- ]glucose,

535-590. DOI :10.1080/10408398.2010.549596 μ Ci/mL) 4 3 diluted solution diluted

in vitro in

H-glycerol (5 μ g protein/mL) or 13 Comment citercedocument : C

1 ]glycerol and [1,2,3,4- and ]glycerol

14 C]oleoyl-CoA and and C]oleoyl-CoA μ 14 Ci/mL) or C-acetate (1 125 I-apoA-I-

14 -acetate 125 I-apoA-I 3 H-oleic

Increasing doses Incubated from Incubated from Incubated from Incubated from thrice1 g 10, 20,and 50 1 mM 0.005 and 0.01 0.002 and 0.005 0.002% of diet 250 mg/kg 25 mg/100 g 25 mg/100 g to2gthree 1 3 to 6 g Incubated from From 0.05 to 3.0 From to3.0 0.05 500 mg 0.25 to 3 mM 0.25 to 3 mM 0.25 to 3 mM 0.25 to 3 mM mL mkmoles/0.9 100 % of diet % of diet catheter) a y with (intragastrical b.w. injected b.w. injected times 0.25 to 3 mM mM mM mg 4times) toup(500 2g

4, 48 and 168 168 and 48 4, - 2 weeks 30 min 6 hours(acute 1 month hours 48 hours 48 hours 48 hours 48 hours 72 hours 48 5 weeks - 30 min - - - 10 days 10 days For Peer Review Only Review Peer For hours hours niacin + 4 n with preincubatio hours niacin + 2 n with preincubatio hours niacin + 2 n with preincubatio hours niacin + 16 n with preincubatio on) administrati on) administrati (chronic URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↓

↓ ↑ ↓ ↑ ↑ ↓ ↓ ↓

serum cholesterol suggesting marked reduction in hepatic plasma cholesterol (-32%) total DGAT activity (dose-dependent with a maximum3.0 mM at apoB degradation, but less than with niacin alone (+10% at 0.5 ApoB degradation (effect isdose-dependent: +3%at 0.25

accumulation ofapoA-I in the incubation medium (min. of+19 biliary output of cholesterol (+26%) and lecithin (phospholipids, acetyl-CoA concentration (+39%, mmol per incubation), acetyl- neutral fat(-43%), FA(-46%) fat (-45%) total and non-esterified TL(-45%), lipid phosphorus (-31%) and cholesterol (-31%) - and -68 -40, -11%),TG (resp. -8and -39, (resp. cholesterol incorporation of glycerol into plasmatic VLDL-TG ( ( plasma into production VLDL-TG incorporation of incorporation of incorporation of -100%) and -70 -45, activity -19, ACC (resp. fat percentage (resp. -8 and no change) -29%) and -16 (resp. fat percentage (-12%) fat percentage 125 plasma activity VLDL-TG mmol/L and+13% at 3 mmol/L) particle (up to 17%) uptake for 0.25mmol/L and max. of +47% for 1-2 mmol/L) +17%, NS); CoA beingproduced contents (inmg/100 mg N) contents; (resp. -34, -42%and no change) contents 100%), total lipid (resp. -34, -47 and -28%) and lipid phosphorus synthesis enrichment ( hour and mmol/L, +27% at0.5 mmol/L and +36% at 3 mmol/L) 20 to-40%) niacin: -35 to 50% inhibition, n =6 experiments) and fasting and just before acute administration of nicotinic acid) I-ApoA-I(up HDL to 16%) and ↑ ≈ TG content (+7%)

-40% -40% at 6hour); ≈

-21%at 1hour and Critical ReviewsinFoodScienceandNutrition 3 3 14 H-oleic acid into TG( H-glycerol into TG ( C-acetate into TG (

via β -oxidation ↓ plasmatic VLDL-TG palmitate

125 ≈ ≈

-40% at 6 hour)

I-apoA-I-containing HDL -33% after anovernight ≈ ≈

-20 to -40%) and FFA (

-20 to-40%) ≈

-10 to -15%) ≈

-45% at1 ≈

- (Ganji et al., 2004) (Wang et al.,2001) (Jin etal.,1999) (Jin etal.,1997) etal., (Grundy 1981) (Fomenko et al., 1979) (Yeh, 1979) (Hartfiel and Kirchner, 1973) (Baker et al.,1973) (Vaishwanar et al., 1972) (Parsons, 1961) (Nunn etal., 1961) 8 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Niacin Niacin Niacin Niacin Copper nicotinic acid Pantothenic acid Pantothenic acid Ca-pantothenate Ca-pantothenate Pantothenic acid Pantothenic acid Pantothenic acid Pantothenic acid Pantothenic acid Pantothenic acid B3 - Pantothenic acid complex (vitamin B5) B5) (vitamin

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

HepG2 cells first loaded24 h with cholesterol HepG2 cells APOE*3Leiden.CETP Rats fed high-carbohydrate (40% starch and HepG2 cells preincubated with or without niacin Hyperlipidemic male patients fedtherapeutic Guinea pigs fed pantothenic acid-deficient diet Cats fed calcium pantothenate-deficient (0, 1 Rats fed pantothenic acid-deficient diet Rats fed pantothenate-deficient diet Rats fed control diet Patients with various liver damages Rats fed high-sucrose (59%) and pantothenic by with liver Rats provoked steatosis Rats fed high-glucose (73%) and pantothenic Dogs fed high-sucrose (66%) and pantothenic and 3 mg/kg) diet 3mg/kg) and acid intramuscularly injected with pantothenic acid-deficient diet phosphorus (1 and 2.5 mg) acid-deficient diet andinjected i.p. with PAB acid-deficient diet 125 40% sucrose) and fat-free semi-syntehtic diet sn for 48 hours, then incubated 16 hours with lifestyle changes diet type diet used for treatment of CVD) fed aWestern- drugs manner to ahuman-like in respond atherosclerosis upon cholesterol feeding and I-labeled HDL (5-10 (5-10 HDL I-labeled -1,2-dioleoylglycerol -1,2-dioleoylglycerol 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

transgenic mice (develop μ g/mL)

No No 1, 3 and1, 3 mM 5 5mM and 1 0.25, 0.5 and 1 500 mg from 1 0.03, 0.1, 0.3 or 400 mg/kg Cu- No No No 0.002% of diet 5 mg 20 mg 0.001, 0.002 or 0.0025 or mM mM weeks from 9to 12 2g weeks and from 5to 8 1 g 4weeks, to 1%diet of tubing) (stomach complex nicotinate 0.005% of diet 0.005% of diet

48 hours hours 48 hours 48 48 + 16 hours 12 weeks 3 weeks 1, 2, 3 and 4 ≥ 25 days 2-9.5 months and2, 4 6 10 weeks 5 days 6 hours 16 days 30 days 4 months 4 weeks weeks weeks Only Review Peer For weeks (means) URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Plasma ApoB-48 in TG-rich lipoprotein Plasma ApoA-II Plasma ApoA-I Marked fatty fatty metamorphosis Marked Marked increase of fat droplets in the centrolobular and periportal Pantothenic acid deficiency exists inpatients with liver diseases ↑ ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↓ ↓ ↓ ↑ ↓ ↑ ↓ Plasma ApoB-100 in TG-rich lipoprotein

plasma concentration HDL-C (+35%) plasma (-14%) TC and TG(-49%) concentrations dose-dependently uptake of TG(-38%), TC (-21%), FC (-15%) and CE (-22%) contents TLcontent (resp. -47, -59, -70 and -82%) CoA content (+39%) CoA content at 1(+34%) and 2 (+18%) days; TLpercentage (respectively -51, -51 and -62%) TLpercentage (respectively -48 and -55%) acetylation percentagePABA of fat percentage (+202%); necropsy reveals fatty livers intracellular (resp. cholesterol ABCA1 (resp. surface expression of ATP synthase 8, -24 and -27%) and -27%)and -24 and 8, and production rate production rate (+21%); nosignificant effectupon fractional catabolic rate (resp. -17, -34 -35%) -34 and -17, (resp. 1 transcription levels and 1.95-fold) gene expression; no significant effect upon ApoA- and fractional catabolic rate CoA concentration (-51%);

areas at 4and 6 weeks, and in mid zonal areas at4weeks synthesis that involves CoA, and themetabolism of leading toimpairment ofliver functions, notably hypuric acid ascribed to and cholesterol formation with lipids evenly deposited (no zonal preference) process and fatty acid constitutive of acetyl-CoA a coenzyme necessary for acetylation 1 and 2.5 mg injected PABA; pantothenic acid being selectively (no change) 3-5 days (-8, -28 and -15%) niacin and and niacin ( niacin and -88% at 1% niacin) -88%at1% and niacin μ g/mg protein); ↑ ↑ fractional catabolic rate (+46%); nosignificant effectupon fractional catabolic rate (+48%); nosignificant effectupon ≈ ↓ ↓

-42% at-42% 1%niacin) DGAT-2 activity (-100%),not DGAT-1 activity

: food intake) intake) food : noeffect upon concentration, production rate and ≈ ↑ 1.35 and 1.45-fold) and PPAR Critical ReviewsinFoodScienceandNutrition concentration (+16%) and production rate (+16%) andproduction concentration ↓ CETPmRNA expression (-74% at 0.1% ↓

125 β I-labeled HDL uptake by HepG2 cell HepG2 by uptake HDL I-labeled -oxidation)

↑ and fine and coarse vacuolar vacuolar coarse and fine and 125 fatconcentration (+1112%, also I-activity by liver ( liver by I-activity ≈ -20, -36 and -32%)

(-27% and -45%for respectively β chain in cellHepG2 (resp.- : : ↓ concentration (+-28%) ↓ concentration(+-39%) ↓

CoA content from content CoA α (resp. (resp. ≈

-35% at 0.1% α -keto acid ≈ 1.35

(Siripurkpong and Na-Bangehang, 2009) etal., (Zhang 2008) (Lamon-Fava etal., 2008) (Van Der Hoorn et al., 2008) (Salama etal., 2007) (Hurley et al., 1965) (Gershoffand Gottlieb, 1964) (Wirtschafter Walsh,1962) and (Aiyar et al., 1959) (Causi et al., 1958) (Ueshima et al., 1956) (Turchetto etal., 1955) (Catolla Cavalcanti and Levis, 1950) 1948) Hegsted, and (Riggs (Schaefer etal., 1942) 9 Page 176of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 177of267 Pantothenic acid Pantothenic acid and Pantothenate Ca-pantothenate Ca-pantothenate Calcium pantothenate Pantothenate D Pantothenic acid Pantothenic acid -Pantothenic acid, pantethine deficiency precursors) derivatives (CoA hemi-calcium salt

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Rats i.p. injected with a single dose of CCl of dose asingle with injected i.p. Rats Weanling rats fed pantothenate-deficient diet Rats fed daily a vitamin tablet of 0.2 mg Duckling fed pantothenate-deficient diet fedRats low-protein (5% casein)diet for3 fedRats low-protein (5% casein)diet (18%) (6%) low- fatand or high- fed Rats Offspring of a transitory pantothenic acid Valproate Dogs fed commercial-type foodmash initially Mice with hypothalamic obesity induced by by induced obesity Mice with hypothalamic Rats fed pantothenic acid-deficient diet for 4 pantothenic acid days 4 for diet standard commercial then weeks deficiency duringgestation in guinea pigs each weeks) thenfor4 weeks, 50,and 100 mg/kg/day 200 (pantothenic acid antagonist, 30 mg/kg/day supplemented with calcium hopantenate containing 0.0025% pantothenic acid and acid derivatives during the last 10 days 6 weeks aurothioglucose injected i.p. (300 mg/kg) for acid during the fifth week weeks, then supplemented with pantothenic of 20 mL/kg) pantothenate-deficient diet acid/pantethine daily i.p. injection mL/kg) after 5 days pantothenic 535-590. DOI :10.1080/10408398.2010.549596 d -treated suckling mice (s.c. injection → supplementation with pantothenic Comment citercedocument :

4 (0.5 (0.5 100 of dose i.p. 500 of dose i.p. No No No 0.01% of 150 mg/kg 100 mg/kg 2 mmol/kg co- Same quantities 0.01% ofdiet 0.003% No injected hopantenate as calcium standard diet commercial acid) (pantotehnic mg/kg (pantethine) mg/kg

Deficiency 11, 22,or 33 75-116 days 21 days 4 days 3 weeks 6 weeks 90 min 8 weeks or12 24 hours ≈ 10 days 1 week For Peer Review Only Review 44 days Peer For 10 during the week and 6 th , 9 th th

, 7 th

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

At 24 hr: At 24 hr: Killed at7 days ↑ ↓ ↓ ↓ ↑ ↓ ↑ ↓ ↓ ↑ ↑ Phosphopantothenate At 12 hr: Antagonist produces hepatic steatosis by inducing pantothenic acid Pantothenic acid At 12 hr: Killed atbirth Pantethine Pantethine

stearic acid percentage ( total (resp. +50 and +25%), acid-soluble (resp. +44 and +29%) CoA (+46%), acetyl (+70%,CoA and NS) medium-chain acyl microsomal PCcontent (-40%); no significant effect on NS); (+17%, percentage lipid ( percentage acid arachidonic peroxisomal -18, -24, (resp. CoA free -27%), and -36 -28, -10, (resp. CoA total oleic acid percentage ( TG content ( TG content (-23%); in total PL content; content; PL total in (-15%, NS) and CE (-46%, NS) contents; no significant change were not observed in dogs supplemented with pantothenic acid CE (+10%, NS) CE (+8%,CE NS) contents CE (+10%, NS)contents NS, -57, -38 and -41%) concentrations; (resp. +2%, acyl-CoA long-chain and -38%) and -13, NS NS, NS, -42 and -52%), short-chain acyl-CoA (resp. -8, NS, +12, change in total PL content; CE (-48%, NS) and FFA (-5%, NS) contents; no significant diet ratio (resp. -6, -2, NS,-24 and -17%), synthetase activity after pantothenic acid deficiency complete restauration upon pantothenic acid supplementation fat percentage (-7%)/7 fat percentage commercial standard diet activities standard diet oleic acid percentage ( and microvesicular steatosis on light microscopy deficiency: 6/7 dogs had macroscopically fatty liver and all had contents NS) contents and long-chain acyl CoA (resp. +64 and +18%) contents CoA (+31%)CoA levels microsomal PE,PI,PS, Sph and lysolecithin contents 60%) concentration and the CoA biosynthetic precursor (resp. -24, -37, -43 and - percentage (-21%)/6 stearic acidpercentage ( ( ≈

-40%) relative to commercial standard diet ↑ arachidonic acid percentage ( ↓ ↓ ↓ ↓

: : TG (-8%, NS), total cholesterol (-13%) and CE (-20%) TG content(-34%), TG (-16%), total cholestero TG content(-37%), ↓ TG (-29%), total cholesterol (-24%), free cholesterol freecholesterol (-24%), total cholesterol TG(-29%),

: ≈ β

↑ -oxidation (-38%) and -79%) relative tolow-protein dietand : fat percentage (resp. fatpercentage : ↑ Critical ReviewsinFoodScienceandNutrition fat percentage (resp. (resp. fatpercentage : ↑ ↑ total-coA (+4%) and acyl-coA (+21%) (+21%) and (+4%) acyl-coA total-coA ↓ FFAcontent (+38%) TG (-38%), total cholesterol (-7%, NS), NS), (-7%, cholesterol TG(-38%), total th ≈

week deficiency -42%) relative tolow-protein diet and th ≈ ≈

week deficiency week -27%) relative tocommercial standard +25%) relative to low-protein diet and ≈

+10%) relative to commercial ↑ ≈ ↑ ↑ ↑ free cholesterol content (+11%) content freecholesterol

totalcholesterol (+12%, NS) and totalcholesterol (+13%, NS) and +75%) relative to low-protein diet total cholesterol (+5%, NS) and ≈ ↓ ≈ l (-6%, NS) and l (-6%,NS)and CE (-10%,

+35, +18 and +25%); long-chain acyl-CoA ≈ +9%) relative to

+33, +260+33, and +13%); ↓

total solubilized CoA ↓

CoASH/total CoA → suchdamages ↓

TG content →

↓

fat ↓ ↓

↑

(Naruta and Buko, 2001) (Youssef et al.,1994) Hauhart, and 1992) (Thurston (Noda et al.,1991) (Nagiel-Ostaszewski andLau-Cam, 1990) (Moiseenok et al., 1987) 1975) (Mahboob, (Saheb and Demers, 1972) (Osumi et al.,1969) (Williams et al., 1968) 10 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Folic acid Folic acid deficiency Folate Folic acid Folic acid Folic acid Folic acid B4 - Folates (vitamin B9)

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

Rats fed high-fat (51%) diet and injected 3 times Rats fed high-fat (51%) diet with + 2 mg/day Rats fed high-fat (51%) diet Rats fed high-sucrose (66%), 2% ribonucleic Rats fed high-sucrose (58%) and 10% glycine Rats fed high-sucrose (68%) diet Rats fed high-sucrose (56%), 10% glycine and Rats fed high-sucrose (58%) and 10% glycine Micropigs fed standard diet with excesscholine Micropigs fed standard diet Fetal liver fromfemale rats fedfolic acid- acidand vitamin (5 B12 diet 2% ribonucleic acid diet diet deficient (AIN)-76 formula diet diet formula (AIN)-76 deficient weekly with 1 cholineand +1 mg/kg b.w.) (675 methionine and b.w.) mg/kg (60.3 energy) choline in solutions requirement (14 energy) energy) 535-590. DOI :10.1080/10408398.2010.549596 ±

folates and and folates μ

g vitamin B12 and 2 mg μ Comment citercedocument : μ g vitamin B12/day

g/kg b.w.) μ g/100 g) diet ± ± folates in excess excess in folates ethanol (40% of ± ethanol (40% of

No No vitamin mix) deletion from No (complete

2.5 0.0005%diet of 0.0005%diet of 0.0005%diet of 0.0005%diet of 0.0005%diet of 25 25.0 25.0

week) week)

μ μ

g (3 μ μ g (3 g (3 x week) x x

gestation 21 days of 14 weeks 14 weeks 64 days 64 days 64 days 64 days 45 days 45 days 45 days 60 days 60 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↓ ↓ ↓ ↓ Panthenol ↓ ↓ ↑ ↓ (3.60-fold) gene expression dehydrogenase (2.10-fold) and farnesyl diphosphate synthase • Without ethanol With ethanol With Affects fat metabolism Affects fat Liver histology Ethanol - folates -folates Ethanol No significant effect of folate deficiency on MS activity Ethanol + folate folate + Ethanol • Normal Significant effect on gene expression in relation with lipid Ethanol - folate -folate Ethanol

Standard diet -folates diet Standard fat percentage (-48%) (-48%) fat percentage (-6%) fat content fat content (+11%) (-13%) fat content cholesterol content (-51%) and cholesterol content (-6%, NS); cholesterol content (-8%, NS); (-56%) FAcontent total (-36%) FAcontent total Ethanoldiet - folates (7.39-fold) gene expression geneexpression (7.39-fold) dehydrogenase (2.50-fold) and farnesyl diphosphate synthase ACC ( mRNA expression ( nuclear protein( deficiency had no effect on FAS mRNA expression and nuclear protein ( 8%); folate deficiency had no effect on FAS mRNA expression regulation); dienoyl-CoA isomerase (+44%) relative abundance ( trimethylaminobutyraldehyde dehydrogenase (+44%) and expression +ethanol) groups (normal folates, folate deficient and normal folate of steatosis, necrosis and inflammation compared to other 3 metabolism fat fatty acid percent (-94%); (-94%); percent acid fatty fat content; 16%) and (-54%)CE contents; no significant change intotal PL (+124%, NS) NS) (+43%, fat fatty acid percent (-89%); (-89%); percent acid fatty fat (-84%); fat percent vs ≈

: normal -folates +50%) and SCD ( ↓ ↑ TG content (-42%), total cholesterol (-26%), CE (- FFA content (+43%) FFAcontent : folate deficiency vs ↑ : abnormal histopathology demonstrating features L-CPT-1 (+174%) and L-CPT-1 : folate deficiency deficiency : folate vs control (standard diet +folates): vs vs Critical ReviewsinFoodScienceandNutrition normal + folates + normal ≈ normal +folates ethanol +folates ethanol

+78%) expressions; folate deficiency ≈ ↑ : : ≈

PL percent (+7%, NS) (+7%, PL percent : +20%) and

↓ ↑ +125%) expressions; folate deficiency long-chain acyl-coenzyme A ↓ PEBP (+36%), 4- long-chain acyl-coenzyme A : ↓ ≈

methionine level (-25%) +160%) mRNA+160%) expressions; folate ↑ ↓ ↓ SREBP-1c mRNA ( mRNA SREBP-1c ↑ ↑ ↓

phospholipide fatty acid percent phospholipide FApercent

total FA content (-46%); (-46%); content FA total (-46%); content FA total total FAcontent (-75%); ↑ : ↓ SREBP-1c mRNA ( :

: ↓ SCD mRNA expression ( ↓

↑ methionine level (-68%)

methionine level (-39%)

BHMT (+14%) ↓

CD36 (-40%) gene ≈

+11%) and and +11%) i.e. i.e. ≈

+67%) ↑ up- ↓ ↓ ACC ↓

neutral neutral neutral ≈

↑ -

(Mcneilet al.,2009) (Esfandiari et al., 2005) (Halsted etal., 2002) (Laird et al.,1965) (Drill, 1954) (Kelley et al., 1950) 11 Page 178of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 179of267 ABBREVIATIONS acid oxidation by activating hepatic AMP-activated protein kinase); Sph, Sphingomyelin; SREBP, Sterol Regulatory Element-Bindin Regulatory Sterol SREBP, Sphingomyelin; Sph, kinase); protein AMP-activated hepatic activating by oxidation acid PPAR PhosphoLipids; PL, PhosphatidylInositol; PI, Protein; PhosphatidylEthanolamine-Binding o inmethylation (involved Synthase MS, Acid; Methionine RiboNucleic messenger mRNA, Enzyme; ME, Malic LysoPhosphatidylCholine; (mainly 1,2- CCl and ATPCL); esters Lyase, ATP-Citrate (or Enzyme Cleavage Citrate CCE, weight; body b.w., MethyTransferase; Homocysteine Betaine d c b interpretations relevant a No data given in the reference in reference the No data given Allterms used in the Table are preciselythose of the article considered: for exemple,the hepatic content in TG was named “co Valproate is an antiepileptic drug and it may inhibit fatty acid oxidation in rat hepatocytes (Coudé et al., 1983) and produces and 1983) al., et (Coudé hepatocytes in rat oxidation acid fatty may inhibit it and drug antiepileptic isan Valproate tothe control, compared lipotrope by the induced percentage increased or thedecreased Indicates triglycerides betweenthe

sn Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), - species); FAS, Fatty Acid Synthase/Synthetase; FA, Fatty Acid; FC, Free Cholesterol; FFA, Free Fatty Acid; G6PDH, Glucose-6-P G6PDH, Acid; Fatty Free FFA, Cholesterol; Free FC, Acid; FA,Fatty Synthase/Synthetase; Acid FAS, Fatty species); - : ABCA1, ATP-Binding Cassette transporter A1 (also known as the Cholesterol Efflux Regulatory Protein or CERP, effluxes excess excess or CERP, Protein effluxes Regulatory Efflux Cholesterol asthe known (also A1 transporter Cassette : ATP-Binding ABCA1, lipoproteins, lipoproteins, 535-590. DOI :10.1080/10408398.2010.549596 e.g.

mediates the transfer Comment citercedocument :

of cholesteryl

ester s

from HDL to pro-atherogenic apoB-lipoprotein pro-atherogenic HDLto from

α i.e.

, Peroxisome Proliferator-ActivatedReceptor alpha; PS, Phospha steatogen diet (NS - Not Significant - means absence of significativity for the change observed; in other cases, the effect w the effect cases, other in observed; the change for of significativity absence means - Significant Not (NS- diet steatogen For Peer Review Only Review Peer For important decreases in hepatic freeCoA, acetyl-CoA and free carnitinelevels (Thurston et al., 1985) ntent”, “concentration” or “level”, and in some case no term was used; studies reporting both lipotrope-like and non-lipotropic and lipotrope-like both reporting studies used; term was no case in and some or “level”, “concentration” ntent”, g Proteins; TC, Total Cholesterol; TG, TriGlyceride; TL, Total Lipids; VLVL, Very Low Density Lipoprotein Lipoprotein Density VLVL, Very Low Lipids; Total TL, TG, TriGlyceride; Cholesterol; Total TC, g Proteins; 4 , Carbone tetrachloride; CD36, fatty acid translocase (long chain fatty acid transporter); CDP-E, CytidineDiphospho-Ethanolamin CDP-E, transporter); acid fatty chain (long translocase acid fatty CD36, tetrachloride; , Carbone URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] s f homocysteine into methionine); NAFLD, Non-Alcohol Fatty Liver Disease; NASH, NonAlcoholic SteatoHepatitis; NS, Not Significa NS,Not SteatoHepatitis; NonAlcoholic NASH, Disease; Liver Fatty Non-Alcohol NAFLD, methionine); into f homocysteine );CoA,Coenzyme A;L-CPT, Livertype Carnitine PalmitoylTransferase; DDT, DichloroDiphenylTrichloroethane;DGAT, DiacylGlycer cellular cholesterol to ApoA-1 to form nascent HDL); ACC/CBX, Acetyl-CoA Carboxylase; Ain, American Institute of Nutrition; ALT hosphate DeHydrogenase; HCl, HydroChloric acid; HDL, High Density Lipoprotein; HU, Hounsfield Unit measured by computed tomogra tidylSerine; resp., respectively; SAM, S-AdenosylMethionine; s.c SAM,S-AdenosylMethionine; respectively; resp., tidylSerine; Critical ReviewsinFoodScienceandNutrition as either significant or no information was given in the article) article) the in given was information no or significant either as ., subcutaneously; SCD, Stearoyl-CoA Desaturase (catalyzes the rate-limiting step in the biosynthesis of monounsaturated FAand monounsaturated of biosynthesis the in step rate-limiting the (catalyzes Desaturase Stearoyl-CoA SCD, ., subcutaneously; effects ( effects e; CE, Cholesteryl Esters; CETP, Cholesteryl Ester Transfer Protein ( Protein Transfer Ester Cholesteryl CETP, Esters; CE,e; Cholesteryl i.e. an increase in hepatic lipid content and/or lipogenic enzyme activities) are alsopresented to allow compa ol AcylTransferase (plays a central role in esterification of fatty acids to form TG); DRG, DRG, to TG); form acids offatty in role esterification a central (plays ol AcylTransferase nt; PABA, Para-AminoBenzoic Acid; PC, PhosphatidylCholine; PE, PhosphatidylEtha PE, PhosphatidylCholine; PC, Acid; Para-AminoBenzoic nt; PABA, , ALanine aminoTransferase; ApoA/B, Apolipoprotein A/B; ATP, Adenosite TriP Adenosite ATP, A/B; Apolipoprotein ApoA/B, aminoTransferase; ALanine , phy; i.p., intraperitoneally; IR, Insulin Resistance; LDL, Low Density L plasma protein that facilitates the transp the facilitates that protein its deficien its 12 h r c n o i D 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Supplemental Table 2

DL DL dl compounds Lipotropic acids,short-chain fatty melatoni DL DL DL DL DL DL Carnitine Carnitine

Carnitine

-carnitine -Carnitine-HCl -Carnitine, -Carnitine -Carnitine -Carnitine -Carnitine -Carnitine -Carnitine lysine + hydrochloridre methionine precursors) or (carnitine methionine carnitine + lysine +

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

L L - - L L - - DL - Rats fed choline-methionine-deficient, high-fat (from homogenates rats) Liver slicesfromrat Liver Homogenates and slices from rat liver

Rats fed control diet and Rats fed threonine-imbalanced diet In vivo Rat liver slices incubated with C Rats fed low protein and methionine diet and Rats fed ethanol-rich (36% of calories) diet diet of (36% energy) fedethanol liquid Rats diet fedethanol liquid Rats Rats fed ethanol-rich (36% of calories) diet diet TPN hypercaloric with infused Rats free- and from high-sucrose ratsfed Hepatocytes Protein-depleted rats fed a 8% protein diet from Rat liver particulates incubated with C (30%) and 10%( and (30%) octanoate, laurate, palmitate andstearate chain FA (from 63to 142 (from 63 to to 142 63 (from supplemented with: (casein) diet and malonyl-CoA formation) formation) malonyl-CoA and 14,514 (inhibits hepatic fatty acid synthesis fat diet incubated with glucagons and RMI plant sources killing ethanol (4 g/kg b.w.) 24 and 12 hours before and stearate

In vivo - -

or 0.2% 0.3% 535-590. DOI :10.1080/10408398.2010.549596 in vitro , L ex vivo ex L -methionine -methionine n, tocotrienol, policosanol and and policosanol tocotrienol, n,

models

Comment citercedocument : α M), -protein) or 9% protein and and i.e. i.e. then injectedi.p. with

octanoate, palmitate μ in vitro M) 14 long-chain FA long-chain i.e. i.e.

butyrate, butyrate, 14 studies reportingeffects lipidmetabolismhepatic on following long- daily dose Supplemented 1% of diet1% of 0.5+ 0.2% 1%, diet1% of diet1% of 10,and 50 100 1 mM - 0.5 and 0.1 0.2%diet of 0.2%diet of 0.2%diet of diet of 0.00016% 0.5 mM 0.1 or 1 mM 0.5 mM 0.3 mM 0.3 mM c and 0.2% and lysine-HCl ( diet or 1.7% of mg/100 gb.w. methionine, 2 ethanol injected with mg/kg b.w. ± para 0.5% -aminobenzoic acid L - L -

exposition exposition lipotrope Duration of 56 days 56 days 8 weeks 8 weeks 14 days 15-60 min 32 days and 4, 8, 12, 16 hours 24 14 days 14 days 14 days 14 days 30 min 30 min 30 min 30 min 1 hour For Peer Review Only Review Peer For a

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

Hepatic effect(s) ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↑ ↑ ↑ Ethanol

Ethanol TL (-24%), TG TL (-46%), CE (-24%), FC(-11%), TC (-22%),PL(- (-28%), TL TG (-62%), CE (-28%), FC(-14%), TC (-26%),PL(- ( TL TL(-43%), TG (-48%), TC (-26%), FC(-8%) and PL (-27%) TL(-44%) and TG(-62%) contents; -32% a and on d.w.b.) -12, -27 (resp. fatpercent (+56%)([1- ketogenesis and (+29%) oxidation ofFA stimulation cholesterol fat (TG, andFFA) content; TLcontent (resp. -19 and -18%) TGcontent (-43% at 0.5 mg/kg b.w.); tended to TGcontent (-47%) TGcontent (-35 and -21%, NS, n = 2 experiments) TGcontent (-53%) TL palmitate conversion into CO palmitate conversion into CO palmitate oxidation (resp. CO in oxidation FA of group carboxyl in oxidation FA ketones (resp. b.w. (+16%) lesser extent only (+9.5%) conversion into lipids (free of FFA); FFA); (freeof lipids into conversion for octanoate to +111% forstearate) 14 stearate) andin carboxyl group of for octanoate to +470% forstearate) 20%) and FFA (+9%, NS) content found in rats fed adequate protein diet FFA ( into neutral glycerides ( and CO C]oleate converted into respectiv convertedinto C]oleate 3 (-38 for ≈ -50%), TG ( vs vs ≈ 0and ethanol+carnitine ethanol+lysine+methionine 2

and ketones) ketones) and α -protein-based diet and-25%for casein-based diet)

≈

-50%) -50%) ≈ Critical ReviewsinFoodScienceandNutrition +260 and ≈

-50%), cholesterol ( 2 (from +1.5 for octanoate to +106% to for (fromfor octanoate +1.5 ≈ -47%) and PL ( ≈ +50and : ≈

+400%); no effect on plmitate 2 2 ( (resp. deficiency or supplementation or deficiency of ≈

+22%);

β ely total acid-soluble products products total acid-soluble ely β -ketonic acids(from +3.3% ≈ ↓ : ≈ -ketonic (from acids -ketonic +3% +7°%) b +30 and cholesterol content but to a andin CO ↓ ↓ palmitate conversion into ≈ fat content tonormal -50%) and and PL ( -50%) ↓ palmitate conversion ≈ -39%) ≈ +37%) and

↑ at 0.1 mg/kg at0.1mg/kg 2 for stearate

≈ -50%) References (Sachan etal., 1984) Sachan, 1983) and (Rhew (Sachan and Rhew, 1983) (Sachan and Rhew, 1982) et al.,1981) (Tao Foster, 1979) and (Mcgarry 1975) (Hu, 1975) Bexton, and (Hosein (Khairallah and Wolf, 1965) (Fritz, 1964) (Fritz, 1959) carnitine, hydroxycitric acid carnitine, hydroxycitric

, organosulfur compounds, mono- and poly-unsaturated 13 f Page 180of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 181of267

L DL L DL L L Carnitine-deficiency Carnitine-deficiency Carnitine Carnitine Carnitine deficiency

-Carnitine L-tartrate -Carnitine-HCl -Carnitine -Carnitine -Carnitine -Carnitine

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Normal and cirrhotic rats(treated 10 weeks with jvs Rats fed high-fat (30%) or high-cholesterol (1% 3 females onhome parenteral nutrition Rats fed liquid ethanol-rich (36% of calories) Pregnant rats fed wheat gluten (unsupplemeted, diet fedethanol liquid Rats Perfused livers from mildronate-treated rat (fed rat(fed mildronate-treated from livers Perfused Mildronate (that yields carnitine depletion)- Ovariectomized rats fed AIN-93M diet Rats fed vegetarian food poor in carnitine and CCl develops aswollen fatty liver) + 0.25% cholic acid) treated rats (fed rats(fed treated fed THP (20 mg/100 g/day) fat) / moderate or severe steatosis, standard liver function tests (notably (carnitine deficiency) with abnormalities in diet are nonpregnant rats level (lysine is a carnitine precursor); controls lysine)-based diet at a low or high protein i.e. jvs 4 1%lysine, supplemented or with7or12% mice (homozygous mutant strain that ) then submitted toTPN(40% energy as 535-590. DOI :10.1080/10408398.2010.549596 vs Comment citercedocument : fasted state) i.e. i.e.

grade ≥ 2) - - 0.015% of diet - 100 mg/kg b.w. 1 mg injected i.p. 0.3%diet of 1 gdailyi.v. 0.1, 0.4,0.8, 1.2 12%7 or of 0.1, 0.4,0.8, 1.2 56 days mg from 30- days, then 2 10-30 from diet or 1.6% of proteins or 1.6% precursors) carnitine

90 min 10 days 8 weeks 6 weeks 1 week killing weeks for and2, 4 8 1, 2, 3 weeks 1 month 46 days 21 days of 45 days For Peer Review Only Review or 10 days Peer For gestation URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] No significant effect onTG, Pl andcholesterol contents for both un- TL 2 weeks: 1 week: TG Normal rats: Normal rats: from 8: - atweek Fed state from 4: - atweek Control FC Cirrhotic rats: Cirrhotic PL TC ↓ ↓ ↓ ↑ ↓ ↓ ↓ Histological observations Cholesterol Cholesterol High-fat No significant effect onTG content (resp. +4, +34 and +25%) CE Liver histology (light microscopy) No signicant effect onPLcontent Low proteinlevel Fasted (18 hours) state 3 weeks: Ethanol High proteinlevel No significant effect oncholesterol content for bothun- and Fasted state total TGcontent (-38%) CPT I activity (-24%) and [1- relative CPT IImRNA abundance: nonesterified FAconcentrations (NS): resp. +0.3, +16, +19, +19 TGcontent for nonpregnant rats (resp. -48 and -34%, NS) and - -66, -31, -6, -38%) and -12, -53 TG(resp. (resp. -55, and TL -33, (-27%), TL TG (-47%), CE (-31%), FC(-14%), TC (-28%),PL(- and pregnant rats +5%); pregnant rats NS) : resp. +5 (NS), -8(NS),-6(NS) +5(NS), -4 (NS), (NS) -16 : resp. and : resp. -11 (NS) -33, -55, -47 and -38% -38% and -47 -55, -33, (NS) -11 resp. : : resp. (NS),-14 -1(NS),-10 (+78%); (+78%); and cholesterol (-22%) levels grade of steatosisgrade of 8%, NS) levels; activity ( and +25% pregnant rats (resp. -45%, NS, and -32%, NS) 63 and -53%) concentrations 2%, NS)and FFA (+24%, NS) 48%); acyl-CoA (-11%, NS) and malonyl-CoA (-17%, NS) contents contents NS) (-17%, (-11%, malonyl-CoA NS)and acyl-CoA levels levels 13%,and NS)(+32%) FFA VLDL production; NS) contents (-33%, NS)and malonyl-CoA (-4%, total acyl-CoA PL (-36%), : resp. -2 (NS), -6 (NS), -15, -6 (NS) : resp. (NS),-15, and (NS) +6% -6 -2 (NS), (NS) -5 (NS), (NS) +9% : resp.(NS),-15 and -4 -3 (NS), : resp. -4 (NS), -31, -64, -61 and -52% vs vs ↓ ↓ : vs TL (-12%, NS), TG (-20%) and cholesterol (-30%) levels ↓ ↓ PLcontent in pregnant rats (resp. -9%, NS,and -14%, ↑ ↑ Carnitine (3 weeks) (3 Carnitine (-15%) levels cholesterol and TG(-19%) TL NS), (-7%, (-1%,NS) cholesterol (-12%, TLTG NS)and (-24%), ethanol+carnitine+lysine+methionine total CoA in total liver (+39%) and liver cytosol cytosol liver and (+39%) liver total in CoA total high-fat TG content (+275%); TGcontent : ≈ ↓ vs +36%) total CoA in liver mitochondria (-32%); (-32%); mitochondria liver in CoA total ↓ ↓ palmitate oxidation/metabolisation level ( TG (-57%) TG andcholesterol (-32%) contents chol+carnitine (10 days) ↓ TG(-51%) and cholesterol (-22%) contents : ≈ ≈ : Critical ReviewsinFoodScienceandNutrition 2.8to 2.7to ↑ +

cholesterol level (+16%, NS) carnitine ↑ :

acidperoxisomal fatty acyl-CoA oxidase ↑ TG(+815%) and FFA (+70%) contents; : ≈ ≈ 1.2-fold compared to control (+/+) control at 1 comparedto 1.2-fold (+/+) control at 1 comparedto 1.5-fold ↓ severity of steatosis : : 14 ↓ C]palmitic acid (NS), -2%(NS), -7(NS),and TL (-3%, NS), TG TL(-3%, (-10%,NS) NS), ↓ in nonpregnant rats -4 and (resp. in nonpregnant : nosignificant change in the PL(-22%), FFA -7%, NS),total : ↓

TL (-7%,NS) andTG(- β : -oxidation (- ↑ hepatic ≈ -50%); ↑ ↓

(Degrace etal., 2007) etal., (Clark 2007) (Spaniol et al., 2003) (Liang etal., 1999) (Hotta et al., 1996) (Shimura andHasegawa, 1993) etal.,1988) (Bowyer Sachan, 1986) and (Rhew 1989) (Ortega, Sachan, 1984) and (Rhew 14 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 (-)- (-)-Hydroxycitrate Hydroxycitric acid L (-)-Hydroxycitrate Sodium (-)-

-Carnitine cambogia (from (HCA) cambogia Garcinia (from lactone hydroxycitrate sabdariffa (from hydroxycitrate Allo -

Garcinia Hibiscus Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), ) ) ) Rats fed 7 days with high-glucose (70%) diet, Rats fed 12 days with high-glucose (70%) diet, Liver high-speed supernatants collected 5-7 days

Liver slices fromrats killed 5-7 days after being Rats fed high-fat (hydrogenated fat - HF - rich in Rats fed 12 days with high-glucose (70%) diet, Rats fed 10-15 days with high-glucose/high- Citrate +purified CCE from liversof rats feda Citrate +purified CCE from liversof rats feda diet fatty acids, asenergy) 30% monounsaturated hours after beginning of feeding then i.v.injected with [ hours after beginning of feeding then i.v.injected with [ hours after beginning of feeding diet, and added with 5 or 10 after feeding rats with a high-glucose (70%) vs with [ fed with a high-glucose (70%) diet, and added week): 14 saturated fatty acids acids fatty saturated then i.v.injected with [ tissue) high-fructose diet high-fructose enzyme) levels of high diet(toreach high-fructose C]citrate 3 killed 45-60 min after fructose (58%) diet, then i.v. injected with fasted state) with [1- H 2 ± O 45 min after i.p. HCA injection and exercise (1 hour swimming 6 days a 14 C]alanine (fatty acid precursor, 10 i.e. 535-590. DOI :10.1080/10408398.2010.549596 sedentary (S) Comment citercedocument : vs peanut oil - PO - rich in 14 14 14 14 3 C]alanineand killed 3 C]alanineand killed 5 C]alanineand killed 5 C]palmitic acid H vs 2

O injection exercised rats(E) μ mol/mL of [1,5- of mol/mL

μ Ci/g 3.5 mM and 35 From 0.1to 4.0 0.5%diet of

5.26, 3.95, 2.63, 5.23 mmoles/kg 0.017 mmol/kg From 5to 5000 From 0.01 to 2.0 5 mM, 50 and

b.w. mmoles/kg mmoles/kg 1.32 or 0.66 tube) (by stomach b.w. fed orally i.v. b.w. injected mM mM 5000 5000 μ (d.w.b.)

M μ M

20 min i.p. injection ≥ 24 weeks 60 min From 2hour Injected 0, 60 min ≥ 15 min 15 For Peer Review Only Review Peer min 15 For incubation injection feeding before of feeding beginning after 4.5 hours to before pulse radioactive before min 120 30,and 90 incubation 3 before before min45 incubation incubation H 2 O URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] High-fructose

↓ ↓ ↓ ↓ ↓ ↑ ↑ ↓ ↓ Fed state ↓ High-glucose At 3.5mM:At At 50 At 5 mM: changes CCE activity (-19% for 0.9 mM and+7% for At 5000 5000 At

↓ FFAcontents (+18% for HFS, andNS +20% forPOS, NS) and +44% for HFS, (resp. +22%, NS, for POS, content cholesterol HFS,-14% (-31 for content TG and

At 35

cholesterol synthesis (resp. -69, -40, -35, 0 and 0%) dose-dependently FA synthesis (resp. -80, -71, -68, -33 and -23%) rate of lipogenesis 2.0 (-54%), 1.5 (-64%), 1.0 (-77%) and 0.5 (- dose-dependently rate of lipogenesis (from 16 to 79% for 5 mM FAsynthesis (-25-30% at 0.1 mmole/kg b.w.) dose-dependently rate of lipogenesis (from 7to 57%)

(-48% for HFE and -42% for POE) -42%for HFEand POE) for (-48% +33% for for HFE+33% +11%, and NS, for POE) POE) NS,for -23%, and rate of lipogenesis (resp. -42, -52, -60 and -34%) 0.6, 1.3, 2.3 and no change at 0, 2.5 and 4.5 hours after beginning of feeding 76%) hour before and 1.0 hour after (-4%)beginning of feeding; citrate andfrom 6 to 59%for 10mM citrate) 0.8 and 1.5 mmoles/kg b.w.) ACO ( FABPpm ( 24 mM citrate) citrate) LPL and FAT/CD36mRNA levels mRNA, mtGPAT, microsomal DGAT1, CTPpct, ApoB, LDLR, ApoB, PPAR LPL and ApoB, mM citrate) esterification level into PL ( PL into level esterification palmitate esterification level into TG ( citrate) LDLR ( LDLR +3%, NS, for -2%, POE) NS,for HFE and NS, for +3%, ↑

total fat content (-2%for for HFS, POS, NS -12%, NS, fatcontent total

μ μ M: changes activityCCE (+3% for 0.3 mM and-4% for 9 M:

: no change for levels of oxidation and esterification; μ ≈ +335%) and PPAR M: ≈ ↓ +120%), FAT/CD36 (

CCE activityCCE (-65 and -31% for resp. 0.3 and 9 mM ↓ : : ≈

↓ CCE activity (-62%for CCE 24 mM citrate) -50%); no change in CPT I CPT in change no -50%); ↓ ↓

CCE activity (-81 and -22% for resp. 0.3 and 9 mM

FA synthesis ( synthesis FA FA synthesis ( synthesis FA Critical ReviewsinFoodScienceandNutrition

4.0 mmoles/kg b.w.) 4.0 mmoles/kg γ

2 mRNA levels; α ≈ ≈ ≈ ( -35%); no change in CTPpct, -55, -74 and -85% atresp. -67, -73, -77 and -82% at resp. , NS, for POS, -12%, POS,-12%, NS, for HFE , NS,for ≈ +20%, NS) mRNAlevels ≈ +40%), FABpm (

≈ α +116%); ↑ and CPT I DGAT1 ( DGAT1

↓ palmitate

≈ β +40%), ≈ +90%), isoforms, ≈ 0.3, ↓

≈

↓

(Sullivan etal., 1972) (Lowenstein, 1971) (Watson et al., 1969) (Karanth and Jeevaratnam, 2009) 15 Page 182of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 183of267 (-)-Hydroxycitrate (-)-Hydroxycitrate ( (-)- ( (-)-Hydroxycitrate (-)- (-)-Hydroxycitrate (-)-Hydroxycitrate ( (-)-Hydroxycitrate ( ( + + + + + )-Hydroxycitrate )- )-Hydroxycitrate )- )-Hydroxycitrate (Na) Hydroxycitrate Hydroxycitrate Hydroxycitrate Hydroxycitrate Allo Allo Allo Allo - - - -

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Liver from rats fed 70% glucose diet for 7 days Liver high-speed supernat Rats fed 13 days with high-glucose (70%) diet, Rats fed 70% glucose diet for 9 days and killed Rats fed high-fructose (70%) diet for 6 days and Fed and fasted rats fed a 10%-fructose solution diet (70%) high-glucose rats fed Zucker Obese 3-hr meal-fed rats diet fed 70% Rats glucose Rats fed 70% glucose diet for 30 days and killed Rats fed 70% glucose diet for 9 days and killed Rats fed high-glucose (70%) diet for 6 days and Liver from rats fed 70% glucose diet for 30 days, [ and killed 30 min after i.v.injection of hours after beginning of feeding diet, and added with 5 or 10 after feeding rats with a high-glucose (70%) then i.v.injected with [ 30 min after i.v. injection of [ 3 3 14 i.v. injected with [ with injected i.v. hours for 28 30 min after i.v. injection of [ 30 min after i.v. injection of [ then incubated incubated then H H 14 C]citrate C]alanine or or C]alanine 2 2 0 0 535-590. DOI :10.1080/10408398.2010.549596 3 in vitro H 2 Comment citercedocument : 14 0 C]alanine or with 10 mM[ with 10 14

C]alanineand killed 3 ants collectedants 13days μ 14 14 14 mol/mL of [1,5- of mol/mL C]alanine or C]alanine or C]alanine 3 H

2 O 14 C]citrate C]citrate 2.63 mmol/kg 1.32 mmoles/kg 1.32 mmoles/kg - 1.32 mmol/kg 0.66, 1.32or 0.33, 0.66, 1.32 0.17, 0.33, 0.66, 2.63, 5.26or 2.63 mmoles/kg 2.63 mmoles/kg 0.1mM and 1.0 intubation) intubation) b.w. (oral times three twice b.w. (orally) b.w. 2.63 mmol/kg tube) ( mmol/kg b.w. or 2.63 killing vitro mM added (orally) (orally) mmol/kg b.w. 1.32 or 2.63 last day the (orally) mmol/kg b.w. 10.52 beore killing the last day (orally) b.w. stomach tube) b.w. (by tube) (by stomach b.w. fed orally via stomach after after ± 1 in

and3, 6 21 hours 28 7-13 days hours 24 11 days 30 days 11 days 30 days 4 hours 2, 4,6, 8, 60 min 20 min hours hours Only Review killing before Peer hours 24 or 21 18, For 10, 12,15, feeding before tube) (stomach URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

Rate of lipogenesis from [

No significant effect onTL content (7%) Without 10 mM hydroxycitric acid added

Rate of lipogenesis from ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↑ ↓ ↑ ↓ ↑ ↓ With 10 mM hydroxycitric acid added Rate of lipogenesis was lower adding when 1 mM hydroxycitric

rate of lipogenesis (-2%) rate of lipogenesis (+16%) rate of lipogenesis (-42%) rate of lipogenesis (resp. -10 and -6% at 5 mM citrate; -12 and - rate of lipogenesis (resp. -72 and -52% at 5 mM citrate; and -54 - FA synthesis rate from [ FA synthesis rate from [ FA synthesis rate from [ cholesterol synthesis significantly the rate of FA synthesis over 8-hr period when lipidcontent (-9%, NS) rate of lipogenesis from rate of lipogenesis from [ rate of lipogenesis from rate of lipogenesis from [ rate of lipogenesis (resp. -42, -78 and -89%) rate of lipogenesis (+4%) rate of lipogenesis (resp. +31 and +4% at 5 mM citrate; +8and rate of lipogenesis (resp. +55 and +4% of control at 5 mM citrate; 37%) +3% at 10 mM citrate) +31% of control at 10mM citrate); and citrate (-10%) and -43%) 3 ≈ at21 hrs (NS)and +520% 2% at 10 mMcitrate) 35% at 10 mM citrate) control animals had elevated rates acid 54% at 6hrs,54% 0, (NS) and (NS) and (resp. (resp. hrs, at 12 hrs (NS), H +17%at 15 hrs (NS), 2 ≈ O (fed: -36%; fasted: -39%) -39%) fasted: O (fed:-36%; +18%, NS, 3 ≈ in vitro in H

-64% at 6 hrs, ≈ 2 +13, NS, O (resp. -31% -59, and effect) no ≈

+60% at 24 (NS) at24 hrs +60% (from ≈ -39%at 8hrs, ≈ ≈ Critical ReviewsinFoodScienceandNutrition

+55, -52% at15 hrs (NS), ≈ +25%, NS, NS, +25%, ≈ -54 -54 to ≈

-64% at 8 hrs,

≈

3 +105 and 14 14 14 3 3 ≈ H 14 H H 14 14 +19% at18 hrs (NS), C]alanine (resp. -57, -62% and effect) and no (resp. -62% C]alanine -57, -62%) fasted: and (fed:-40%; C]alanine C]alanine (-63%) and C]alanine 2 C]alanine (resp. -27, NS,-21, -76 NS, C]alanine (resp. -6, NS, -29 and-49%) 2 2 0 0 (resp. 0, -20 and -32%) 0 (resp. -22, NS, -13, NS, -49 and - ≈ ≈ :

-53%) +175% at 24 at24 hrs +175% ≈ -52% at 2 hrs, ≈ ≈ -30% at 10 hrs (NS), +56, ≈ +118%) : ↓ : ≈ ≈

-76% at 2 hrs, at2hrs, -76%

rate of lipogenesis at 10 mM ≈ -49% at10 hrs (NS), ↑ +104 and ≈

rate of lipogenesis (resp.

+33% at 18 at18 hrs (NS), +33% : ↑

rate of lipogenesis

≈ -61% at 4 hrs, 3 ≈ H +63%at 21 hrs ≈ 2 +108%) O (-47%) ≈ ≈

-71% at 4 0at12 hrs,

≈

+18% ≈ ≈ -

≈

(Sullivan etal., 1977) (Sullivan etal., 1974c) (Sullivan etal., 1974a) (Sullivan etal., 1974b) 16 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Calcium- Hydroxycitric acid SuperCitriMax-600- (-)-Hydroxycitrate (-)-Hydroxycitrate (-)-Hydroxycitrate Hydroxycitrate (-)-Hydroxycitrate Petroleum ether-, S Sulfur-containing Organosulfur -allyl cysteine cysteine -allyl atroviridis from (water soluble) hydroxycitrate SXG cambogia from 60% HCA extract potassium saltof (from acalcium- cambogia from 60% HCA extract potassium saltof (from acalcium- garlic fresh of fractions water-extractable methanol- and amino acids compounds

® Garcinia Garcinia Garcinia (60% HCA) (60% HCA) Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), ) )

Hep G2 cells incuted 3 hours with Obese women Rats fed high-carbohydrate or high-fat diet Rats fed high-fructose (48%) diet subjects Obese subjects Obese Overweight subjects Hyperinsulinemic obese subjects fed controlled

Hepatocytes isolated from rat liver and incubated Rats fed high-cholesterol (1%) diet Hep G2 cellsHep incuted with [1,5- Hepatocytes isolated from rat liver and incubated Hep G2 cellsHep incuted with Hep G2 cells incuted 2.5 hours with (from μ i.v. injectedi.v. with Triton WR1339 high carbohydrate diet (68%energy) with 0.5 mM [1- mg/kg) 3 with 0.5 mM [1- H]glycerol ( g/mL) ≈ 4to 535-590. DOI :10.1080/10408398.2010.549596 ≈ + 38 oleic acid or

14 14 μ C]acetate or0.1mM [2- C]acetate g/mL) Comment citercedocument : 3 H + 2 acetic acid) O 14 C]citrate 125 4bis

125 (10 I-LDL (250 (250 I-LDL

0.018% of diet 1 0.05, 0.1, 0.5, 0.5%diet of mg 2800 mg 2800 750 mg 6 g 2 mM 2.5 mM 1 mM ≥ 2.63 mmol/kg 1.15 g 1.6 or 3.2% of x 0.01 and and 0.01 medium) incubation 2mL to powder added dry garlic mg 1.25 and mM mM intubation) intubation) b.w. (oral 4.0 mM 1.0, 2.0and or 5 times times atrovitridis diet x Garcinia Garcinia ( ≅ ≤ 0.25 10 10 3

4 hours 4 hours 2 weeks 2 months 8 weeks 26 days 8 and 4 Middle time 8 weeks 6 days hours 16 hours 18 hours 18 2.5 hour 6 hours For Peer Review Only Review Peer weeks weeks For 8 and 8 weeks) (0

↓ ↑ ↓ ↓ ↓ ↑ ↑ ↓ ↓ ↓

No decrease in hepatic At 1

Tends to rate of [1- rateof -methyl-cysteine -allyl- -methyl-

post-prandial lipid content ( receptor-mediated binding to ofLDL Hep G2 cells ( LDL-receptor-mediated association ( blood LDL (resp. -4%, NS, and -12%), TG - -4%, -12%), NS, and (resp. LDL (resp. blood NS,and -4%, blood TG (-7%), VLDL(-15%, NS) and LDL (-6%) levels cholesterol (-73%) and FA(-34%, NS) syntheses incorporation of [1,5- FA synthesis rate from serum TG (-23%) and TC (-5%, NS) contents; -13%),-6%,NS) LDL (resp.-3%,blood TG(resp. and NS, -7 ↑ ↓

(+3%, NS) (+3%, [2- [1- μ 62 and -64%) (resp. -10%, NS, -15%, NS,and -53%) and FA (resp. -9%, NS, - and -64%) and FA (resp. -29, -59 and -62%); +107%) 9%) and TC (resp.-3%, NS, and -6%) concentrations; and TC(resp. -3%, NS, and -7%) concentrations; concentration (resp. -3%, and -3%,NS, NS) (concentration given 50% inhibition) = 0.01-0.5 mM concentrations NS) +4%, and NS, +7%, (resp. VLDL and +8%) and +5 (resp. concentration (resp. +0.3%, NS,and +11%); or fructose infusion 24%) and cholesterol/PL (-18%); no effect on PL content concentrations and 4.0 (-27%) mM; nosignificant changes at other and cholesterol/PL (-11%, NS); noeffect on contentPL and cholesterol/PL (-18%); noeffect onPL content g/mL x x concentration concentration 3 14 H]glycerol incorporation rate into TG (resp. +8%, NS, +15% L C]acetate incorporation rate into -cysteine sulfoxide L ↓ 125

-cysteine sulfoxide -cysteine ATPCL/CCE activity and 14 I-LDL and C]acetate incorporation into

Critical ReviewsinFoodScienceandNutrition ↓ TL (-1%, NS), NS),FC(-9%,NS) TC (-10%, NS), TL(-1%, : : ↓

[1- 14 ≈ de novo

C]citrate into FA and cholesterol: IC +41% at 3 H 14 C]acetate incorporation into cholesterol : 2 O (-43%) ↓ TL (-5%, (-21%),NS), TC FC (-24%) ≈ : +67%) ↓ lipogenesis measured after fasting TL(-11%, NS), TC (-18%), FC (- ≈

↑

μ CPT activities CPT ≈ g/mL

cholesterol (resp. -36,-44 +49%) and degradation ( cholesterol at2.0(-21%) 125

I-LDL) ↓ ↑

VLDL serum HDL level

↑ blood HDL HDL blood ≈

+64%at

14 ↑ C]acetate

HDL

≈ ≈ 4

Yeh,1994) and (Yeh (Itokawa et al.,1973) (Roongpisuthipong et al., 2007) etal.,2007) (Roongpisuthipong (Hong etal., 2007) etal., 2006) (Brandt (Preuss et al., 2004a) (Preuss etal., 2004b) (Badmaev etal., 2002) (Schwarz etal., 1999) (Berkhout etal., 1990) 17 Page 184of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 185of267 Kyolic Water- (WEF), Water- (WEF), Organosulfur Organosulfur S

-methyl cysteine cysteine -methyl Allium sativum (fromcomounds organosulfur and lipid-soluble Kyolic fractionsgarlic, of extractable ether-(PEF) and petroleum (MEF) methanol- Allium sativum compounds (from Allium sativum compounds (from Allium cepa sulphoxide (from Allium sativum (fromcomounds organosulfur soluble

d and water- and Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), 5 , water- ) ) ) ) ) Hepatocytes isolated from rats fed a standard non HepG2 cells incubated with [2- Hepatocytes (fromratsfe Hepatocytes Diabetic (alloxan-treated) rats

HepG2 cells incubated with [2- [2- purified diet and incubated with sodium saltof WEF at 1.25 WEF at1.25 compounds g/L) organosulfur or incubated with[ 3 H]glycerol and garlic extracts (MEF, PEFand 14 C]acetate 535-590. DOI :10.1080/10408398.2010.549596 14 C]acetate or [ Comment citercedocument : d a standardized diet) 14 14 C]acetate C]acetate or[2- 14 C]mevalonate

From 0.1to 1000 200 mg/kg b.w. 0.05-0.8 mM 0.05-4.0 mM 0.05-4.0 mM μ tube) (by stomach M

- - 4 hours 2 hours 45 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Lipid soluble Kyolic + Water-soluble compounds

- diallyl- disulfide: -22(10 - Water-soluble - allyl mercaptan: -10 (100 (100 -10 mercaptan: - allyl S ↓ ↓ ↓ ↓ ↓ ↓ Water-soluble compounds Water-soluble glutamate derivatives Lipid-soluble compounds Kyolic ( Kyolic - allyl mercaptan: -4% (NS) at 100 mM, -8% at250 mM and-13% - diallyl disulfide: -3% (NS) at 100 mM, -9% at250 mM and-15% - allicin: -11% (NS) at 50mM and -32% at 500 mM IC incorporation of[2- incorporation of[2- incorporation of[ incorporation of[ biosynthesis of nonsaponifiable neutral lipids from [ (-10%), TG contents and PL (-6%) TC (-13%) -allyl- and and -allyl- ↓ 99% (1000 cholesterol cholesterol (maximal inhibition of 40-60% at2.0-4.0 mM) cysteine to 1.72 mM for sulphide/disulfide and methyl allylsulfide): sulfonylalanine: noeffect on incorporation of[2- trisulfide, dipropyl sulphide and dipropyl disulfide): cysteine, cysteine, 1.88 ( mercaptocysteine): incorporation of[ mM) 14 WEF, MEFWEF, andPEF), but only inpresence of acetate, not FA 36% for PEF, -64% for WEF, -77% for PEF,- WEF, for -64%Kyolic 36% for -77% and fromand 42 to 55% maximal inhibition (IC allyl/methyl/propyl cysteine): lipids ( cytotoxic at 1.0-4.0 mM 0.2 mM and-55% at 0.4 mM: equivalent to 0.2 and 0.4 mM of into cholesterol (from -20 to -35%) to-35%) (from-20 cholesterol into propyl-cysteine, propyl-cysteine, dose-dependently incorporation of [2- cysteine - and -and cysteine allyl-cysteine) incorporation of[2-

oleic acid -21 and -21%) in presence of acetic acid -20%) PL -26, -9and and (resp. -21, (resp. diacylglycerols 12%), and +9%, NS) and PL(resp. at 500 mM at 500 mM 50 [2- C]acetate into cholesterol (from -10 to -15% at 0.05-0.5 mm); -15%at0.05-0.5 to (from -10 cholesterol C]acetate into of water-soluble compounds: from 0.34 (S-propyl cysteine) to 3 H]glycerol incorporation rate into TG (resp. -14, -9 and -

: : further : further γ ↓ ≅ -glutamyl -glutamyl ≈ incorporation of [2- 0.3 mM S -38%): 1,2-vinyl-dithiin at 1000

-propyl cysteine (0.4mM) cysteine -propyl γ ≈ S -glutamyl-

42 to 100% at4 mM -propyl cysteine -propyl

compounds (diallyl sulphide/trisulfide, dipropyl μ alliin, M) ↓ ≈ incorporation of[2- -22% for

Critical ReviewsinFoodScienceandNutrition S γ 14 14 S -glutamyl- 14 -allyl-cysteine) + - propylcysteine) mM C]acetate into cholesterol: C]mevalonate into nonsaponifiable neutral C]acetate into FA from 0to S 3 14 ↓ 14 H]glycerol into TG (from TG -14% for -9 into to H]glycerol -allyl acetylcysteine-allyl and C]acetate into cholesterol (-44%for MEF, - incorporation of [ S C]acetate into cholesterol -propyl cysteineand

(diallyl sulphide, diallyl disulfide, diallyl diallyl disulfide, diallyl sulphide, (diallyl

( ( μ

γ -glutamyl- μ S M), -56 (100 S S -allyl cysteine at 2 mM) M), -16 (200 -allyl, -allyl-cysteine, : no effect at0.05-0.2 mM 14 S C]acetate into cholesterol (-30%at -allyl cysteine, cysteine, -allyl ≈ 0, +9 and +28%) in presence of ↓ incorporation of [2- S 50 ( -ethyl and and -ethyl

: similar additive effect on

14 from 0.58 for from for 0.58 S γ S C]acetate into cholesterol -glutamyl -allyl-cysteine (0.4 0.8 (0.4 and -allyl-cysteine -propyl cysteine) cysteine) -propyl 14

C]acetate into cholesterol μ C]acetate into FAfrom μ

M), -93(200 M) and -77% (1000 μ S M S -ethyl-cysteine,

↓ -allyl -allyl incorporation of [2- γ S S -glutamyl- -propyl cysteine): cysteine): -propyl -allyl -allyl S ≈ - 25% at 0.05 mM ≅ 14 S C]acetate into 0.4mM -methyl 14 14 ↓ C]acetate

C]acetate:

μ M) and - S -methyl S S

-allyl -allyl - μ ↓ M)

S - ↓

2003) Yeh, (Lee and Liu, and 2001) (Yeh 2000) Yeh, and (Liu 1996) Beck, and (Gebhardt (Kumari et al., 1995) 18 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Methyl linolenateMethyl linoleateMethyl and poly- Mono-

Methyl linoleateMethyl Cysteine-containing Cysteine-containing S Organosulfur Organosulfur -methyl cysteine cysteine -methyl (C18:3) acids unsaturated fatty compounds compounds Allium cepa sulfoxide (from compounds compounds (C18:2) (C18:2) stearate (C18:0) palmitate (C16:0)

Rats fed high-cholesterol (1% and 0.2% cholic Rats fed high-cholesterol (1% and 0.2% cholic Diabetic (streptozotocin-induced) mice Mice fed high-fat (18%) diet Mice fed choline and methionine-deficient diet Mice fed high-fat (70% energy) diet Rats fed fat-free and high-sucrose (72%) diet (72%) fed diet Rats fat-freeand high-glucose Mice fed 18 days with linoleic acid-deficient diet injected with 1,2- acid)diet,then killed 3hours afterbeing acid) diet diet cholesterol), then with methyl linoleate-rich (2% hydrogenated coconut oil +1% 535-590. DOI :10.1080/10408398.2010.549596 14 Comment citercedocument : [C] sodium acetate (50mM)

drinking1 g/Lof drinking1 g/Lof 200 mg.kg b.w. 200 mg.kg b.w. drinking1 g/Lof drinking1 g/Lof diet3% of diet3% of 2% of diet (in water water water water coconut oil) place of

7 weeks 4 weeks 45 days 45 days 4 weeks 4 weeks 7 days 7 days 10 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] S S Linolenate Linoleate Stearate ↓ S S S ↓ ↓ S S S S N S S S N n -ethyl cysteine -ethyl -allyl-cysteine

incorporation of[ PL( -propyl-cysteine -methyl-cysteine cysteine -ethyl cysteine -allyl -propyl-cysteine -methyl-cysteine cysteine -allyl -ethyl cysteine -ethyl -propyl-cysteine -ethyl-cysteine -acetyl cysteine FAS activity ( -acetyl cysteine -acetyl cysteine CoA reductase activities significant effect uponTC content and malic enzyme and HMG- incorporation intofatty acids ( activities, andrate of FAsynthesis from [U- FAS ( FAS ( ME (-18%) and FAS (-26%) activities ME (-12%) and FAS (-22%) activities SREBP-2 ( 25%) and SREBP-2 ( 23%) and SREBP-2 ( 22%) activities; malic enzyme(-28%), FAS (-37%) and HMG-CoA reductase (- (-11%) and FAS (-29%) activities 26%), HMG-CoA reductase ( level contents; 20%) activities; malic enzyme(-26%), FAS (-30%) and HMG-CoA reductase (- ME (-19%) and FAS (-24%) activities activities, andrate of FAsynthesis from [U- activities, andrate of FAsynthesis from [U- CoA reductase activities significant effect uponTC content and malic enzyme and HMG- NS) NS) 25%) activities; malic enzyme(-22%), FAS (-35%) and HMG-CoA reductase (- activity (-10%) ≈ -7%), cholesterol (

≈ ≈ : -13%), HMG-CoA reductase ( -20%), HMG-CoA reductase ( ↑ : FAS (+36%), G6PDH (+25%) and ME (+20%, NS) (+20%,NS) ME (+25%)and G6PDH (+36%), FAS : ↓ ↓

↓ FAS (-40%, NS), (-37%)G6PDH and ME(-40%) ME (-13%) and FAS and activities ME(-33%) FAS (-13%)

≈ FAS (-55%),FAS G6PDH (-62%) and ME(-40%, NS) -17%) -17%) : : : : ≈ : : : -78%) and level of malonyl-2- ↓ ↓ ↓ ↓ : ↓ : : ↓

↓ TG content ( TG TG (-37%) TG and cholesterol (-23%) contents (-11%) TG and cholesterol (-24%) contents; : : : TG (-7%) and cholesterol (-11%, NS) contents; contents; NS) (-11%, cholesterol TG(-7%) and : : TG (-30%) and cholesterol (-11%, NS) contents TGcontent ( TG( ↓ ↓ ↓ ↓ ↓ ↓ Critical ReviewsinFoodScienceandNutrition ↓ ↓ ↓ TG ( TG ↓ ↓ TG(-33%)andcholesterol (-25%) contents contents; (-23%) cholesterol and TG(-5%) 14 mRNA expression of ME ( mRNA expression of malic enzyme ( mRNA expression of malic enzyme ( TG ( TG contents (-28%) cholesterol TG and (-43%) NS) (-15%, cholesterol TG and (-14%) TG(-25%) andcholesterol (-9%, NS) contents TG(-15%) and cholesterol (-24%) contents; C] acetate into cholesterol (-3%); ≈ ≈ ≈ -20%) -31%) -24%) and TC ( ≈ ≈ -15%) and TC ( TC -15%) and -19%) and TC ( and -19%) ≈ -13%) and TG ( TG and -13%) ≈

≈ -47%); ≈ -53%); -18%), SREBP-1c ( ≈ -85%) ↓ ≈ ≈ ↓ FASactivity (-30%); no -34%), SREBP-1c ( -30%), SREBP-1c ( ≈ FASactivity (-35%); no -26%)concentrations; ≈ ≈ -32%) concentrations; -33%)concentrations; ≈ -20%) levels; 14 14 14 ≈ 14 C]glucose (-24%, C]glucose (+27%, C]glucose (-50%) -25%), FAS ( FAS -25%), C CoA C CoA ≈ -27%) and ↓ FFA (-14%) (-14%) FFA ≈ ≈ -29%), -27%), ↓ ME ≈ ≈ - - ≈ - ↓ ↓ ME

↓ ↓

↓

(Lin etal., 2008) (Linand Yin, 2008) 2007) Augusti, and (Kumari (Hsu et al., 2004) (Lin etal., 2004) (Clarke et al., 1977) (Allmann and Gibson, 1965) 19 Page 186of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 187of267 Methyl linoleateMethyl Methyl linoleateMethyl Linseed oil (ALA- n-3 long-chain PUFA Omega-3 fatty acids Omega-3 fatty acids ester ethyl EPA Triolein 3-thia-TODT Methyl Arachidonic acid linoleateEthyl (C18:2) (C18:2) oleate (C18:1) vs linolenate (C18:3) rich) rich) 0.9/1.5) (EPA/DHA, estersethyl (from fish oil) (from fish oil) (C18:2) palmitate (C16:0) methyl methyl

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), vs vs methyl methyl methyl methyl Mice fedhigh-carbohydrate and fat-free diet for Rat hepatocytesincubated with [1- Rats fed aconventional pelleted chow diet and Rats fed liquid ethanol (50 g/L) and fat-free diet Leptin-deficient B6.V- Leptin-deficient Male and female hamsters fed high-fat diet Patients with NAFLD Mice fed fat-free and high-carbohydrate diet Leptin-deficient Leptin-deficient Transgenic mice fedlow carbohydrate (4.25%) Rats fed fat-free and high-glucose (72%) Rats fed for diet fat-free and high-glucose (72%) fed diet Rats fat-freeand high-glucose (72%) fed diet Rats fat-freeand high-glucose high-carbohydrate andfat-free diet injected palmitic acid (control) (12.5% butter + 2.5% sunflower oil:control) sunflower +2.5% (12.5% butter and high-protein (71%) diet with 7 days then supplemented with PUFA, injected 19 days, then chow 3 H 2 535-590. DOI :10.1080/10408398.2010.549596 O and killed 20 min after injection ob/ob ± PUFA for 10 days days 10 for PUFA Comment citercedocument : mice (obesity model) fed Lep ob mice fed standard 14

C]oleic acid acid C]oleic diet3% of 15.4 % of diet 1 g 600 2.4 g/kg b.w. 2.4 g/kg b.w. 15% triolein+5% 10%diet of Ratio methyl 3- 150 mg/kg b.w. 1 g/L diet5% of Resp. 3%

cholesterol) cholesterol) water+0.027% d with 1.6% (complemente i.v.) vs tuna fish oil EPA or 20% 2.5:1 TODT:BSA = thia- intubation) (gastric μ 7% L (oral or or L (oral vs 3%

7 weeks 12 months 19 days 30 days 10 days 7 days 17 days 4 hours 10 days 30 days 1, 2, 3 or 4 7 days 7 days For Peer Review Only Review Peer For days URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] ↓ Males SREBP-mediated suppression of FAS promoter Linoleate Palmitate Linolenate Palmitate Linoleate Had only minormicro-vesicular steatosis No difference in fat percentage ↑ ↓ ↓ ↓ ↓ ↑ ↑ ↑ ↑ ↓ ↓ ↓ ↓ Females Suppress expression of SREBP-1-target lipogenic genes (FAS and Oleate Induced expression of PPAR

Dopler perfusion index (inversely associated with histological ( oxidation FA 2,4-dienoyl-CoA of CPT-II (+69%), mRNA levels relative CPT (+66%), 2,4-dienoyl-CoA reductase (+18%), ACO (+200%), mitochondrial (+37% with palmito

SREBP-1 nuclear form expression ( FAS (resp. 0, -19%, NS,-44 and -56%) and ACC (resp. -11%, NS, FA synthesis (resp. 0, -25, 41 and -59%) fat content (resp. -70 and -62%) fat percentage (-41%, magnetic resonance spectroscopy) and only (resp. TG PL contents NS)and (-3%, (-10%, (-42%), cholesterol TG TGPL(-5%, (-83%), NS) and levels CE (-95%) fat (-63%), macrovesicular steatosis (-10%,digital image analysis with palmitoyl- Acyl-CoA:CAT (-33%)Acyl-CoA:CAT activities absence/mild/moderate/severe) with no or steatosis of various degrees: 0/19/45.3/35.7 to 23.8/33.3/28.6.4/14.3 (percentage of subjects SCD1)and of S G6PDH (0%) and ME (+3%, NS) activities activities ME(+3%, (0%)and NS) G6PDH contents and [U- oxidation 16%) contents ; no effect on PLcontent 14 ↓ and rate of FA synthesis from [U- grade of fatty liver, +62%): reductase (+191%) and ACO (+72%) and (+29%)CTPpct activities; and +78%in mitochondrial fra acyl-transferase glycerophosphate activities, and and -11%, NS, -39 and -57%) activities slight macrovesicular steatosis (histological observations) NS) contents FAS activity (-20%, NS) and rate of FA synthesis from [U- C]glucose (-18%, NS) 14 : ↓ ↓ : C]glucose (-24%, NS) and

↓ rate of FA synthesis from rate of FA synthesis from ↓

: TC (-25%), FC (-13%), CE(-26%) and TG(-20%)

FAS (-38%), G6PDH (-39%) and ME (-31%) activities, : : : : ↑

PL content (+3%) ; no effect on TC, FC, CEand TG : ↑ ↑ ↓ ↓ ≈

FAS (+6%, NS), GPDH (+30%) ME(+17%,NS) FAS(+6%,NS),GPDH(+30%) and andME G6PDH(+15%, NS) (+8%, NS) activities, and ↓ FAS (-50%), GPDH (-64%) and ME (-48%) activities, FAS activity (-13%, NS) and rate of FA synthesis from

-26 and FAS (-63%), GPDH (-69%) and ME(-57%) activities, (-63%), and FAS (-69%) GPDH ≈ ↑ +142%) rate of FA synthesis from L 14 Critical ReviewsinFoodScienceandNutrition -carnitine as substrate) and peroxisomal gene ≈

-44%) and TC(resp. α ↓ and ACO

degree of steatosis from ction), Acyl-CoA:DGAT(+190%) ↓ 3 3 3

H H HMG-CoA reductase (-80%) and and (-80%) reductase HMG-CoA H

14 2 2 2 yl-CoA yl-CoA as substrate and+35% (+137% inmicrosomalfraction O (-60%) (-60%) O (-54%) O ≈ O (-6%, NS); no effect on C]glucose (-26%) and

3-fold lower) 3-fold ≈ 3 H

-11%, NSand 2 O (+8%, NS)

β 3 ≈ H -

-15%, 2 O (- (Morise etal., 2006) (Capanni et al., 2006) etal.,2005b) (Alwayn (Alwayn et al.,2005a) (Sekiya et al., 2003) (Moon etal., 2002) 1997) al., et (Willumsen (Goheen et al., 1983) (Toussant et al., 1981) 20 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 LA (18:2 n-6), DPA Linseed oil (ALA- DPA andDHA EPA, PUFA PUFA SCFA Propionate Short-chain fatty DHA (22:6 n-3) (20:5 n-3) and (18:3 n-3), EPA 20:4 n-6), ALA 18:1 n-9), AA 22:5 n-6), OA rich) acids

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Wild-type (WT) and PPAR (WT)and Wild-type db Subjectswith non-invasive diagnosisNAFLD of Rats fed ethanol diet containing 0.3% 18:2n-6

Liver cells frommale ra Liver HepG2 cells Isolated liver cells from rats fedstandard chow obese symptoms) fed high-sucrose (46%) diet 0.3%18:3n-3 and incubated with[1- sunflower oil:control) female mice fed high-fat diet (13% butter +4% 14 / C]mevalonate (1 mM) and diet and incubated with db mice hyperlipidemic, (with diabetic and 535-590. DOI :10.1080/10408398.2010.549596

Comment citercedocument : 14 C]acetate (5 mM) and [2- ts standard fed chow

3 α H -null (KO) male and 2 3 O and O and H 2 O (2 mCi)

14 C-labelled

1.2 mM 0.1-25 mM 6, 60 or 120 120 or 60 6, 15.4 % of diet diet1% of twice 1 g 0.5% 20:4n-6

(propionate cholesterol) cholesterol) 0.027% water + d with 1.6% (complemente (DHA) 0.5% 22:6n-3 and (AA) μ M

hours 21 5 weeks 4 weeks 6 months 9 weeks 30 min 60 min For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Male KO DHA Male WT AA Female KO DPA OA

DHA ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↓ Propionate ALA EPA LA Female WT EPA andDPA EPA

TC (resp. TC +21%, NS, +9%, andNS +22%, NS) and (resp.PL TG content (resp. -14%, NS,-42% and -61%) degree of steatosis from 0/0/39/61 to 33.4/22.2/44.4/0 (percentage ( TG liver histology score ( dose-dependently cholesterol (from-1%, NS, to -40%) synthesis dose-dependently cholesterol (from-16%, NS, to -61%) synthesis dose-dependently cholesterol (from-3%, NS, to -58%) and FA peroxisomal effects on other enzymes; SREBP1c and SREBP2 expressions mRNAlevels ACC, of FAS and ACO; concentration ( (+32%); ACO,and CPTand ACO activities; mRNA levels of FAS, and SREBP-1ACC2 and PAPactivities, and had nosignificant effect onrelative and ACO activities; ACO and concentrations, mRNA levels of ACC, FAS and CPT1, and CPT no effect on PPAR ↓ L expressions NS, for NS) no effect on ACO activity; SREBP1c expression (+80%) (+80%) expression SREBP1c +6%, NS, +10%, NSand +12%, NS) contents no effect on CPT and ACO activities; noeffect on PPAR SREBP2 expressions; 68%) +98%) and noeffecton PPAR+98%) concentrations, mRNA levels of fat contentfrom absence/mild/moderate/severe) of subjects with no or steatosis of various degrees: from [2- from from from -93%) [1- synthesis NS,to -3%, (from mRNA level of -FABP, ACC, and FAS ACO; : : :

↓ ↓ ↓ : : : : : SRE-luciferase activity (resp. SRE-luciferase activity (resp. SRE-luciferase activity (resp.

↓

↓ ≈ ↓ SRE-luciferase activity (resp. ↑ ↓ -29%) and cholesterol ( SRE-luciferase activity (resp. SRE-luciferase activity (resp. 3

FAS (-40%) andME (-32%) activities and no significant and H

: no effect onTGconcentration,

: nosignificant effect onTGand cholesterol β 2 14 O; no change forFA synthesis : ↑ -HB and -7%,NS,for acetoacetate) concentrations; C]mevalonate; no change for FA synthesis :

PPAR : nosignificant effect onTG and cholesterol ↓ ↓

↓ SRE-luciferase activity (resp.

intracellular citrate (-20%) TG ( TG

: no significant effect onFAS, ME, CPTand β -oxidation (in mitochondria and liver homogenate), ≈ -20%); no significant effecton mRNA levels of

Critical ReviewsinFoodScienceandNutrition α ≈ ≈

-49%) and cholesterol (

51-75% to expression (+61%) and no effect onPPAR α -FABP (-58%) and CPT1 (-66%), no effect on

, ↑ mRNA levels of of levels mRNA ≈ PPAR -54%), -54%), ↓ PPAR ↓

ACC2 relative mRNA level (-57%) (-57%) mRNAlevel ACC2relative ↑ γ SREBP1c expression (+133%) and

≈ and ≈

-25%) levels

i.e. γ >25% γ expression (-99%) and and (-99%) expression

, SREBP1c and SREBP2 ↓

L mRNA level ofCPT1 (-36%);

SREBP2 expressions expressions SREBP2 ↓ -FABP, ACC, FAS,CPT1and ≈ ≈ ≈

hepatocellular vacuolation and -55, -55, -55, NS, -4%, ≈ ≈ ≈

-55, ↑ -12%, NS, -19%, NS, PPAR and ketone body (-25%, L

↓ -FABP (+41%) and ACO ↓ CPT activity (-12%) and ≈ ≈ cholesterol cholesterol -80 and -84 and ≈ ≈ ≈ -86 and and -86 +7%, NS, -10%) concentrations;

14 α C]acetate

≈

expression ( expression -30 and ≈ ≈ -55 and -67 and ≈ ≈ -70%) -80%) ≈ -84%) -84%) ≈ -67 and and -67 ↑

≈

-20%, α ≈ ≈ ≈ and

-64%)

-59%)

↓ γ

, FA FA ≈ - (Di Nunzio et al., 2010) (Morise etal., 2009) al., 2009) et (Gotoh etal.,2008) (Spadaro (Song et al., 2008) (Demigné et al., 1995) etal., (Wright 1990)

21 Page 188of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 189of267 Acetic acid Propionate SCFA mixture eaoi Melatonin Melatonin Melatonin bacteria) producedcecal by productsSBF of fermentation simulating and butyric acids acetic, propionic sodium salts of

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Mink ( Rats fed high-cholesterol (1% +0.5% bile salts) Rats fed fibre-free and sucrose-based or sugar fed orsugar Rats sucrose-based fibre-free and Hepatocytes isolated from Zucker HepG2 cells transfected with a negative-control Mice fed high-fat (27.1%) diet Liver slices fromrats fed 14 days sucrose-based

diet human number 1siRNA or validated siRNAs targeting from carbohydrates coming from fat, 46% from proteins and 21% beet fibre (10%) diets andi.v.injected the last day (10%) and incubated with acetate (2mM) or[1- and 0.6mM)and treated (10% of diet) Zucker rats (resp.0.3 concentrations foundin portal veinfructan- of and with propionate at higher and mean diet ( of glucose, glutamine and acetate substrates innear-physiological concentration control diet, and incubated with [1- Mustela vison

≈ α 535-590. DOI :10.1080/10408398.2010.549596 65%) or sugar beet fiber-base diet 2 (catalytic subunit) AMPK

Comment citercedocument : ) fed diet with 33% energy energy 33% with ) fed diet 14 C]-palmitate (0.2 mM) 3 H 2 O fa/fa

14 ratsfed C]- 3 H 2 O

100, 200 or 500 0.31.5% or 0.6mM and 0.3 3.5% acetate, Subcutaneous 12.5 mg/kg b.w. 10 μ tube via administered mL/kg b.w. solution at 10 diet (14days) butyrate in rat 9% and propionate 2.2% (acetate) 2mMand butyrate) and implant, 2.7-mg i.p.

M μ astomach g daily i.e.

≈

≈ 3 hours 42 days 180 min 14 days 1.5 hours 30 days 4 months

2-3 months For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Females Acetate Propionate + acetate Males Propionate + butyrate Butyrate

↓ ↑ ↑ ↓ ↓ ↓ ↓ ↑

No change in HepG2 cells transfected with a validated siRNAs

cholesterol level (-21%) PPAR PPAR

TG (resp. -15 and -17%) and TCcontents (resp. -13 and -14%) TL (intracellular +extracellular) synthesis (resp. -30%,NS, andcholesterol synthesis rate cholesterol synthesis rate cholesterol synthesis rate β NS, for 30%) 0.73-and 0.79-fold, NS) from from NS) synthesis from synthesis NS) NS, 51-70% for 0.3-2.5 mM acetate/0.6 mM propionate and NS) contents; no change in polar lipid content (+0.3%, NS); concentrations; 1-[ 65%) and FFA (-10%, NS) contents; targeting human negative-control 1.85-fold) mRNA levels in HepG2 cells transfected with a FA synthesis ( lipase esterase activity (-1%, NS) body (0% for ( 70% for 0.3-2.5 mM acetate/1.2 mM propionate) and cholesterol ( 1-[ 55% for 0.3-2.5 mM acetate/1.2 mM propionate) synthesis from (+200% for (+200% ( 35%); no effect on TG synthesis mRNA level/expression; 1.03-fold, NS) mRNAlevels/expression; no effectSREBP-1on fold), CPT-1 (resp. 1.42- and 1.28-fold) and ACC (resp. 1.03- and ≈ ≈ ≈ -HB and-HB +121% for acetoacetate) concentrations -36%) -27-64% for 0.3-2.5 mM acetate/0.6 mM propionate and -55%) and cholesterol ( 14 14 : C]butyrate C]acetate; noinhibition of FAand cholesterol synthesis from ≈

3 ↓ 1.65- and and 1.65- : α α H : polar lipid (-3%, NS), cholesterol (-5%, NS), TG levels ( : ↑

↓ (resp. (resp. 1.15- and 1.16-fold), ACO (resp. 1.78- and 1.60- β intracellular citrate (+19%,NS)and ketone body (+25%, 2 ↑

cholesterol (-29%), TGlevels (

intracellular citrate (+89%) and ketone body (+275% for -HB and +14%, NS, for acetoacetate) concentrations β

-HB and +93% for acetoacetate) concentrations; ≈ β ≈

-HB and-HB -14%, NS, for acetoacetate) 1.45-, +18%, NS) and ≈ ↓

Critical ReviewsinFoodScienceandNutrition

α (resp. CPT-1 and 1.9-fold) FA ( 2 AMPK :

↓ : 3

H ↑ intracellular citrate (-2%, NS)and ketone ≈

≈ intracellular citrate (-80%) and ketone body body ketone and (-80%) citrate intracellular 2

-50%)andcholesterol ( 1.7- and O vs vs vs ↓ ≈ mRNA level/expression of FAS (resp. (resp. ofFAS mRNA level/expression

-30%) synthesis from fibre-free diet or sugar beet fibre diet sugar beetfibre diet ( fibre-free diet ( ≈ ↓

1.65-fold), ACO (resp.

cholesterol synthesis( ↓ lipase esterase activity (- - 87%) and FFA (-25%, ≈ +60%, NS) ≈

1.4-, ≈

-30%) synthesis 3 ≈ H -14%, NS) ≈

2 1.6- and O; ≈ ↓ ≈

-12%, -12%, FA ( FA ≈

1.2-, -62- ≈ ≈ ↓ -33-

≈

↑ -

- (Nieminenal., et 2001) Tang, 1995) and (Chan (Kondo et al., 2009) etal., 2009) (Kondo (Daubioul etal., 2002) (Hara et al., 1999) 22 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 f e d c b interpretations relevant a

Mixture of high-molecular-mass aliphated alcohols isolated and purified from sugar cane wax (main component is octacosanol foll octacosanol is component (main wax cane sugar from purified and isolated alcohols aliphated high-molecular-mass of Mixture

Contains 23.3% of 23.3% Contains in reference the No data given Allterms used in the Table are preciselythose of the article considered: for exemple,the hepatic content in TG was named “co Kyolicis an agedgarlic extract containing tothe control, compared lipotrope by the induced percentage increased or thedecreased Indicates

γ α

ooreos d Tocotrienols Melatonin Melatonin Melatonin Melatonin Melatonin Para Para Policosanol or Policosanol Policosanol Policosanol Tocotrienols (isolated Tocotrienols

-tocotrienols

- -tocotrienols α acid acid geraniol distillate) from palm oil FA -tocotrienol -aminobenzoic -aminobenzoic

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), g f

α -tocotrienol, 50.8 of 50.8 -tocotrienol, Man 2 g 4 times 2g4 Man Mice fed high-fat (34.9%) diet Rats fed high-fat diet pellets standard fed Rats Rats fed high-cholesterol (2%) diet Mice fed high-cholesterol (1.5% + 0.5% cholic HepG2 cells incubated with [2- HepG2 cells HepG2 cells incubated with [2- Hamsters fed high-fat (20% corn oil) diet for 45 Male guinea pigs efd with standard pellets HepG2 cells incubated with [2- White Leghorn cockerels fed commercial diet for Broiler cockerels fed commercial diet for 21 Mice fed for 7 days control diet and i.v. injected Rabbits fed27%-casein diet Liver microsomes diet standard fed Rats acid) diet isolation ofmicrosomal membranes 3 days (refeeding period) before killing 4 weeks, then fasted 2 days andinjected i.p.for days, then fasted 2 days and refed for 3 days with Triton WR1339 (hypercholesterolaemic diet)

days γ -tocotrienol, 24.6% of of 24.6% -tocotrienol, s 535-590. DOI :10.1080/10408398.2010.549596 -allyl cysteine, Comment citercedocument : s h -ethyl cysteine and

3hoursbefore killing δ -tocotrienol, 0.2% 0.2% -tocotrienol, 14 14 14 C]acetate, then C]acetate C]acetate

-propyl cysteine cysteine -propyl α -tocopherol and1.1% of 10 mg/kg i.p. 10 and 50 mg/kg 1.0 and 0.5 2.5,and 5 10 10 mg/L of 10 or 67 mg/kg 50 mg/kg b.w. 5 or 505 or 500 mg/kg b.w. 10 mg i.p. 5, 8ormg 10 From 0.5to From 3to 300 10 From 0.3to 30 From 5to 25 mg to From 0.00025

i.e.

μ μ injected i.p. b.w.injected injected i.p. mg/kg b.w. injected mg/kg i.p. drinking water b.w. tocopherol 11 injected i.p. 0.002% of diet mg mg steatogen diet (NS - Not Significant - means absence of significativity for the change observed; in other cases, the effect w the effect cases, other in observed; the change for of significativity absence means - Significant Not (NS- diet steatogen μ M M

μ α

M μ -

g/mL γ ± -tocopherol -tocopherol 5 ≈

10-

12 weeks 8 weeks 45 days 12 weeks 7 days 30 days 60 min 4 weeks 6 last days 6 days 4hours 2 or hours 16 4 hours 4hours 2 or 3 days + 3days21

≈

5 days ntent”, “concentration” or “level”, and in some case no term was used; studies reporting both lipotrope-like and non-lipotropic and lipotrope-like both reporting studies used; term was case no in and orsome “level”, “concentration” ntent”, Only Review Peer For owed by triacontanol and hexacosanol; other alcohols – tetracosanol, heptacosanol, nonacosanol, dodriacontanol and tetratriacon and dodriacontanol nonacosanol, heptacosanol, tetracosanol, – alcohols other hexacosanol; and triacontanol by owed URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↓ ↓ ↓ ↓ ↓

No significant effect on HMG-CoA reductase activity

Histological analyses ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓

dose-dependently cholesterol synthesis (resp. HMG-CoA reductase protein level ( dose-dependently HMG-CoA reductase activity ( dose-dependently cholesterol synthesis (resp.

eu hlseo ee -2) (Failey and Childress, 1962) serum cholesterol level (-12%) newly synthesized cholesterol (resp. -24 and -28%) cholesterol biosynthesisfrom cholesterol biosynthesisfrom HMG-CoA reductase activity (-48 and -13%, NS, with HMG-CoA reductase activity (resp. -50, -30and -8%)

steatohepatitis and markers of oxidative stress cholesterol (resp. TC (resp. TG and -7%, NS,-17 (resp.-9%, and-28%) NS, -9%, cholesterol ( HMG-CoA reductase (from -7%, NS, to -319%) and cholesterol (from cholesterol reductase and NS, to-34%) HMG-CoA -13%, mean histological grade for steatosis from the highest level (with 6

protein level ( μ (resp. activity (from+4%, NS, to +26%) grade I for 10 mgmelatonin injected/kg) 8rats at lowest (with the to diet) IVfor high-fat rats atgrade tocopherol) (from +18%, +40%)(fromNS, to +18%, inhibition at 300 inhibition at 30 NS, and -17%) contents 7 7

α M) α -hydroxylase (from -11%, NS, to -37%) activities; (from -7%, activities; NS,to-22%) -hydroxylase

≈

-57 and -58%) and FFA (resp. ≈

-63%) and TG levels ( ≈

+75%) μ Critical ReviewsinFoodScienceandNutrition

≈ μ M)

-71 and -71%), and PL-71 (resp. M) : ameliorates liver steatosis 3 3 H H 2 2 O ( O (-26%) ≈ ≈ ≈ -35%) -35%)

-48%) -75%) andLDL receptor

≈

-34 and -36%) levels

≈

-36 and -37%), TG ≈ ≈ - - 41 and 71 and ≈

-74% at ↑

↑ FAS activityFAS

α FAS FAS ≈ ≈ - - - 58% 81% ≈

10-11 as either significant or no information was given in the article) article) the in given was information no or significant as either (Shieh etal., 2009) (Kuzu et al., 2007) (Subramanian etal., 2007) al.,(Pan et2006) (Sener etal., 2004) (Wu et al., 2005) (Wu etal., 2005) (Menendez et al., 1997) (Menendez et al., 1996)

(Khorand Ng, 2000) (Khor et al., 1995) (Parker et al.,1993) (Qureshi et al.,1986) effects ( effects tanol - are minor components) components) minor are - tanol i.e. an increase in hepatic lipid content and/or lipogenic enzyme activities) are alsopresented to allow compa 23 r Page 190of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 191of267 ABBREVIATIONS carn (induces TrimethylHydraziniumPropionate THP, TriGlyceride; TG, Cholesterol; Total TC, Proteins; Element-Binding Regulatory (c Desaturase Stearoly-CoA SCD, acid); (5-(tetradecyloxy)-2-furoic 14,514, RMI Acid; Fatty Poly-Unsaturated PUFA, lipogenesis); esterification inglycerolipid (involved AcylTransferase Glycerol-3-Phosphate mitochondrial mtGPAT, Acid; RiboNucleic messenger MethylGlutaryl Coenzyme A reductase; IC Cholestero FC,Free hepatocytes); into lipids of intransfer involved protein FAT(membrane as known 36 also of Differentiation DocosaHexaenoic Acid; synthesis); DHA, biosynt acid in fatty step animportant Lyase, (or ATP-Citrate Enzyme Cleavage Citrate CCE/ATPCL, weight; body b.w., Albumine; h g Geraniol is a monoterpenoid alcohol Triton WR1339 induces hyperlipidemia by inhibiting lipoprotein lipase and thus preventing catabolism of TG-rich lipoproteins lipoproteins of TG-rich catabolism thus and preventing lipase lipoprotein by inhibiting hyperlipidemia induces WR1339 Triton

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), : AA, Arachidonic Acid; ACC, Acetyl CoA Carboxylase; ACO, Acyl-CoA Oxidase inlong (involved chainoxidation: AA, CoA Carboxylase; ACO, FA ArachidonicAcyl-CoA inACC, Acid; Acetyl peroxisomes) 50 535-590. DOI :10.1080/10408398.2010.549596 DPA, DocosaPentaenoic Acid; DocosaPentaenoic DPA, d.w.b., dry weig , concentration required for 50% maximal inhibition; i.p., intraperitoneally; i.v., intravaneously; LA, Linoleic Acid; LDL, Low Acid; LA, Linoleic i.v.,intravaneously; intraperitoneally; i.p., inhibition; 50%maximal for required , concentration Comment citercedocument :

ht basis; EPA, EicosaPentaenoic Acid; FABP For Peer Review Only Review Peer For l; FA, Fatty Acids; FFA, Free Fatty Acids; l; FA,Fatty Acids; Acids;Free Fatty FFA, atalyzes the rate-limiting step in the biosynthesis of monounsaturated FA and itsdeficiency increases fatty acid oxidation by ); NAFLD, Non-Alcohol Fatty Liver Disease; NS, Not Significant; OA, Oleic Acid; PL, PhosphoLipid; resp., respectively; POE/S, POE/S, respectively; resp., PhosphoLipid; PL, Acid; OA, Oleic Significant; Not NS, Disease; Liver Fatty Non-Alcohol NAFLD, ); itine deficiency); TL, Total Lipids; TODT, ThiaOctaDeca-6,9,12,15-Tetraenoate; TPN, Total Parenteral Nutrition; VLDL, Very Low- Very VLDL, Nutrition; Parenteral Total TPN, ThiaOctaDeca-6,9,12,15-Tetraenoate; TODT, Lipids; Total TL, deficiency); itine pm/L-FABP, Fatty Acid Binding Protein plasma membrane (small protein involved in the intracellular transport of long-chain fatt long-chain of transport intracellular the in involved protein (small membrane plasma Protein Binding Acid Fatty pm/L-FABP, hesis; CCl URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 4 , Carbon tetraChloride; CE, Cholesteryl Esters; CoA, Coenzyme A; CPT, Carnitine Palmitoyl Transferase; CTPpct, CTP:phosphocholi CTPpct, Transferase; Palmitoyl Carnitine A; CPT, Coenzyme CoA, Esters; Cholesteryl CE, tetraChloride; , Carbon ; AIN, American Institute of Nutrition; ALA, Alpha-Linolenic Acid; AMPK, AMP-activated protein Kinase (key enzyme relative to e relative (keyenzyme Kinase protein AMP-activated AMPK, Acid; ALA, Alpha-Linolenic ofNutrition; Institute American ; AIN, Critical ReviewsinFoodScienceandNutrition

-Density Lipoprotein; LDLR, Low-Density Lipoprotein Receptor (involved in transfer of lipids into hepatocytes); LPL, LipoProtei LPL, ofinto hepatocytes); lipids in transfer (involved Receptor Lipoprotein Low-Density LDLR, Lipoprotein; -Density β

-HB, β -hydroxybutyrate; HCA, HydroxyCitric Acid; HCl,HydroChloric acid; HDL, High-Density Lipoprotein; HF, Hydrogenated Fat; HFE/S, activating hepatic AMP-activated protein kinase); SCFA, Short-Chain Fatty Acid; SRE, Sterol Regulatory Elemen Regulatory Sterol SRE, Acid; Fatty Short-Chain SCFA, kinase); protein AMP-activated hepatic activating Peanut Oil Exercise/Sedentary; PPAR, Peroxisone Proliferator-Activated Receptor (transcription factorof y acids in the liver and regarded as a sensitive marker for liver cell damage); FAS, Fatty Acid Synthase; F Synthase; Acid Fatty FAS, damage); cell liver for marker asensitive as regarded and liver the in yacids Density Lipoprotein Lipoprotein Density ne cytidylyltransferase (involved in PL synthesis); DGAT, DiAcylGlycerol Transferas in PL DGAT,DiAcylGlycerol (involved synthesis); ne cytidylyltransferase nergy adjustment in the cells and sensor of fuel level); ApoB, Apolipoprotein B; BSB; Apolipoprotein ApoB, level); offuel andsensor cells in the adjustment nergy n Lipase (involved in transfer of lipids into hepatocytes); ME, Malic Malic ME, hepatocytes); into lipids of transfer in (involved nLipase High-Fat Exercise/Sedentary; HMG-CoA reducta 24 A g E s A e 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Supplemental Table 3 Table Supplemental Wheat bran (GMD: pectin Citrus Particulate (alfalfa, Methylcellulose (low, Neutral detergent pectin Citrus Neutral detergent Cellulose, lignin or Alfalfa, cellulose or Cellulose (from citrus), Pectin Fibre compounds Lipotropic Metamucil gum fiber (guar or soluble/noionic and (pectin) soluble/ionic bran), wheatcellulose or and HV) viscosity: LV, MV medium and high bran) wheat fiber (from (purified) blackgram) fiber (from pectin lignin and agar acacia powder) gum arabic (from

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

® ) Exp. 1 - liver slices from rats injected i.p. 3 hours - liver slices incubated with [U- diet: fibre-free feda and 11%-fat Rats diet 0.5%cholesterol fat and fed10% Rats diet 1%cholesterol fat and fed10% Rats adequate fat fed10% dietcontaining Rats Rats fed high-sucrose (49%) diet containing 5% diet fiber-free fed Rats diet fed a14%-fat Rats Rats fed sucrose-based diet Rats fed diets with various contents in fedstandardRats dietcontaining 14%cellulose In vivo In Exp. 2

In vivo zinc marginal or abundant (0.12% of diet) dietary amount of dietary copper with either and protein (P: 9-37%), (L: 9-19%) lipid (C:40-60%), carbohydrate cholesterol dietwithcellulose 0% [ then fed once a day the diet for 9 days with cholesterol dietwithcellulose 0%for 14days before killing with 1 mL of [1,2- mM (5 acetate 50mM (5 14 C]glucose in the last meal before killing : Rats fed fed : Rats : Rats fed once a day a 10%-fat and 0.2%- or 535-590. DOI :10.1080/10408398.2010.549596

in vitro in μ and Ci) ad libitum models ex vivoex

Comment citercedocument : μ Ci)

studiesreporting effectsonhepaticlipid metabolismfollowing a 10%-fat and 0.2%- i.e. n = 32 dietsn = 14 C]glucose 10 14

C]Na- daily dose Supplemented 5, 7.5 or 10%of 1, 3, 6 or 10% of 5 (pectin and 8% ofdiet 0-14%diet of 10% ofdiet 30% ofdiet 5% ofdiet 5% ofdiet 16%8 or of diet 5.0% ofdiet 5.0% ofdiet

diet diet ofMetamucil) fiber and (particulate 10% guar gum)or

exposition lipotrope Duration of 6 weeks 10 days 28 days 5 weeks 1 month 28 days 28 days 23 days 14 days days 26 days 28 9 weeks For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Marginal zinc content

- 44%C, 11%L and from 37.01 to 27.31%P From 2.83 to 11.17% fiber, fiber, to11.17% From 2.83 Fine beetfiber Hepatic effect(s) ↓ ↓ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↓ ↑ ↑ ↓

MV and HV - from 44to 56%C, from 17 to 11%L and from 15.31 to 31.01%P Pectin Alfalfa - 56%C, 17%L and from 19.01 to 9.31%P Cellulose Cellulose Lignin Lignin Abundant zinc content

cholesterol (resp. (resp. cholesterol and PE(resp. -11, 0, -10, -14, -11 and -6%) and Sph (resp. -53, -23, - PCcontent (resp. +25, +8,+10, +24, +13 and +11%) PLcontent (resp. 0, -27, -5, 0, 0 and -11%) and cholesterol content (resp. +20, +16, 0, +20, +14 and +23%) incorporation of[1,2- incorporation of[U- TL (-68%) and TC (-63%) contents cholesterol concentration (-9%); cholesterol (resp. -49, -6%, NS, and +8%, NS) and long-chain FA cholesterol (resp. -14,-5%, and-3%,NS, NS) lipogenesis (resp. -59, -29, NS, and -18%, NS) (resp. -34, -36 and -23%, NS) -23%, -36 and levels; -34, (resp. concentrations and TG (-24%) contents and +13%) and lipid (resp. -16 and +1%) concentration ↑ HMG-CoA/mevalonate ratio by 36%) ↓ 15%) contents 6%) and 20, -39, -25 and -26%) contents (resp. -20,-11%, NS,and -20%) levels NS) and TG (resp. (+15%) contents synthesis and on cholesterol concentration 11%, NS) compared to LV; noeffect onrate of cholesterol NS, and-55%, NS); NS, contents -5, 0, +17, -3, +8 and +4%) contents and -5%) and lipid (resp. -13 and -17%) concentration

cholesterol (+14%) and TG (+9%) contents (-85%) content TG ↓ ↓ : LPC (resp. -8, +3, +7, -15, TG content (resp. +23, -5,+8, -2,-32 and -26%) : : no significant effect onTC (-19%) and FC (-1%) contents;

: nosignificant effecton TC (-3%), FC (+2%) and TG (- ↓ ↓

TC (-75%), FC (-27%, NS) andTG(-58%) contents

TC (-66%), FC(-18%, NS) and TG (-18%, NS) contents : : no significant effect on TC (+15%), FC(+8%) and TG ↓

TC (-30%, NS), FC (-22%, NS) (-36%, NS),FC TG TC (-30%, and ↑ : TG content(+47%) ↓ :

rate of FA synthesis compared to LV (resp. -22%, ↓

TG (resp. -20, -34 and -37%) cholesterol -34 and and -20, (resp. TG supplementation of soluble andinsoluble fiber, phytic acid an Critical ReviewsinFoodScienceandNutrition ≈ -7%, NS, -7%, 14 : nosignficant effect ≈ : nosignficant effect oncholesterol (resp. +8 -23%, -23%, NS, C]glucose into cholesterol (+80%) 14 ↓ C]Na-acetate into cholesterol (+258%)

TG concentration (resp. -14%, NS, and - i.e. ≈ +8.34% of fiber

-9%, NS, ↑ +8 and +15%) and PI+PS (resp. ≈ HMG-CoA reductase HMG-CoA (

-41, ≈ ↓

≈ -59 and [ :

14 -11%, NS, and and NS, -11%, on cholesterol (resp. -7 -7 (resp. cholesterol on : ↓ C]long-chain FA, FA, C]long-chain

↓ cholesterol content (-

cholesterol (-14%) b and long-chain FA long-chain and ≈

-73%) ≈ i.e.

-13%,

i.e. ↓

: (Klopfenstein, 1990) Horii, 1989) and (Ide (Kritchevsky et al.,1988) (Topping et al., 1988) (Stewart et al., 1987) (Rotenberg and Eggum, 1986) (Thomas etal., 1983) etal., (Story 1981) (Looney and Lei, 1978) (Kelley andTsai, 1978) References

d oligosaccharides a

25 Page 192of267

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 193of267 Psyllium husks β Dietary fiber Psyllium and pectin Cellulose, guargum, Guar gum bran,oatRice bran, Oat bran Prune fiber or pectin gum, guar bran, Oat Wheat bran, psyllium Fiber from defatted Guar gum or psyllium Pectin, Oatbran, pectin or -glucan concentrate concentrate -glucan

492 (436 (436 complex arabic mannan or gum pectin, konjac or psyllium xylan cellulose or husk or oatbran wheat oat, barley or oat bran psyllium fiber beet (185

μ μ m), orcoarse m) sugar m) andfine Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), d

Quails fedQuails 5% cellulose diet diet 0.3%-cholesterol and fed10%-fat Rats diet 0.3%-cholesterol and fed10%-fat Rats Mice fed standard AIN-93M diet Rats fed modified AIN-93G diet containing Rats fed AIN-76A diet containing 10% cellulose Male, female ovariectomized and guinea pigs Rats fed high-fat (15% fish oil) diet Rats and gerbils fed high-fat (40%) and 6.5% Rats fed 0.25%-cholesterol diet containing 5% Rats fed high cholesterol (1% + 0.1% cholic Rats fed high cholesterol (1% + 0.1% cholic Hamsters fed hypercholesterolemic (0.1% Rats fed basal diet containing 9.09% wheat bran, cholesterol (1% fedhypercholesterolemic Rats containingcellulose 10% containing 7.5%cellulose cellulose (GMD: 179 179 (GMD: cellulose 0.25% cholesterol cellulose diet cellulose 76dietacid)AIN acid) AIN-76 diet fat)diet and10% cholesterol 4.00% psyllium15.38%husk or oatbran 5% cellulose and 0.25% sodium cholate) diet containing tocotrienol-rich fraction (from palm oil) fed control diet control fed 535-590. DOI :10.1080/10408398.2010.549596

Comment citercedocument : μ m) ± 50 ppm of

10% ofdiet 5% ofdiet 10% ofdiet 5% + 5% of diet 10% ofdiet 6.5% ofdiet 5% ofdiet 7.5% of NSP+ 3 or 6% of diet ≈ 7.2-7.6%fiber of Resp. 1.9,2.8 5% ofdiet 10% ofdiet 7.5% ofdiet 10% of diet lignin insoluble fiber 4.4% or 3.1, 2.2 and fiber soluble 0.6 and diet

8 weeks 4 weeks 14 days 28 days 4 weeks and 15 10, 3.5, 9 days 444 or weeks 3 weeks 3 weeks 3 and 10 10 and 3 28 days 21 days - (gerbils) 21

(rats) days days (rats) 19 and Only Review Peer 18.5 months For weeks URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Rats At week 3 Soluble fiber No tocotrienol-richNo fraction Gerbils Pectin and psyllium With tocotrienol-rich fraction ↓ ↓ ↓ ↑ ↓ ↑ ↓ ↓ ↓ Coarse beet fiber 3% prunefiber

Histological observations Histological

CE TG Insoluble fiber Wheat bran(5% only) Oat bran Cholesterol 3% pectin 6% prunefiber

TC content ( content TC cholesterol content (-17%); TG -34(resp. -33%), -51, and TL (resp. -60, -36, bile acid synthesis (resp. +65, +118, +60% and no effect) TC content (resp. -21, -41 and -47%) cholesterol pool(-23%) cholesterol (-18% for oat bran, NS, -24% for guar gum, NS,and - -14%) TC and TL (resp. and (resp. -33, -24 -35%) and -68, -56 CYP7A1 activity (+45%) and mRNA level -21%); and -13%, NS); no effect on cholesterol content (resp. +1% and 29% for xylan, NS) concentration; levels (resp. +2%, NS, -14 and -27%) and levels +2%, NS, -14 (resp. 59, guar gum cellulose) concentration cholesterol level (+3%, NS) genes involved in lipid biosynthesis ( oxidation ( and 18.5 months for wheat bran and psyllium) psyllium) and bran for months wheat 18.5 and months) months) 11% for wheat, NS)concentration (resp. -3%, NS, -12% and -37%) levels -37%)levels and NS,-12% -3%, (resp. and -40%) levels -40%) and 16%, NS); and -17%, NS) and cholesterol content (resp. -6%, NS, and - and -8%for wheat, NS) concentration 29% and 24%) contents effect on CE:TC contents : no significant changes (except a slight tendency to (+5%, NS) : no significant changes (except a slight tendency to : ↓ TL (-39%), and ≈ : -38 and and -38 ↓ : TC (-47%) and FC (-10%) contents, and ↑ : : Up-regulation of genesinvolved in fattyacid ↓ TL (+12%, NS) and TC (+17%) levels ↓ : no significant changes (except a tendency to

cholesterol synthesis at 44 weeks (-18%, NS)

≈ cholesterol (-36%), CE:TC (-5%, CE:TC (-36%), NS)and (-33%)TG cholesterol : -17%, NS) contents

≈ e.g. ↑

↓ : -30%)

: :

cholesterol synthesis at44 weeks (+7%, NS) cholesterol (-31% for oat, -49% for barley, and - and -49%forbarley, for oat, (-31% cholesterol ↓ ↓ ↓ ≈

cholesterol (-4% for foroat, NS, -5% NS, barley, -36%) and cholesterol (resp. cholesterol and -36%) Critical ReviewsinFoodScienceandNutrition cholesterol (-29%), CE:TC (-11%, NS) and TG (- cholesterol (-25%) and TG (-27%) contents; no 1.6-foldfor CPT1a)and down-regulation of ↓

TG (resp. -24, -35 and -51%) and cholesterol : ↓

: TL (resp. -29 and -29%) and TC -54 TC (resp. -29%)and -29 and TL (resp. ↓ ↑

TG content (-8%, NS); noeffect on TC (-50%) and FC (0%) contents : ↓ :

size of lipid vacuoles with pectin and ↓ ↑ :

TG content (+36%, NS) lipid percentage (resp. -14%, NS,

↓

lipid percentage (resp. -28%, NS,

↑

cholesterol (+44% for for cholesterol (+44% e.g. 3.7-fold for SREBF1

≈ -30, -30,

≈ ↑ -30,

TL content ≈ -67, ↓ ↓

≈

at 18.5 at 18.5 β -65, ↓ -

≈ at 15 -49, -49, ≈ - ≈ - Heng, 2008) and (Chan (Gallaher and Plate, 2005) 2005) Tepper, and (Kritchevsky (Roy etal., 2000) Tsai,1999) (Tsai and 1995) Asp, and (Onning (Chezem etal., 1996) etal.,1994) (Jackson etal., (Tinker 1994) (Jonnalagadda et al.,1993) (Schneemanand Richter, 1993) (Oda etal., 1993) (Hood and Sidhu, 1992) (Arjmandi et al., 1992b) (Arjmandi et al., 1992a) 26 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Sodium phytate Sodium phytate Sodium phytate Sodium phytate Sodium phytate Sodium phytate Sodium phytate acidPhytic Tartary buckwheat Sugar beet fiber- Inositol

rate) 9.83% extraction removed and bran extract (oil bread based white wheat (IP6) hexakisphosphate

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

Rats fed high-sucrose (50.3%) and Rats fed high-sucrose (50.3%) and ICRAged male mice fedpurified diet with 15%

Diabetic KKmice fedpurified diet with15% Rats fed standard chow diet +0.07% DDT Rats fed high-sucrose diet fedhigh-sucrose/starchRats (65%) diet Rats fed diet with orotic acid (1.5%) Rats fed high-sucrose (65%) diet Rats fed high-sucrose (65%) diet Rats fed high-fat (10%) diet Rats fed AIN-93G diet containing 30% white wheat bread powder and 5% cellulose deficient diet +0.07% DDT deficient diet lipids lipids

535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

myo myo

-inositol- -inositol-

1.02% ofdiet 1.02% ofdiet 0.5, 1.0or 1.5% 0.5, 1.0 or 1.5% 1.02% ofdiet 0.1, 0.5 or 2.5% 0.5% ofdiet 1.03% ofdiet 0.515% of diet 0.5% ofdiet 0.2 (low), 0.5 (low), 0.2 10% ofdiet of diet of diet of diet gavage) (stomach g/kg b.w. 1.0 (high) (medium) and

6 weeks 4 weeks 14 days 14 days 12 weeks 8 weeks 14-15 days 12 days 12-13 days 8 days 13 days 29-30 days

For Peer Review Only Review Peer For

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Sucrose effectNo on LDL-receptor, HMG-CoA, SREBP-2, CYP7A1, Histology (light microscopy) (light Histology ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↓ ↓ At week 10 Starch

TL(-40%), TG (-48%) and cholesterol (-19%) levels, TL(-13%, NS), TG(-26%, NS) and cholesterol (-7%, NS) levels, TL (resp. -10, NS, -31 and -34%), TG (resp. -11, NS,-44, TG -11, and (resp. -34%), -31 NS, TL (resp. NS, -10, -31%), (resp. and TG -14,TL (resp. NS,-7, -27, -29 - NS, and lipogenic enzyme activities: ME(-40%), FAS (-58%) and TL (-36%), TG (-56%) and cholesterol (-30%) levels; no change TL (resp. -29, -42 and -50%) and TG (resp. -42, -73 and -81%) (+19%, NS) cholesterol PLand NS), TL (+16%, NS), TG(+21%, TL (-33%), TG (-82%), cholesterol (-12%) and PL(-5%, NS) NADPH,H (-13%) and TG(-75%) cholesterol TL (-52%), levels; LI (resp. -10, NS, -4, NS, and -1%, NS) TG (resp. -60, -44 and -37%) and TC(-60, -49 and 42%) levels, cholesterol content (-36%, NS) 32%, NS) activity/mg protein NS), CC (-34%, FAS NS), 24%, cholesterol synthesis pathway 1.7-fold for FAS); up-regulation of genes involved in activity (-6%, NS) and -53%) and TC (resp. -28, NS, -33 and -34%) concentrations 12%) and cholesterol (resp. -30, -23 and -22%) contents (-43%)G6PDH in PL level levels; (+4%,concentrations; NS) concentrations; and up-regulation of genes involved in lipid biosynthesis ( PE, PS, LPC and Sph percentages/total PL and for PI/PC ratio, ratio, PI/PC for and PL percentages/total Sph and LPC PS, PE, cholesterol and PLconcentrations; nosignificant change forPI, activity/mg protein; cholesterol, PL and FFA levels; cholesterol and PLcontents, no effect onplasma TG, 16%, NS) activity/mg protein 32%, NS), FAS (-38%, NS), CCE (-37%, NS) and ACC/CBX (- cholesterol synthesis pathway (between 1.5- and 1.9-fold) and 4-fold for FAS); up-regulation of genes involved in ↑ oxidation ( (+2%, NS); NS); (+2%, 25%) and 6PGD (-17%) PC percentage (+1.4%) 65%) NS, -21 and -44%) and FAS (resp. -26%, NS, -40%, NS, and - activity/mg protein; (+9%, NS) (+9%, NS) PL level (+8%); (+8%); level PL 0.032 g/kg b.w. diet with in arangesimilar tothat obta SREBP-1c and FASmRNA expressions : no change for lipid status; : ↓ TL (-51%) and TG (-84%) contents, no effect on ↓

: Down-regulation of genes involved infatty acid G6PD (resp. -8%, NS, -28 and -47%),-8%, and ME(resp. NS,-28 -8%, G6PD (resp. + -generating enzyme activities: (-31%),G6PDH ME (- e.g.

Gynostemma pantaphyllum ↓ ME (-8%, NS) and G6PDH (-12%, NS) ME(-8%, (-12%, NS) G6PDH and Critical ReviewsinFoodScienceandNutrition CPT1a, CPT2 and DCI, and 2.3-fold for PPAR for 2.3-fold and DCI, and CPT2 CPT1a, ↓

G6PD (-33%) and ME (-22%) activities activities ME(-22%) (-33%)and G6PD ↓ ME (-2%, NS) and

↓ no significant effect onserum TG, serum TG (-37%), cholesterol (-37%), and serum (-19%) TG : ↓ ↑

severity of fatty liver G6PDH activity (+51%, NS); ↓ ined byined supplementing high-fat E (-23%, ACC/CBX(- E NS) and G6PDH (-33%, NS), ME (- ↓ G6PDH (-45%, G6PDH MENS), (- total glucoside tablet at ↑ G6PDH (+5%, G6PDH NS)

↑ ↑

PL level PLlevel PL

level level e.g. β ↓ -

α ↑ )

(Wang et al., 2009b) etal.,2009b) (Wang (Nakamura etal., 2009)

(Okazaki and Katayama, 2008) (Lee et al., 2007) (Lee et al., 2005) (Okazaki et al., 2003) (Katayama, 1997a) (Katayama, 1997b) 1997) Katayama, and (Onomi (Katayama, 1995) 27 Page 194of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 195of267 Oligosaccharides Oligosaccharides Oligofructose Oligofructose Inulin (from Oligofructose Oligofructose Short-chain FOS Oligofructose Inulin Oligofructose Oligosaccharides te opud 1-Deoxynojirimycin compounds Other Fructans or celluloseFructans or (from soybean) Platycodi radix (from mulberry (from mulberry g

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), e e e e 5

) h f

Obese ZuckerObese Female mice ICR fed high-fat (40%) diet Hepatocytes from rats fed standard or diet fedstandard Rats Rats fed high-fat (14% +0.15% cholesterol) diet Sucrose-fed insulin-resistant rats (diet contains fedstandardRats dietfor then30 days received Rats fed high-sucrose and high-fat diet for 8 Rats fed high-fructose (65%) diet ZuckerObese

Hepatocytes from rats fed standard or diet fedstandard Rats Rats fed high-fat (16%) diet diet fedstandard Rats with 2 mM [1- oligofructose-supplemented diet andincubated fat) 14% and sucrose 57.5% of water for48 hours either10%fructose drinking solutiontap or (80 mg/kg) weeks, then injected i.p. with phenobarbital with 2 mM [1- oligofructose-supplemented diet andincubated chloride) 535-590. DOI :10.1080/10408398.2010.549596 7 or vehicle only(0.9% sodium fa/fa fa/fa 14 14 C]acetate C]acetate rats fed control diet diet control ratsfed diet control ratsfed Comment citercedocument :

5% ofdiet 10% ofdiet 10% ofdiet 10% ofdiet 0.5 or 1% of diet 10% offiet 10% ofdiet 10% ofdiet 10% ofdiet 10% ofdiet 10% ofdiet 10% ofdiet 1 mg/kg b.w. 150, 300 and and 300 150, b.w. 450 mg/kg (direct

45 days 56 days 4 weeks 10 weeks 8 weeks 180 min 3-5 weeks 19 days 3 weeks 32 days 180 min 30 days 4 weeks 6 (for NMR6 (for 8 weeks Only analyses) or Review Peer For

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Fructans Phenobarbital No effect on TC and PL levels Vehicle examination Histological ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ Water ↓ Cellulose No effect on TG (-1%, NS), PL(-5%, NS) and TC (-3%, NS) Fructose

TG level (-21%) level TG LI (-1%, NS, -6 and-10%) lipid droplet accumulation (histological observations) TG concentration (-28%) (-17%, FAS NS) ,ME and PAP (- (-16%), ATPCL(-26%, NS) fatty degeneration of hepatocytes (histological observations) TG (-57%) and PL(-30%) levels LI (resp. -12 and -14%); no effect onTG and TC concentrations TG synthesis from (-46%) ACC(-40%)ATPCL ME (-51%), (-45%), G6PDH and and glycerol-3-phosphate TC(-8%, (-26%),NS) PL(-12%), TG FAS activity (-32% in mU/mg protein and -36% in mU/g tissue) liver weight (-11%) TG synthesis from (-41%), NS), (- (-11%, FAS CPTI(-8%, and NS) GPAT PAP and (-23%),TC (-6%, PL(-10%) levels; TG NS) 8%) activities; acid synthesis) phosphatidate phosphohydrolase activities (key enzymes in fatty histology); no effect onFAS, ME, ATPCL/CCE and of enlarged hepatocytes with micro- andmacrovacuoles ( spectroscopy at 6 weeks) and TG (-37%, NS) contents; scarcity (+13%, NS) levels activities; levels (+58%) 11%) activities NS) and glycerol-3-phosphate (+49%) levels; PAP (-7%, NS) andCPT PS, LPC and Sph percentages/total PL, PL (-23%) concentrations; no significant change for PC, PE, phosphate level (+17%, NS) and glycerol-3-phosphate (+23%) levels; PI percentage (+0.7%) 41%), PAP(-7%,NS) and I(-8%, CPT NS) activities contents was present, notmacrovacuolar : ↓ :

: : TG (-24%), PL (-12%) andTC(-9%, NS); ↓ : ↓ ↓

TG (-38%), TC (-14%, NS) and FFA (-12%) levels

↓

fat ( TG (-18%) and TC (-6%, NS);

fat content ( content fat ↓ :

FAS mRNA/18S rRNA ratio (-42%) ratio rRNA FAS mRNA/18S ≈ ↓

-43%, asmeasured from fatsignal with NMR TG level (-9%,NS); TG level

↓ Critical ReviewsinFoodScienceandNutrition

FAS mRNA (-9%, NS)

(+58%) 14 14 C-acetate (-57%) C-acetate (-53%) ≈

: only microvacuolar accumulation of fat -2%, NS); NS); -2%,

I (-8%,NS)activities

as inthe high-fat diet only ↑

TG content (+21%, (+21%, NS) content TG ↑

TC (+20%, NS) and FFA

↑ ↑ PL (+4%, NS), FFA PI/PC ratio (+8%), PI/PCratio ↓

FAS (-41%), ↑

↑ glycerol-3- FFA (+36%, ↓

FAS (- via

↑

(Tsuduki et al., 2009) etal., 2009) (Tsuduki (Chen et al., 2010a) (Sugatani et al., 2006) etal., 2003) (Busserolles (Daubioul etal., 2002) (Daubioul etal., 2000) (Han etal., 2000) (Delzenne and Kok, 1999) (Kok etal., 1998) (Aghelli et al., 1998) (Kok etal., 1996a) (Kok etal., 1996b)

28 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 e Lipids Total TL, TG, TriGlyceride; Cholesterol; Total TC, PhosphoLipid; resp.,respectively; PPAR, Peroxisone Proliferator-Activated Receptor; rRNA, ribosomal RiboNucleic Acid; PS, Phos LysoPhosphatidylCholine; ME,Malic Enzyme; mRNA,messenger RiboNucleic Acid; NMR, Nuclear Magnetic Resonance;PAP, Phosphatidat Dodecenoyl-CoenzymeA delta Isomerase; DDT, DichloroDiphénylTrichloroéthane;FAS, FattyAcid Synthase/Synthetase; FC,FreeChol in fatt step important (an Enzyme Cleavage Lyase/Citrate Citrate ATP ATPCL/CCE, ratio); in the AMP:ATP to to fluctuations react ABBREVIATIONS h g f d c b interpretations relevant a Glucose-6-Phosphate Dehydrogenase (NADPH,H Dehydrogenase Glucose-6-Phosphate is a polymer of glucose included in the insoluble fiber family family fiber insoluble the in included glucose of polymer is a Fructans are from highly fermented Synergy 1 (Raffinerie Tirlemontoise, Tienen, Belgium) that consists of a 50/50 mixture ofRa mixture of a50/50 consists that Belgium) Tienen, Tirlemontoise, 1 (Raffinerie Synergy fermented highly are from Fructans Oligofructose is from Raftilose P95 (Raffinerie Tirlemontoise, Tienen, Belgium), a mixture of glucosyl-(fructosyl)n-fructose an of mixture glucosyl-(fructosyl)n-fructose a Belgium), Tienen, Tirlemontoise, P95(Raffinerie Raftilose is from Oligofructose in reference the No data given Allterms used in the Table are preciselythose of the article considered: for exemple,the hepatic content in TG was named “co Is synthesized enzymatically from sucrose by inulin-producing enzyme and consists of a linear polymer (average ratio of glucose of ratio (average polymer linear ofa consists and enzyme by inulin-producing sucrose from enzymatically Is synthesized D fiber, prune fiber, date gum, bean locust fiber, rice fiber, pulp apple cellulose, gum, guar pectin, bran, citrus oat Contained tothe control, compared lipotrope by the induced percentage increased or thedecreased Indicates -glucose analogue in which the oxygen atom of the pyranose ring is substituted by an NH group NH byan is substituted ring pyranose the of atom oxygen the in which analogue -glucose alba leaves, )

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Morus Morus : ACC/CBX, Acetyl-CoA Carboxylase (involved in FA synthesis; is ihibited when phosphorylated); ACO, Acyl-CoA Oxidase; AIN, Amer AIN, Oxidase; Acyl-CoA ACO, phosphorylated); when ihibited is FA synthesis; in (involved Carboxylase Acetyl-CoA : ACC/CBX,

535-590. DOI :10.1080/10408398.2010.549596 + -generating enzyme); HMG-CoA, 3-Hydroxy-3-MethylGlutaryl Coenzyme A; i.p., intraperitoneally; ICR, Imprinting Control Region; L Region; Control Imprinting ICR, intraperitoneally; i.p., A; Coenzyme 3-Hydroxy-3-MethylGlutaryl HMG-CoA, enzyme); -generating Comment citercedocument :

i.e. intubation) stomach steatogen diet (NS - Not Significant - means absence of significativity for the change observed; in other cases, the effect w the effect cases, other in observed; the change for of significativity absence means - Significant Not (NS- diet steatogen

and fructo oligosaccharides fructo and For Peer Review Only Review Peer For 4–8 of polymerization of degree average an with (fructosyl)m-fructose d ntent”, “concentration” or “level”, and in some case no term was used; studies reporting both lipotrope-like and non-lipotropic and lipotrope-like both reporting studies used; term was no case in and some or “level”, “concentration” ntent”, /fructose, 1:17) having having 1:17) /fructose, ftilose P95 and raftiline (both are mixture of glucosyl-(fructosyl)-fructose and (fructosyl)-fructose with an average degree of degree average an with (fructosyl)-fructose and glucosyl-(fructosyl)-fructose of mixture are (both raftiline and P95 ftilose y acid biosynthesis); phatidylSerine; Sph, Sphingomyelin; SREBF1, Sterol Regulatory Element Binding Factor 1 (membrane-bound transcription factor tha factor transcription 1 (membrane-bound Factor Binding Element Regulatory Sterol SREBF1, Sphingomyelin; Sph, phatidylSerine; esterol; FA, Fatty Acid; FFA, Free Fatty Acids; FOS, Fructo-OligoSaccharides (mixture of 2-, 3- and 4-linked fructose moieties URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] ↑ ↑ CPTI ( FAS ( ME ( expressions; e Phosphohydrolase (involved in TG synthesis; catalyses the release of orthophosphates from phosphatidylglycerophosphate); NS, phosphatidylglycerophosphate); from of orthophosphates release the catalyses synthesis; inTG (involved e Phosphohydrolase

β ≈ (2-1) linkages of linkages (2-1)

≈

≈ b.w., body weight; CE, Cholesteryl Esters; CoA, Coenzyme A; CPT/CAPT, Carnitine PalmitoylTransferase; CYP7A1, Cholesterol 7 Cholesterol CYP7A1, PalmitoylTransferase; Carnitine A; CPT/CAPT, Coenzyme CoA, Esters; CE,Cholesteryl weight; bodyb.w., +13%, NS), CPT (

-12%, NS) +50%), ACO ( ican Institute of Nutrition; AMPK, AMP-activated protein Kinase (AMPK regulates several several regulates (AMPK Kinase protein AMP-activated AMPK, ofNutrition; Institute ican ↓

PPAR Critical ReviewsinFoodScienceandNutrition D

-fructose with one terminal glucose and and glucose terminal one with -fructose α ≈ mRNA expression (

+110%) and AMPK ( ≈

+56%) and +56%) ACO ( DL, Low-Density Lipoprotein; LDL Receptor, Low-Density Lipoprotein Receptor (involved in transfer of lipids into hepatocytes); hepatocytes); into oflipids in transfer (involved Receptor Lipoprotein Low-Density Receptor, LDL Lipoprotein; Low-Density DL, ≈

-25%, NS) ≈ ≈

+45%) activities; +145%) mRNA as either significant or no information was given in the article) article) the in given was information no or significant as either ↓

intracellular systems including including systems intracellular polymerization of 5 for Raftilose P95 and 10-20 for raftiline); cellulose is from poorly fermented Vivapur Microcrystall Vivapur fermented ispoorly from cellulose 10-20 forraftiline); P95and Raftilose 5 for of polymerization effects ( effects i.e. bound toa glucose molecule); GMD, GeometricMean Diameter;GPAT,Glycerol-3-Phosphate AcylTran an increase in hepatic lipid content and/or lipogenic enzyme activities) are alsopresented to allow compa

t enhances transcription of genes required for fatty acid synthesis); SREBP, Sterol Regulatory Element- Regulatory Sterol SREBP, synthesis); acid fatty for genes of required transcription t enhances β -oxidation of

Not Signficant; PC, PhosphatidylCholine; PE, PhosphatidylEthanolamine; PI, Phospha PhosphatidylEthanolamine; PE, PhosphatidylCholine; PC, Not Signficant; α Hydroxylase (enzyme for the initial rate-limiting step of bile acid synthesis from c fatty acids via phosphorylation of its substrates and control of gene transcripti gene of and control its substrates of phosphorylation LI, Liver Index (liver weight/bod Index (liver Liver LI, 29 r B t y o h Page 196of267

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 197of267

Supplemental Table 4 Table Supplemental Oligonol γ Grape skinandseed Oryzanol Oryzanol oyhnl Oryzanol B1 - Undefined, B - Polyphenols Lycopene Astaxanthin and -Carotenoids A compounds Lipotropic Green teaextract Polyphenon-100 Polyphenol-rich from Polyphenols -oryzanol ) microencapsulated polyphenols ( bran oil extracts mixture or canthaxanthin vs (30% catechin) (30% green tea) and fruit lychee polyphenols from (oligomerized 12%) seed powder safflower defatted extract (from ethylacetate virgin olive oil polyphenols) tea (green

® c c c Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human rice from

Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), c (normal

® ≈ d

AIN-93M-based diet fedstandard Rats Rainbow trouts fed commercial extruded basal In vivo In Mice fed choline deficient and fedRatshigh-cholesterol diet (10% heat-treated Ovariectomized ratsfed Rats fed 1%-cholesterol diet Male rats fed standard diet fedliquidRats ethanol-rich (36%asenergy) diet Hamsters fed hypercholesterolemic (0.1% +5% Rats fed high-cholesterol (1% +0.15% bile salts) Rats fed high-cholesterol (1% +0.15% bile salts) Male leptin-deficient ( leptin-deficient Male diet

In vivo lard, 1% cholesterol and0.5% cholic acid) fat) diet) (Lieber-DeCarli coconut oil) diet diet diet defined diet AIN-93G diet or 535-590. DOI :10.1080/10408398.2010.549596 in vitro in , ex vivo models Comment citercedocument : and ob standard diet (11.5% (11.5% diet standard /

ob in vitroin ) mice fed standard standard ) micefed L -amino acid

studies reporting effects on hepatic lipid metabolism following supplementation of carotenoids, pholyphenols and polyphenol-de and pholyphenols carotenoids, of supplementation following metabolism lipid hepatic on effects reporting studies 1 or 2% of diet 0.02% ofdiet 0.01% ofdiet 1% ofdiet daily dose Supplemented ≅ 0.65% ofdiet 0.01% ofdiet 0.01, 0.05, 0.1, 50 mg/L 1% ofdiet 0.5% ofdiet 0.2, 0.5, 1.0 or quantity quantity virgin olive 30% from extracted g/kg b.w. 0.5 and 0.2 1.2%diet of

6 weeks 4 weeks 4 weeks 4 weeks 5 weeks 23 days 2 months 8.5 weeks 7 weeks 7 weeks exposition lipotrope Duration of 5 weeks 21 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] TG: resp. TG: TC: no effect (+17% at 1 g/kg b.w., NS) Histological assessment oxidation) and

Hepatic effect(s) ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↓ Hepatic histologicevaluation No effect onliver TC (-8%), TG(+35%), total PL(+6%), LPC PL: no effect (+29% at 1 g/kg b.w., NS) No effectNo on TG and PL levels

cholesterol level ( TL(resp. -41 and -39%) fat deposit; up-regulation of PPAR (-8%, TG and (-15%) NS) levels cholesterol CYP7A1activity inmicrosomes (+22%, NS, without olive oil HMG-CoA reductase activity (-41%) in microsomes (without HMG-CoA reductase activity (-15%, NS) TC(-26%), FC (-5%), CE (-31%), TG(-19%, NS) and PL (-26%) TC(resp. -14, -17, -17 and -22%), (resp.CE -16, -21, -19 and - LI (resp. -19%, NS, and -23%)an NS,and -19%, LI (resp. distribution alrge number of lipid vacuoles with alarge extent of to that observed in liver of rats fed basal diet, and absence of a evidence of steatosis, a highly organized structure comparable (+4%), PC ( PC (+4%), and +88% with olive oil) olive oil); no effect with olive oil contents -17%) and (resp.-2, +3, -1 FC content (resp. -14,-38, -33 and-29%) contents; no significant effect on 22%), TG(resp. -7%, NS, -37%, -27%, and NS, -33%) and PL grey-scale values for differential hepatic histochemical staining) and -34%, NS) level (as evaluated byimage analysis, steatosis; 4/16 obese mice maximally responded to green tea and -15%) -15%) and ≈

0, +20%, NS, ↑ ≈

0), PE(+1%) and microsomal TC(-15%) β Critical ReviewsinFoodScienceandNutrition -oxidation enzyme expression ≈ -34%) and and -34%) : signficantly less hepatic damages, ≈ b

and unsaturated lipid (resp. -5%, NS, 0, +36%,NS,+45and +47% : marked reduction in the degree of of degree the in reduction : marked ↑ TG level ( level TG

d cholesterol level (resp. -19 γ coactivator-1 ≈

+6%,NS) α (promotes

i.e. i.e.

mean mean β no - etal., 2008) (Bruno (Tojo et al., 2008) (Suh etal.,2005) (Cho etal., 2004) (Benkhalti et al., 2002) (Nakamura etal., 2001) (Sun etal.,1999) etal., 1997) (Rong (Seetharamaiah and Chandrasekhara, 1993) (Seetharamaiah and Chandrasekhara, 1988) (Alshatwi et al., 2010) (Page et al.,2005) References

rived compounds a

30 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Provinol Anthocyanin-rich Polyphenol-rich Polyphenol-rich Silymarin (extract Polyphenol extract Polyphenol-rich extract water flower longans ( longan polyphenols) sabdariffa Hibiscus extract from marianum seeds, from milk thistle flavonoids) 56% and acids (14.8% phenolic nucifera from ( from walnut extract (45%) extract, 95%) wine polyphenol Dimocarpus Juglans regia

® Nelumbo f Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Silybum Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), h (powdered Lour.) leaf ( ) ≈ 74% g

L.) Rats fed high-fat (19%) high-sucrose (30%) diet diet (30%) (19%) high-sucrose fedhigh-fat Rats Ethanol-fed(3.7 g/kg b.w. fedhypercaloric diet Rats HepG2 cells HepG2 cells Male hamsters fed calorie-rich-fat (0.2% Hamsters fed high-fat (10%) diet containing HepG2 cells Mice fed high-fat (32%) diet for 6 thenweeks, cholesterol and 10% coconut oil) diet diet oil) coconut and10% cholesterol 0.2% cholesterol 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : ± Provinol for 6weeks via intragastric tube) tube) intragastric

10,or 30 100 50, 100 or 200 0.2% ofdiet 125, 250 or 500 1.25 or 2.5% 0.05 or 0.5 0.1, 0.5 or 1.0 0.1 or 0.2% of 0.01% ofdiet 1 or 2% of diet 100 or 10 1,

μ μ once a day given orally water and suspended in mg/kg water drinking as (w/v) mg/mL mg/mL diet g/mL g/mL

45 days 9 weeks hours 18 6 hours 10 weeks 10 weeks 10 weeks hours 48 13 days 6 weeks For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Tended to significantNo effect oncholesterol content Histological examinations Histological examinations Histological

appearance tothat ofcontrol (4%fat) which bulky fat vacuole distends the hepatocyte, and similar Hepatic steatosis grading

↓ ↓ ↓ ↑ ↓ ↑ ↑ ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↑

Histological examination Histological No effectNo on AMPK and TG content TG (resp. dose-dependently TL (resp. TC(resp. -7%, NS,-7%, NS, and -13%) and TG (resp. -8%, NS, - LDLR (resp. - -19 and (resp. (resp.-27%) cholesterol -5%,NS,and and TG LDL uptake (resp. AMPKphosphorylated (resp. +49, +46 and +45%), PPAR and HMG-CoA -75%) and FAS(resp.-14, -53 dose-dependently (resp. cholesterol (resp. cholesterol cholesterol (-22%) and TG (-25%) levels cholesterol (resp. -27 and -40%) and TG (resp. -10 and -39%) PPAR TGaccumulation within cells (resp. +47, +42 and +43%) PPAR expression ratio and 19%) contents reductase (resp. -7, -46 and -69%) protein expression; levels mRNA expression expression ratio increased by the high-fat diet ACOX1 (resp. was dramatic extract, resulting in grade 1histologic score; for most, effect number of lipid vesicles increased by the high-fat diet +20%, NS, and +43%, NS) NS) +43%, +20%, NS, and 43, and UCP2 (resp. and -18%, NS) and expression; CPTA1 (resp. (resp. CPTA1 66, -64 and -69%) protein expression (resp.- SREBP-1c and 79%) -75 and (resp. 0, reductase CoA parenchyma; hepatic the >66% of and <33%, 33-66% occupying hepatocytes tofatty respectively correspond and 3 2 1, (grades concentration (resp. 49%) levels and ACOX1 (resp. 10%, NS, and and NS, 10%, +44 and +144%) protein expression +14, +22 and +37%; dose-dependent) and LDLR (resp. +42, ≈

≈ α -54 and α -41%)concentrations; nosignificant effect on cholesterol ( (resp. ≈ ↓ 1.65-fold at 1 mitochondrial ≈ ↓ +50 and and +50 ≈ SREBP-1c (resp. 0 and ≈ 1.45-fold, NS, 1.7-fold and 1.4-fold, NS) and ob -62%) contents Critical ReviewsinFoodScienceandNutrition ≈ ≈ ≈ -16%) mRNA expression NS) 4-fold, NS,and NS, 1.15-fold, 1.2-fold, 1.6-fold, 1.4-fold and 3.3-fold) mRNA / ≈ ≈ ≈ vs vs ob -28%, NS, -53 and 0,-19 and -19%) ≈ ≈ +14%, NS, and +10 and 65%) and65%) +10 control control; nosignificant effect on CPT1A micegraded are 3) ≈ ↑ 1.3-fold, 1.3-fold and 1.3-fold) mRNA ≈ cytosolic cytosolic

-7 and and -7 β : 2.0 at 1% green tea extract and 2.1 at 2% ≈ : no preponderance of large droplets in

+88%), PPAR

: significantly dose-dependently and : significantly μ actin protein expression β g/mL and 1.7-fold at 100 -oxidation (resp. -15%, NS,-29%, NS, ≈ ≈ -58%) and TG (resp. -21 and and -21 ≈ ≈

-48 and

+13%) β -oxidation (resp. +28%, NS, ≈ +16%, NS) mRNA ≈ -39%) and -39%) and TG (resp.

↓ ≈ α -14%) and FAS (resp. number of lipid vesicles ≈ (resp. (resp. -79%) and TG (resp. (resp. TG and -79%) ≈ +43and ≈

-39 and μ g/mL), ↓

HMG- ≈ α +50%) (resp. (resp. ≈ ≈ - -20 ↓

≈ ≈ - - (Hou etal., 2010) (Yang etal., 2010a) etal.,2010b) (Yang (Lin et al., 2009) (Shimoda et al.,2009) etal.,2009) (Feillet-Coudray 31 Page 198of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 199of267 Ellagic acid Ferulic acid acid Gallic 3-Faood - Flavonoids B3 Ferulic acid, Ferulic acid Ferulic acid B2 - Phenolic acids Naringenin or Naringenin Naringenin or (fromHesperetin Tannic acid Epigallocatechin Soy isoflavone Naringinhesperidin + Jasmine green tea hesperetin hesperetin citrus) gallate (EGCG) isoflavones) powder (83.3% ECG andEGCG) (mainly EC, EGC, epicatechins black rice) extract (from propionic acid dihydroxyphenyl- acid or 3,4- hydroxycinnamic

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), m - i

HepG2 cells Male ICR mice fed 10%-fat (palm oil) diet liver fromFAS chicken Rats fed high-cholesterol (1%) diet diet fed10%-fat Rats Rats fed high-cholesterol (1% +0.15% bile salts) HepG2 cells HepG2cells pre-incubatedh with 24flavonoid HepG2 cells Rats fed 1%-orotic acid diet containing 10% fat Male rats fed standard diet liver fromFAS chicken Rats fed atherogenic diet (9% fat, 1.2% Rats fed high-cholesterol (1%) diet Hamsters fed hyperlipidemic (20% fat and 1% diet and incubated 20 min cholesterol and 0.2% cholic acid) cholesterol) diet as mg/kg b.w. i.g. rats 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : ± 0.1 mM oleate

0.013, 0.011 or injected 0.4% ofdiet 0.075% of diet 1, 3or 10 1% ofdiet 0.5 mM ≈ 20% ofdiet 0.05+ 0.05% of 0.57% ofdiet 50 or 200 50 or 200 10-200 or50- 1% ofdiet 0.1, 0.2, 0.5 and 27-110 diet 200 1.0 g/kg b.w.

diet 0.012% of μ

μ μ M μ M M g/mL

hours 24 (+ hours 24 20 hours 24 10 days 23 days 60 min 63 days 6 weeks 5 weeks hours 24 15 days 3 hours 5 weeks 4 weeks 7 weeks min) min) Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Histopathological examinations No effectNo on TG and cholesterol contents Naringenin Naringenin Naringenin Hesperetin

↓ ↓ ↓ ↓ ↑ Hesperetin ↑ Hesperetin ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↑ ↓ TG: resp. +34, resp.+34, +38, TG: effect no TC: FAS residual activity PL: resp. +17%, NS, +18%, NS, +33%, +29%, NS NS +29%, +33%, NS, +18%, NS, +17%, resp. PL: FAS ( HMG-CoA reductase (resp. TC(-3%, NS) and lipid (-9%, NS) contents TG(-19%, NS) and PL(-23%) contents; cellular TG mass: cellular FCmass: cellular CE mass: cellular (resp. dose-dependently ApoB accumulationinto media: the microsomal ( PAP FAS activity (reversible fast-binding inhibition): IC TG(-33%) and reductase HMG-CoA (-31%) andACAT (-31%) activities cholesterol (-28%) and TG (-21%) contents TG(-44%), FFA (-36%) and cholesterol (-56%) concentrations PPAR SREBP-1c ( mRNA levels of proteins involved in regulation of lipogenesis: SREBP-1c ( ACC( unesterified cholesterol (+17%) concentrations levels (+5%, NS) and CE (+1%, NS) contents NS)contents CE and (+1%, (+5%, NS) (resp; expression ( mRNA 0.60-fold) and NS, 0.63-fold 0.94-fold, (resp. and ACOX1 0.69-fold) NS, and 0.88-fold, 0.63-fold, (resp. 68%),new synthesized ApoB DGAT ( DGAT ( spot 14 ( 9 and -13%) levels relation with lipid accumulation) ≈

-26%,activities NS)

≈ α ≈ -21%, NS), ATPCL (

(resp. 0.59-fold, 0.94-fold, NS, and 0.64-fold), CPT1A 0%), FAS( ≈ -36, : resp. : resp. : from : resp. : resp. : from ≈ ≈ -48%) activities -20%, NS) and adiponutrin ( ≈ ≈ +2%, NS) mRNA+2%, NS) level +8%, NS) vs ≈ ≈ -34 and and -34 -36 and control) Critical ReviewsinFoodScienceandNutrition ≈ ≈ ≈ ≈ ≈ ≈ ↑ +3%%, NS, and -17%, NS,and -39% (50 +4%%, NS,and and NS, -8%, -7% (10 (10 -7% TC (+10%, NS), (+9%,CE NS) and

≈ ≈ ≈ -30%), G6PDH (

0 and +47% -10%, NS) and ATPCL ( ≈ 97% ≈ ≈

-41%) activities

-72%)andsecreted (resp.

μ μ M), NS,to ≈ M), NS,to ≈ -54, -23%, NS), ME ( -23%, NS),ME : ↓ ≈ alterations (apparently in in (apparently alterations -26% ≈ -21% ≈ ≈ ≈ +3%, NS -40 and +7%,NS ≈ -44%), ME(

≈ -83% (200 (200 -83% ≈ ≈ -75% (200 -3%, NS) -3%, ↑ TC (+1%, NS), FC FC NS), (+1%, TC ≈ -51%) and ACAT

≈ -8%, NS) mRNA mRNA NS) -8%, ≈

0%) andG6PDH ≈

≈ 50 μ and -41%)

-27 and μ = 52 M) M)

M) μ M ≈ - (Shimoda et al.,2009) et(Odbayar al.,2006) (Wang et al., 2003) (Kim etal., 2003) (Kamal-Eldin etal., 2000) (Seetharamaiah and Chandrasekhara, 1993) (Wilcox et al., 2001) (Cha et al., 2001) (Nakamura etal., 2001) Tian, 2001) and (Wang (Peluso etal., 2000) (Bok etal., 1999) (Chan et al., 1999)

32 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Flavonoid glycoside glycoside Flavonoid Taxifolin Proanthocyanidins Naringenin or Naringenin or Naringenin or Naringenin Naringenin or Naringenin or leaves matsudana Salix from fraction (from grape seeds) hesperetin hesperetin hesperetin hesperetin hesperetin

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

Female mice ICR fed high-fat (40%) diet HepG2 cells (1% diet lithogenic or fednormal diet Rats HepG2 cells HepG2 cells HepG2 cells HepG2 cells HepG2 cells HepG2 cells incubated with [1- cholesterol + 0.5% cholic acid) presence of10 14 flavonoids) and incubated 5 hours with [1- C]oleic acid or [1- 535-590. DOI :10.1080/10408398.2010.549596 ±

19 hours-preincubation with μ M ACATinhibitor Comment citercedocument : 14 C]acetic acid 14 C]oleic acid in

200 50 or 200 200 - 0.1, 0.2, 0.5 or 1 0.01, 0.05, 0.1, 2% or5% 50 or 200 50, 100 or 200 200

g/kg b.w. g/kg b.w. 0.2, 0.5or 1 μ

M μ μ μ

M M M

μ μ M M

9 weeks hours 24 28 days hours 24 hours 24 hours 24 24 hours or 5 hours 24 5 hours For Peer Review Only Review Peer days For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] - Hesperetin: resp. -8%, NS,-33 and -22% -40% -32 and -19, resp. - Naringenin: hours 24 Naringenin: Naringenin - Normal diet Hesperetin ↓ ↓ ↓ ↑ ↓ ↓ Naringenin: - Naringenin Shifted metabolic pathway from TgtoPL synthesis Hesperetin 5 days With 19 hours-preincubation with flavonoids - no effect on cholesterol (resp. +8%, NS, +10%, NS, -5%, NS, and and NS, +10%, NS,-5%, (resp.+8%, NS, cholesterol effectno on Lithogenic diet - Without 19 hours-preincubation with flavonoids

Hesperetin: Hesperetin: TG (resp. -13%, NS, and -16%) and TC (resp. -27 and -30%) (resp.-27 -16%) and TC -13%,NS, and TG and dose-dependently DGAT activity (-60%), but noeffect of dose-dependently TG synthesis and secretion (resp. -59 and -68% receptor LDL activity: activity: MTP -36%) and (resp. -34 rateofCEhydrolysis ↓ ↓ ↓ LI (-15% at 0.5 g/kg) cholesterol (-25%at 1g/kg, NS), TG(-25% at 1g/kg, and NS) LI (-12% at 0.5 g/kg) (resp. +200%), uptake (resp. +200%), uptake levels +19%, NS) and GAPDH (+21%, NS,and +6%, NS)mRNA and +556%),HMG-CoA reductaseNS, (resp. -10%, and NS, 53%), (resp. MTP +16%, NS, and -47%), LDLR (resp. +16%, (resp. +4%, NS, and -13%, NS), ACAT2 (resp. -13%, NS, and - incorporation ofoleate into TG (resp. NS, and -70%) and PL (resp. -7%, NS, and -12%, NS); and-57%);NS, secretion (resp. -15 and-57%) GAPDH (resp. +30%, NS, and -15%, NS) mRNA levels -84%); -70%); NS) +21%, NS, and +35%, NS) and PL (resp. +20%, NS, and +16%, concentrations 16%, NS) and PL (resp. +8%, NS, 0, -4%, NS, and +17%, NS) - and NS, -14%, NS, -18%, NS, +3%, (resp. TG NS), +14%, +387%), HMG-CoA reductas HMG-CoA +387%), MTP (resp. +8%, NS,and -31%), LDLR (resp. +41%, NS, and (resp. -4%, NS, and-9%), ACAT2 (resp. +9%, NS,and -49%), contents; noeffect onLI quercetin andgenistein; at optimum concentration of 200 and +27%); no effect onrate of incorporation of oleate into PL NS, NS) +29%)PL(resp.+4%, and +2%, and NS, PL (-32% at 1 g/kg) contents (mg/liver) : nearly complete depletion of MTPlarge subunit expression : nosignificant effect onMTP large subunit expression ≈ +18%, NS, and ↑ ↑ : : resp. : resp. : rate ofincorporation of oleate into (resp.TG +4%,NS, rate ofincorporation of oleate into (resp.TG +13%, : ↓ ↓ ↑ ↓ ↓ ↑ and rate of incorporation of oleate into (resp.CE -31%, rate of incorporation of oleate into (resp.CE -22%, rate incorporationof of oleate(resp. intoCE and -60 rate incorporationof of oleate(resp. intoCE and -37 and and : Critical ReviewsinFoodScienceandNutrition ≈ ↓ ≈ ↓ +3%%, NS, and +14%%, NS, and ApoB (resp -1%, NS, and -14%, NS), ACAT1 ACAT1 and-14%, (resp-1%,NS), NS, ApoB ApoB(resp. -13%, NS, and -4%,NS), ACAT1 ↑ rate of incorporation of oleate into TG (resp. ↑

≈ 125 ≈ +67and +164%) ↓ I-LDL cell binding (resp. MTP activity (-27%) e (resp. -14%, NS, e (resp.-14%, and ≈

≈ μ +50%, NS +150%) and degradation ≈ M); +34%, NS ≈ ↓ 0and +9%, NS) PLsynthesis and : :

≈ 0and ≈ 0) and ↑ rateof ≈

(Han etal., 2003) (Theriault etal., 2002) (Nakamura andTonogai, 2002) 33 Page 200of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 201of267 Hesperidin or or Hesperidin Epigallocatechin Epigallocatechin (-)-epicatechin (+)-catechin Epicatechin gallate Hesperetin Genistein Genistein, glycitein Soy extract Daidzein + Daidzein glycitein Flavonoids (flavone)Acacetin Taxifolin Genistein (EGC) (EGC) gallate (EGCG) (ECG) or daidzein n glucosylhesperidi

k Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

l α - k

HepG2 cells incubated or not with ER antagonist HepG2 cells HepG2 cells HepG2 cells HepG2 cells preicubated 22 with taxifolin then HepG2 cells Ovariectomized miceddY fed AIN-93G-based liver fromFAS chicken liver fromFAS chicken liver fromFAS chicken liver fromFAS chicken liver fromFAS chicken Rats fed high-cholesterol (1%) diet Enzyme assay: 5.3 FAS (5 mM) from duck HepG2 cells Ovariectomized ratsfed HepG2 cells HepG2 cells HepG2 cells HepG2 cells

(0.1 (0.1 incubated 2hourswith [ diet reductase/150 fat) taxifolin μ

535-590. DOI :10.1080/10408398.2010.549596 μ

L μ Comment citercedocument : g of MHG-CoA standard diet (11.5% (11.5% diet standard 3 H]glycerol and

4.5 -

200 20 10 mg/L 3.8 0.1, 1or 5 100 or 10 1, 10 10 10 0.01, 0.1 and 1 0.02% ofdiet 200 100 or 200 75-200 Resp. 0.5%and 0.5 mM 0.5 mM 0.5 mM - 0.5 mM - 0.5 mM - 0.02% ofdiet

μ μ μ μ μ 0.7%diet of

μ μ

M μ M M M M μ g/150 g/150

M M μ

μ μ μ

L L μ M M

hours 24 6, 2448 or hours 24 hours 24 0-48 hours hours 24 hours 24 - - - 3 days 4 weeks hours 24 hours 24 hours 24 hours 24 4 weeks 3 hours 3 hours 3 hours - 3 hours - 3 hours - 5 weeks hours Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

No effectNo on TG and cholesterol contents IC Genistein or daidzein: ↓ ↓ ↓ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↓ ↓ ↓ ↓ ↓ FAS residual activity FAS residual activity FAS residual activity FAS residual activity FAS residual activity IC IC

IC newly synthesized TG in cytosol (-39%), and microsomal dose-dependently ApoB secretion ( -16%) TG(resp. (resp.-16 -15%)and and -20and TC HMG-CoA reductase ( PPAR PPAR PPAR PPAR CPT1 gene expression: mRNA levels of genes involved in peroxisomal mRNA levels of genes involved inmitochondrial SRE-regulated expression of HMG-CoA synthase (resp. SRE-regulated expression of HMG-CoA synthase ( mature SREBP-2form and HMG-CoA reductase levels, and (-50%) reductase HMG-CoA (-64%) reductase HMG-CoA -28, -7%, -32 NS) TG(resp. and and -35 -39, (resp. cholesterol and TG (-17%, levels NS) (-12%, NS) cholesterol and non-competitively DGAT activity (-35%), and MTPactivity ( 50 50 50 50 EGC (n.i.) LDL receptorLDL ( (resp. +4%, NS, and -6%, NS) mRNA levels NS)mRNA -6%, +4%, (resp. NS, and fold) and MCAD ( and fold) ketone body metabolism, metabolism, body ketone ≈ effect onSREBP-1 reductase levels, and HMG-CoA syntahse mRNA level; no at 24 hours :ACO1 ( (n.i.), ( (111.69), galangin (> 100), flavone (n.i.), flavonol (n.i.), rutin kaempferol (10.38), fisetin (18.78), myricetin (27.18), baicalein membrane (-26%) and lumen (-38%) concentrations HMG-CoA syntahse mRNA level; no effect on SREBP-1 NS) -2%, contents and 41%); post-transcriptional regulation of DGAT activity +25%, NS, and and NS, +25%, ACS ( +460% with ER antagonist antagonist ER with +460% +200%)

( =3.8mM =1.6mM =42 -30%, NS, and μ ↑

M): morinM): (2.33), luteolin (2.52), quercetin (4.29),

DGAT-1 (resp. +3%, NS, and+8%, NS) and DGAT-2

α α α α

transcriptional activity (resp. protein level: maximum at 24 hours mRNA level: maximum at24 hours (3.9-fold) mRNA level (resp. ≈ μ ± 2-fold), MCAD ( MCAD 2-fold), M )-taxifolin (41.16), hesperetin (68.86), ( (41.16), (68.86), hesperetin )-taxifolin Critical ReviewsinFoodScienceandNutrition ≈ ≈ +55%, NS) +280%) and LDL receptor (resp. ≈ +80%,NS) ≈ ≈ ≈ ≈ ≈ ≈ 5-fold) 5-fold)

↑ 91% 21% 93% 100% 21% mature SREBP-2 form andHMG-CoA ≈ ≈ 7-fold), ACO2 ( ACO2 7-fold), -41%) and ACAT and ( -41%) ≈ +330% without ER antagonist and and antagonist ER without +330% ≈ 5-fold) and HMGCS2 ( e.g ≈ +80, . at 24hours: CPT1 ( ≈ +280 and and +280 ≈ -62% at 200 ≈ +150, ≈ 5.5-fold), ECH1 ( ≈ -45%) activities ≈ ≈

+169and

+240%) β ±

-oxidation,

)-EC (n.i.), (-)- μ β M) -oxidation and ≈ ≈ ≈ 4-fold) +315%) and and +315%) ≈ 6-fold), +25%, NS, +25%, ≈ ≈ +370,

≈ 3- ≈ e.g

≈ - . ≈

(Kim etal., 2004) (Mullen et al., 2004) (Sung et al., 2004) (Li and Tian, 2004) (Cho etal., 2004) (Casaschi et al., 2004) (Chiba et al., 2003) (Wang et al., 2003) (Kim etal., 2003) 34 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 C-iso Isoflavone aglycone- (fromCatechins Naringenin and ((-)- gallate Catechin Green teaextract Quercetin dehydrate Genistein moieties) moieties) or 32.0% aglycone powder (resp. 26.3 or glucoside-rich ( green tea extract green tea) and flavonoids) hesperetin (citrus CG) and rutin (from soy) and genistein daidzein, glycitein ≥ 58%catechins) n , U-iso

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), n , HepG2 cells Male ICR mice fed 10%-fat standard diet FAS from duckliver Male ICR mice fed 10%-fat (palm oil) diet Mice fed high-fat (18%) diet HepG2 cells diet fed10%-fat Rats 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

0-200 0-200 1% ofdiet ≈ ≈

1% ofdiet 0.2% ofdiet 10 ng/L 0.365 or 0.3%of 1-42 3.5-60

diet

μ μ

M M μ g/mL

hours 24 21 days - - 15 days 12 weeks hours 24 40 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] No effect on TG, cholesterol and PL levels

- PPAR Significantly IC - PPAR to3.5-fold from- CPT2: 2.6- to2.5-fold from- CPT1: 2.3- No effect on FC and chenodeoxycholic acid concentrations concentrations acid chenodeoxycholic and FC on effect No IC ↓ ↑ ↓ ↓ ↓ ↑ ↑ ↓ ↓ ↓ Gene expression of FA metabolism - 7-dehydrocholesterol reductase: from 1.05- to 0.25-fold - ACAT 1: from 3.90- to 4.20-fold - squalene expoxidase: from0.19- to 1.12-fold to 1.10- transferase 1:from 0.35- farnesyl - farnesyl diphosphate - carnitine - ACO:from 1.70- to 3.05-fold - FAS:from 0.32- to 1.17-fold EGCG Naringenin: significantly Gene expression of cholesterol biosynthetic pathway enzymes

LI (-7%), and TL (-42%), TG (-20%) and and NS) TC (-13%, TG(-20%) TL(-42%), and LI (-7%), PPAR linoleic acid saturation index of liver PL, and and LDLreceptor binding activity (resp. mRNA levels of proteins involved in regulation of lipogenesis: ACC(resp. (resp. FAS β 50 50 -oxidation enzyme activities: peroxisomal palmytoyl-CoA ATPCL (resp. 24% for PE 33%) mRNA levels NS) activities and PL (resp. +4%, NS,and +4%, NS)levels desaturase ME ( resp. ME (resp. -45%) and SREBP-1c (resp. contents 6)/(18:2n-6): resp. spot 14(resp. (resp. P-450 IV A1); no effect of hesperetin receptor protein ( +28%, NS, CoA dehydrogenase(resp. mitochondrial trifunctional enzyme subunit peroxisomal bifunctional enzyme and 3-ketoacyl-CoA thiolase, fatty acid oxidation (carnitine octanoyltransferase, ACO, cell lathosterol ( lathosterol cell ECG) fold fold CoA hydratase(resp. ketoacyl-CoA thiolase (resp. and oxidation (resp. =1.5 ≅ 12.2 ↑ ↑ CYP7A1(resp. TC -10+7%, (resp. and NS),TG -23(resp. -7%, and NS) :

≈ γ α α +26%, NS), CPT (resp. : from 3.4- to 4.9-fold : from 2.2- to 5.3-fold (resp. (resp.

≈ μ +105,

O g/mL (16-fold and 12-fold higher than EGCG and μ -octanoyltransferase: from 1.15- to 4.40-fold to 4.40-fold from 1.15- -octanoyltransferase: g/mL (< IC ≈ m ↑ ≈ -40 and -17%, NS), ATPCL (resp. (resp. ATPCL NS), -17%, and -40 -44 and -21%, NS), FAS (resp. ≈ LDL receptor binding activity ( (resp. ≈ -37 and -26%) and G6PDH (resp. +118 and +86%) at 100 ≈ ≈ ≈ +40, Critical ReviewsinFoodScienceandNutrition ≈ +325, -45 and -20%, NS), adiponutrin (resp. (resp. adiponutrin -20%, NS), and -45 -245 and -28%, NS) and ME (resp. ≈ ≈ +46%) concentrations (max. at 200 +58and ≈

+146%), medium cholesterol ( ≈ ≈ -40 and -15 and ≈ ≈ 50 +150, +20%, NS,and ≈ ≈ of EGCGand ECG) ↑ +27and +375, mRNA levels of enzymes involved in in involved enzymes of levels mRNA ≈ ≈ +25%, NS%), ACO(resp. ≈ ≈ +10 and ≈ +45, ≈ -38%) activities activities -38%) -15% PC, for and -15% ≈ -13, NS,and -3%, NS) ≈ ≈ +24and +17and +235 and ≈ : +9%, NS) , 3-hydroxyacyl- ≈ -20 and ≈

+50%,NS, μ ≈ ≈ +30%, +30%, NS) and +5%, NS) and +5%, NS) 3- M ≈ ≈ i.e. +10%,NS) +10%, NS),enoyl- +10%, ≈ +130%)

(20:3n-6 + 20:4n- (20:3n-6

≈ ≈ β ≈ -50 and -24%, NS), +220%), LDL +45%) and PPAR and cytochrome cytochrome and ≈ ≈ -54 and -27%), -54 and -11%, ≈ ≈ -24 and +20%, NS, ≈ +27%)and ≈

-43 and - μ ≈ M); ≈ - 87and Δ +60 6 ≈ - : ≈

(Bursilland Roach, 2006) etal., 2006) Thanh Thi (Doan etal., 2006) (Zhang et(Odbayar al.,2006) (Kim etal., 2005) (Ricketts etal., 2005) (Kawakamial., et 2005) 35 Page 202of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 203of267

Total flavonoids Total derivative Daidzein (-)-epigallocatechin- Chamiloflan Green teaextract Tellimagrandin II Tellimagrandin I Pedunculagin Epigallocatechin-3- Chamiloflan, AP7Glu (LRXH609) (LRXH609) 3-gallate catechins) (29.2% total (tannin) (tannin) (tannin) gallate (EGCG) flavonoids) (59.5% total coreana leaves of from thedried or ALU7Glu recutita Chamomilla (flavonoids from

o p

Three-, 24 or 27-28-months old rats fed standard Rats fed high-fat ( fedhigh-fat Rats Rats fed high-fat (10 mL/kg b.w. high-fat diet miceMale ICR (45%) fed high-fat Mice fed high-fat (34.9%) diet Hepatocytes isolated from 90- and 720-day-old Rad fed high-fructose (60%) diet HepG2 cells HepG2 cells HepG2 cells diet with with 700 diet emulsion) diet for 4 weeks male rats andincubated with 30 mM ethanol

535-590. DOI :10.1080/10408398.2010.549596 μ L ethanol/kg b.w. ≈ 15%) diet Comment citercedocument :

0.5 or 1.0% of 1, 3or 10 1, 3or 10 1, 3or 10 1 mg/kg b.w. 0.01, 0.02or 25,and 50 100 0.32% ofdiet 500 160 mg/kg b.w. 160 mg/kg b.w. diet μ intake) 100% of fluid (as water in drinking administered ( 0.04%diet of mg/kg b.w.

via

M or 30 μ g/mL, 30

gavage)

μ μ μ

g/mL g/mL g/mL μ M

6 weeks hours 24 hours 24 hours 24 26 weeks 5 weeks 30 days 16 weeks 244 or hours 1 week 3, 2427-28 or For Peer Review Only Review Peer For months URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] No effect onceramide conten Gross examination Histological/microscopic examinations Histological/microscopic ↓ ↓ ↓ ↑ ↑ ↓ ↓ ↓ ↑ ↓ ↑ ↑ ↓ ↓ ↓ No effect on TG content Morphological evaluation No effectNo on PPAR LI (-22%), fatty liver incidence (from 21/22 mice in high-fat ceramide production from [ effect, (resp. no SM)content of ceramide (precursor PC(resp. no effect, active transcription factor form ofSREBP-1 ( TCconcentration ( SREBP1c (resp. (resp. SREBP1c (resp. -72%),TC-12%, TG and -72and (resp. -8%, NS, NS), FC PPAR PPAR PPAR PPAR TG (resp. activity LPL (resp. dose-dependently TC (resp. -14%, NS, -20 and -31%) and FFA (frommembrane fraction) to undetectable levels (>76% of hepatocytesaffected) to 0/10; nuclear cell fraction) and 28%); no effect on sphingoside production group to 4/22 mice in high-fat high-fat mice in to 4/22 group 0%) contents -16%, NS and -19%, CE (resp. NS, and NS)and -6%, (resp. (resp. -15%, NS, -32 and -37%) concentrations, and TG contentTG (-69%) ( at 1 fold SCD1 (resp. +26 and to control group (4.3% fat) mRNA expression ( 1.69-fold) and NS, 1.33-fold (resp. 1.12-fold, ACOX1 and NS), CPT1A (resp. 1.02-fold, NS, 1.09-fold, NS, and 1.23-fold) mRNA expression at 10 and FFA (resp.and FFA fold at 1 fold 70%) 1 rats withno steatosis) percentage of hepatocytes affected (resp. 0/10, 1/10 and 4/10 SREBP-1, MCD, FAS and ACC gene expressions expression at 1 10 1.56-fold and 1.42-fold) and ACOX1 (1.13-fold, NS, at 3 and mg/kg concentration at the dose of 25 (+20%, NS) and 50 (+12%, NS) concentration (-11%, NS) at the dose of 100 mg/kg; accumulation similar to control group (4.3% fat)

vs μ

control), and μ g/mL (0.84-fold)

g/mL) mRNA expression ( expression mRNA g/mL) α α α α (1.08-fold at3 (1.08-fold (resp. 0.60-fold, 0.58-fold, and 0.82-fold), CPT1A (0.63- gene expression( protein expression (

≈

≈ μ μ -14, -20 -14, and -27%) ,TC(resp. +75%) contents g/mL and 0.82-fold at 3 g/mL and 0.74-fold at 3 ≈ -48 and Critical ReviewsinFoodScienceandNutrition

≈

μ andsimilar size/volume lessin 3-fold : around

≈ -50 and α -20, -41 and -62%) contents g/mL (0.79-fold) ↑ ≈ mRNA expression; ≈ PPAR -28%) ≈ 0,-17 and -46%) +92and

vs μ control); g/mL, NS,and 1.14-foldat 10 : fom 7/10 rats withsevere steatosis ≈

-62%), HMG-CoA reductase (resp.

≈

μ α ACO, effecton CPT-1, no +160%); ≈ -75%), FAS (resp. ↓ 14 g/mL (1.31-fold) and ACOX1 (1.20-fold) ≈ t and on ceramide/Sph ratio inactive precursor form of SREBP-1 +89%) C]palmitic acid pre-labeled Sph (- ≈ +92%) and SM (resp. no effect, + vs EGCG-supplemented group and and group EGCG-supplemented ↓

control);

PPAR

μ μ g/mL) mRNA expression g/mL) ACOX1(0.63- and : marked ↑

CPT1A (resp. 1.42-fold, α ↓ ≈ dose-dependentlythe mRNA expressionat -22, -33 and -44%) ↓ ≈ ACOX1 mRNA mRNA ACOX1 +42-56%, from ≈ ↓ -50 and

in liver lipid ≈ -46 and

↑ ↓ μ TG TG g/mL, ≈ -68%), -68%), ≈ ≈ - - ≈

(Shrestha et al.,2009) (Shimoda et al.,2009) (Chen et al., 2009) (Wang et al., 2009a) (Guo etal., 2009) (Bose et al., 2008) 2006) Shakhova, and (Babenko 36 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Sesamin (1:1 mixture Sesamin (1:1 mixture Sesamin Sesamin Silybin- B4 - Lignans episesamin) of sesamin and silybin) the flavonolignan compound from (derived dihemisuccinate

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

Postmitochondrial supernatant of ratliver Rats fed 10%-fat diet diet fed10%-fat Rats Whole-liver homogenates fromrats fed a Liver from rats fed standard chow fedstandardchow from rats Liver Liver from rats fed standard chow fedstandardchow from rats Liver vitro In 9,12-octadecadienoic acid)(100 μ with [1- homogenates and rat liver slice incubated with a[1- sesamin-free and 15%-fat diet, and incubated linoleic acid (linolelaidic acid, contribution of endogenous linoleic acid) of isomer (to differentiate fromrelative perfused 4 h with an exogenous di- (100 acid oleic exogenous 4hwith perfused M) incubation mixture of liver homogenates 535-590. DOI :10.1080/10408398.2010.549596 14 C]acetate or 14 C]palmitoyl-CoA substrate substrate C]palmitoyl-CoA Comment citercedocument : 3 H 2 O trans

± ± μ sesamin, and sesamin, and

M) trans ,trans-

0.2% ofdiet 0.1, 0.2and 0.2% ofdiet 0.2% ofdiet 1 mM 0.1 mM 0.45-0.6 mM 150.6 mg/kg 0.5%diet of b.w.

4 weeks 15 days 14 days 14-16 days +4 i.v. injection For Peer Review Only Review Peer For perfusion hour liver killing min before 30 and 60 URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] No significant effect onTG and cholesterol content of postperfused

↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↑ ↑ ↓ ↓ ↑ ↑ ↓ ↓ ↓ ↑ ↑ No significant effect onTG and cholesterol content of postperfused

NADP-malate-dehydrogenase ACC, ATPCL and FAS activities ( linearly and dose-dependently incorporation of [1- incorporation of[1- TC (-39%) and lipid (-9%, NS) contents NS)contents (-9%, lipid (-39%) and TC TG(resp. 0, -8%, NS, and -14%, NS) and cholesterol (resp. -5%, FAS and dose-dependently gene expression of peroxisomal FAoxidation dose-dependently gene expression of mitochondrial FA oxidation dose-dependently hepatic FA oxidation enzyme activity: CPT I ( dose-dependently mitochondrial ( cumulative secretion of TG(-56%), cholesterol (-16%, NS) and cumulative production of ketone bodies (+46%) PLcontent of postperfused liver (+20%) NS)contents (-9%, lipid (-39%) and TC cumulative secretion of TG(-40%) and cholesterol (-2%, NS) cumulative production of ketone bodies (+21%) PLcontent of postperfused liver (+49%)

β β -hydroxybutyrate/acetoacetate ration (-34%) -hydroxybutyrate/acetoacetate ratio (-24%, NS) liver peroxisomal bifunctional enzyme ( trifunctional enzyme subunits expression ( 3-ketoacyl-CoA thiolase ( CoA reductase ( long-chain acyl-CoA dehydrogenase ( +143% in mitochondria and liver sesamin); and 0.5% sesamin), acyl-CoA dehydrogenase ( 3 hydroxyacyl-CoA dehydrogenase ( sesamin) and gene expression (resp. thiolase ( +18 and +30%) concentration +835%) mitochondrial 3-ketoacyl-CoA thiolase ( NS, -5%, NS, and -15%) concentrations; -5%, NS, -15%) concentrations; NS, and enzymes: acyl-CoA oxidase ( enzymes: CPT I ( PL (-37%) oxidase ( oxidation rate peroxisomal ( abundance no effect on ACAT1, ACAT2 and MTPrelative mRNA (resp. (resp. 69 and H 2 O in FA ( Δ 3 , ≈ Δ -29%, NS, and ≈ L 2 -56%), ABCA1 ABCA1 (resp. -56%), -enoyl-CoA isomerase ( -pyruvate kinase activities (resp. -44 and -62% at 0.5% ≈ ≈ +1050%), enoyl-CoA hydratase ( hydratase enoyl-CoA +1050%), +360-650%), 2,4-dienoyl-CoA reductase ( ↑ MEactivity ( ≈ ≈ +100% at 0.5% at0.5% sesamin) +100% -25%) ≈ Critical ReviewsinFoodScienceandNutrition +1300% at 0.5% sesamin) palmitoyl-CoA ≈ +450%) and ≈ 14 +95% at0.5% sesamin),CPT II ( C]acetate or ≈ -43%, NS) relative mRNA abundance; ≈ +125% at 0.5% sesamin) and gene ≈ +480%) 4 ≈ (-20%) (-20%)

+280% in whole homogenate at ≈ +1400% at 0.5% sesamin), α Δ ≈ ( 3 ≈ 3 -52 and , ≈ H +87% at 0.5% sesamin)and ≈ Δ ≈ +550%) +300%) and -50%) 2 2 ≈ -enoyl-CoA isomerase ( ≈ O in FA ( +4800%) and peroxisomal 380%), 3-ketoacyl-CoA ≈ -42 and ≈ +160%),mitochondrial ≈ ≈ ↑ +360%), 2,4-dienoyl- -33%) and and SR-B1 -33%) PL (resp. +9%, NS, ≈ +130%), acyl-CoA ≈ +106%), 3- ≈ -25%) ≈

-67% at 0.5% β ( 14 ≈ C]acetate or +240%), ≈ ≈ +275%), +534%) ≈

≈

(Kamal-Eldin etal., 2000) (Ashakumary et al., 1999) (Fukuda et al., 1999) (Fukuda et al., 1998) (Schriewer et al., 1979)

37 Page 204of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 205of267 Sesamin or Sesamin (1:1 mixture episesamin episesamin) of sesamin and episesamin) of sesamin and

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Rats fed sesamin-free and 10%-fat diet Rats fed sesamin-free and 10%-fat diet 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

0.2% ofdiet 0.2 and 0.4% and of 0.2 0.2% and of 0.1 diet diet

15 days 15 days 15 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↓ ↑ ↑ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↓ ↓ dose-dependently activity of hepatic enzymes involved in dose-dependently ACC, FAS, ATPCL, G6PDH and pyruvate dose-dependently hepatic FA oxidationenzyme activity: FA FA oxidation enzyme activity: protein level of precursor and mature forms of SREBP-1 (resp. dose-dependently mRNA level of SREBP-1 (resp. dose-dependently gene expression (mRNA levels) of HMG-CoA activity of hepatic enzymes involved incholesterol synthesis: ACC, FAS, ATPCL,kinase G6PDH andpyruvate activities (resp. dose-dependently hepatic FA oxidationenzyme activity: dose-dependently protein level of precursor and mature forms of mRNA level of SREBP-1 (resp. dose-dependently gene expression (mRNA levels) of hepatic +97%) and gene expression (resp. +16%, NS, and +92%) pyrophosphate synthase at 0.4% sesamin at 0.4%sesamin); noeffect onmRNA level of farnesyl dose-dependently mRNA level of HMG-CoA synthase (+172% (resp. +66 and +189%) levelof HMG-CoA synthase (resp.+9%, NS,and+31%) 55%) 84 and -88% effect onHMG-CoA synthase 20 and -29%) and squalene synthetase (resp. -32 and -39%); no cholesterol synthesis: farnesyl pyrophosphate synthase (resp. - 7%) activity (resp. -6 and +13%) and gene expression (resp. +2 and - -52, -50, -48, -64 and -55% at 0.2% sesamin); no effect on ME expression (resp. -35, -36, -28, -36 and -25% at0.1%, and resp. resp. -57, -46, -47, -59 and -44% at 0.2% sesamin) and gene kinase activities (resp. -36, -32, -30, -42 and -19% at 0.1%, and ketoacyl-CoA thiolase (resp. +72 and +116%) hydroxyacyl-CoA dehydrogenase (resp. +56 and +90%) and 3- oxidase (resp. +38 and +112%), CPT (resp. +61 and +135%), 3- peroxisomal oxidation (resp. +22 and +130%), acyl-CoA +129%) and peroxisomal (resp. +63 and +407%) palmitoyl- 0.1% sesamin)and of LDL receptor (resp.-30 and -47%); synthase (-37% at0.2% sesamin), squalene synthase (-34% at farnesyl (resp.pyrophosphate and -42%), reductase -26 sesamin); 37% at 0.2% sesamin and no significant effect at 0.4% significant effect at0.4% sesamin) and squalene synthetase (- farnesyl pyrophosphate synthase (-27% at 0.2% sesamin and no sesamin; and -65%at 0.4% sesamin) w -49, -59, -44, -48 and -66% at0.2%, and resp. -47, -57, -40, -49 -46, -55 and -56% at 0.4% sesamin) and gene expression (resp. -44, -47, -43, -60 and -50% at0.2% sesamin, and resp. -41, -39, +275%) and +139 thiolase (resp. 3-ketoacyl-CoA and 3-hydroxyacyl-CoA dehydrogenase (resp. +148 and +329%) +232%), and +127 CPT(resp. +768%), and (resp. +260 oxidase peroxisomal oxidation (resp. +207 and +600%), acyl-CoA SREBP-1 (resp. and -44%) of LDLrecep synthase (resp. -21 and -35%), squalene synthetase (resp. -30 reductase (resp. -23 and -30%), farnesyl pyrophosphate enzymes involved incholesterol synthesis: HMG-CoA ↑ ↑ dose-dependently ME activity (resp. +24%, NS, and dose-dependently HMG-CoA synthase activity Critical ReviewsinFoodScienceandNutrition ≈ -13%,NS,and -37%) mitochondrial (resp. +73 and and +73 (resp. mitochondrial tor (resp.-22and -28%); ith plateau reachedat 0.2% ≈ -30 and -35%) ≈ -37 and - ↑ mRNA ↑

≈ - (Kushiro etal., 2002) etal.,2001) (Ide 38 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Sesamin (1:1 mixture Sesamin and episesamin (1:1)

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Rats fed 8%-fat (palm,safflower fed8%-fat or fish oil) diet Rats Male hamsters diet fed10%-fat diet 10%-fat fed rats Male Male ICR mice fed 10%-fat diet 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

0.2% ofdiet 0.2% sesamin- 0.2% sesamin- 0.2% sesamin- diet episesamin of diet episesamin of diet episesamin of

15 days 15 days 15 days 15 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] ↑ ↑ ↑ ↓ ↑ ↓ ↑ ↑ ↓ ↑ ↓ ↑ ↓ ↓ ↓ ↓ peroxisomal gene expression (mRNA levels) of FA oxidation mitochondrial gene expression (mRNA levels) of FAoxidation activity ofthehepatic FA oxidation enzymes: mitochondrial ATPCL (-57%), (-66%) pyruvate (-55%),G6PDH FAS and CPT (+119%), peroxisomal FAoxidation (+243%), ACO mRNA levels of FAS (-63%), ATPCL (-45%) and mRNA levels of mitochondrial CPT(+70%), trifunctional peroxisomal FA oxidation (+11%, NS), and 3-hydroxyacyl-CoA (-2%,NS), (-3%, (- CPT FAS (-21%,NS), ACO NS), ATPCL mRNA levels of mitochondrial CPT(+8%, NS), of peroxisomal mRNA levels of mitochondrial trifunctional enzyme subunits peroxisomal acidfatty oxidation (+18%, NS) and ACO activity CPT (-10%, NS), 3-hydroxyacyl-CoA dehydrogenas (-14%, NS), effecton NS);no (resp. -2%, -29%, NS, and content TG lipogenic enzyme mRNA levels: (resp. ACC -35 and-43%), FAS lipogenic enzyme activities: FAS (resp. -59and-52%), ATPCL

+122%), (resp. +31 and +167%), 3-ketoacyl-CoA thiolase (resp. +44 and (resp. +47 and +495%), 3-hydroxyacyl-CoA dehydrogenase CoA oxidation, CPT (resp. +61 and +200%), acyl-CoA oxidase and 2,4-dienoyl-CoA reducatse (resp. +180 and + and 213%) +180 (resp. reducatse 2,4-dienoyl-CoA and (+399%) bifunctional enzyme (+926%) and 3-ketoacyl-CoA thiolase CoA thiolase (+142%), of peroxisomal ACO (+235%), kinase (-64%) +5%, NS, and +50%) 6%, NS) and short-chain mitochondrial 3-ketoacyl-CoA thiolase (resp. +84 and +178%), CoA thiolase (resp. 117 and + 391%) bifunctional enzyme (resp. +156 and +1347%) and 3-ketoacyl- +312%), peroxisomal NS,and (resp. +67%, ACO +73%), enzymes: carnitine octanoyltransferase (resp. +31%, NS, and subunit dehydrogenase (resp. +28 and +50%), trifunctional enzyme enzymes: CPT II (resp. +46 and +110%), long-chain acyl-CoA kinase (-64%) activities activity (+80%) thiolase ketoacyl-CoA (+259%), 3-hydroxyacyl-CoA dehydrogenas (+89%) and 3- enzyme subunits NS) activity dehydrogenas (+16%, NS) and 3-ketoacyl-CoA thiolase (+14%, 32%), G6PDH (-3%, NS) and pyruvate kinase (-13%) activities and NS) (+8%, ketoacyl-CoA thiolase (+38%), ofFAS (+3%,NS), ATPCL ACO (+20%, NS), bifunctional enzyme (+25%, NS) and 3- NS) (+15%, NS) activities (-26%, NS), G6PDH(-37%, NS)and pyruvate kinase(-4%, 3-ketoacyl-CoA thiolase (-13%, NS), FAS (-2%, NS), ATPCL cholesterol content (resp. 0 and +7%, NS); -55%) and and -42 (resp. -41%), G6PDH and -69%), -47 and ATPCL (resp. -64 (resp. pyruvate kinase (resp. -37 and -61%) -54%), -52%) and and G6PDH -52 (resp. and -44 and 2,4-dienoyl-CoA reductase (resp. +114 and +343%) and +114 (resp. reductase 2,4-dienoyl-CoA and 65%) NS) α (resp. +80 and +182%) +182%) and (resp. and +80 Δ 3 ,

Δ β 3 2 , -enoyl-CoA isomerase (resp. +88 and +190%) Critical ReviewsinFoodScienceandNutrition (-27%, NS) and 3-ketoacyl-CoA thiolase (-8%, Δ L 2

-enoyl-CoA isomerase (resp. +122 and +561%) -pyruvate kinase (+13%, NS) -pyruvate α (+145%) and L

-pyruvate kinase (resp. -49 and - β

(+126%) and 3-ketoacyl- (+126%)and β (resp. +70 and +178%), +178%), and +70 (resp. ↑ PL content (resp. L

-pyruvate α (- (Ide et al., 2004) etal.,2004) (Ide (Kushiro etal., 2004) 39 Page 206of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 207of267 Sesamin (1:1 mixture Sesamin Matairesinol episesamin) of sesamin and episesamin) of sesamin and

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), (palm oil)diet fed10%-fat Rats Male rats fed standard diet HepG2 cells Ovariectomized ratsfed fat) 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : standard diet (11.5% (11.5% diet standard

0.2 or 0.4% of 250 mg/5 mL 0.01, 0.1 and 1 0.02% ofdiet diet b.w. olive oil/kg μ M

15 days 3 days 3 days 4 weeks For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

Significantly up-regulated gene expression of late-stage ↑ ↑ ↓ ↓ ↓ ↓ Significantly up-regulated expression ofgenes encoding for PL level: resp. +19, +30 and +19% +19% and resp. +30 PL level: +19, Significantly up-regulated gene expression of early-stage Significantly down-regulated geneexpression early-stage of Cholesterol level Cholesterol Significantly down-regulated geneexpression of TG level TG

mRNA levels of hepatic peroxisomal proteins (carnitine activity ofthehepatic fatty acid oxidation enzymes: peroxisomal -19%, and TG(resp. NS) -27 and -30, (resp. cholesterol TG levels (-12%, and NS) NS) (-6%, cholesterol mRNA levels of enzymes involved in hepatic fatty acid synthesis FAS (resp. -45, -63and -48, NS, %), ATPCL (resp. -53, -60 and β (resp. trifunctional enzyme mitochondrial (very-long-chain acyl-CoA dehydrogenase, for fishoil CoA reductase (resp. for fish +60% oil and for oil +290% fish and CoA isomerase (3.4-fold), enoyl CoA hydratase (3.0-fold), peroxisomal bifunctional enzyme (4.5-fold), 3,2- fold), peroxisomal 3-ketoacyl-CoA thiolase (8.3- and 3.4-fold), hydrolase-like protein (3.4-fold), acyl-CoA hydrolase (2.1- 4.7-fold: different probe position in rat genome), acyl-CoA (114.6-fold), very-long-chain acyl-CoA thioesterase (14.2- and proteins with a lipid-metabolizing function: acyl-CoA hydrolase and -12%, NS) contents +320 and +300%; +300%; and +320 acyl-CoA dehydrogenase, trifunctional enzyme subunits (CPTII, medium-chain acidoxidation fatty inhepatic involved (resp. (carnitine octanoyltransferase) mitochondrial (CPT I like protein and CPT II) and peroxisomal 2.2-fold) and ME(2.8- and (2.1-fold) ACO (2.6- and 2.2-fold), 1 reductase Δ mitochondrial (acyl-CoA syntahse 5) oxidation enzymes +233, +140 and +78%; +78%; and +140 +233, short-chain (resp. oil fish enoyl-CoA isomeraseand 3,2- (resp. for fishoil CoA thiolase, PEX11 and thiolase, CoA octanoyltransferase, ACO, bifunctional enzyme, 3-ketoacyl- palmytoyl-CoA- oxidation (resp. (resp. oxidation palmytoyl-CoA- spotand(ACO, FAS,ATPCL 14) -70%) and G6PDH (resp. -60, -77 and -38, NS, %) activities safflower oil, NS, and -22% for fish oil safflower oil, -22% oil NS, and for fish 3-ketoacyl-CoA thiolase and 2,4-dienoyl-CoA reductase ) reductase 2,4-dienoyl-CoA and thiolase 3-ketoacyl-CoA peroxisomal (ACO, enoyl CoA hydratase, bifunctional enzyme, kinase (0.37-fold) and Apo A-IV (0.48-fold) , 3-ketoacyl-CoA thiolase, 2,4-dienoyl-CoA reductase and 3 , Δ 2 -enoyl-CoA isomerase (3.0-fold), 2,4-dienoyl-CoA : resp. -68, -23 and +136% +136% and -23 -68, : resp. ≈ ≈ ≈ ≈ +267 and +667%), CPT (resp. +163, +200 and +196%; +200, +325 and +400%; +150, +87 and +58%; vs palmoil+sesamin) palmytoylCoA oxidation, ACO vs vs Δ 3 palm oil+sesamin) and peroxisomal (resp. palmoil+sesamin), 3-ketoacyl-CoAthiolase , : resp. -20, -21 and +21% +21% and -21 : resp.-20, Δ Critical ReviewsinFoodScienceandNutrition 2 -enoyl-CoA isomerase) isomerase) -enoyl-CoA ≈

+10% for +110% +10% and for safflower oil, NS, β ≈ vs +247, +177 and +71%; , 2,4-dienoyl-CoA reductase 1, vs ≈ palm oil+sesamin), and 2,4-dienoyl- +10% for safflower oil, NS, and NS,and +40% forsafflower oil, +10%

palm oil+sesamin), CPT (resp. α ) and of mitochondrial enzymes enzymes ofmitochondrial ) and

≈

trans β -33% for safflower oil and -52% -oxidation enzymes ≈ ≈ ≈ +15% for +15% safflower oil, NS, for +50% safflower oil, NS, +550 and +1150%), ACO

-enoyl-CoA isomerase)-enoyl-CoA and β -oxidation enzymes ≈ vs +214and +343%), 3- palmoil+sesamin) L ≈ -type pyruvate +1%for trans Δ -enoyl- ≈ 3 0, -15 ,

Δ ≈ α ≈ +325, 2

and - β - (Arachchige et al., 2006) (Tsuruoka etal., 2005) (Cho etal., 2004) 40 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Sesamin +sesamolin Sesamolin Sesamin

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Rats fed 10%-fat (palm oil) diet (palm oil) fed10%-fat Rats diet (palm oil) fed10%-fat Rats diet (palm oil) fed10%-fat Rats palm (8% oil fed10%-fat Rats diet (palm oil) fed10%-fat Rats Rats fed 10%-fat (8% palm (8% oil fed10%-fat Rats

ester) diet ester) diet 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : + +

2% EPA ethyl 2% DHA ethyl

0.14 0.06or 0.2% of 0.06or 0.2% of 0.2% ofdiet 0.2% ofdiet 0.2% ofdiet diet diet diet + 0.06% of

10 days 10 days 10 days 15 days 15 days 15 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 4 experiments ↑ ↑ ↑ ↑ ↓ ↓ ↑ ↓ ↓ ↑ ↓ ↓ ↑ ↑ All experiments

activity ofthehepatic FA ox activity ofthehepatic FA ox activity ofthehepatic FA ox mRNA abundance of enzymes involved in (from in FA oxidation involved enzymes of mRNA abundance TG(-34%) and cholesterol (-23%) levels; (-67%) pyruvate ATPCL (-56%), G6PDH (-56%), and FAS peroxisomal palmytoyl-CoA oxidation (+148%), and ACO ch and (resp.-30%) -18and TG G6PDH -67%), -55%), and and (resp. ATPCL -34 -35 (resp. FAS peroxisomal palmytoyl-CoA oxidation (resp. +51 and +321%), ch and (resp.-64%) -59and TG G6PDH -57%), -60%),and and (resp. ATPCL -41 -38 (resp. FAS peroxisomal palmytoyl-CoA oxidation (resp. +8, NS, and +46%), mRNA levels of hepatic peroxisomal proteins (carnitine β palmytoyl-CoA oxidation( ( oxidation palmytoyl-CoA- palmytoyl-CoA oxidation( levels; levels; hydroxyacyl-CoA dehydrogenase (resp. +333%) +312%) ketoacyl-CoA thiolase ( thiolase ketoacyl-CoA acyl-CoA dehydrogenase, trifunctional enzyme subunits II, (CPT medium-chain acidoxidation fatty inhepatic involved dehydrogenase ( dehydrogenase ( 3-ketoacyl-CoA thiolase (resp. +250%), enoyl-CoA hydratase ( hydratase enoyl-CoA +250%), synthase) 39%) activities (resp. -49 and -64%) and pyruvate kinase (resp. -15%, NS, and - +65%) activities and +61%) and 2,4-dienoyl-CoA reductase (resp. +37 and (resp. +28 and +89%), 3-ketoacyl-CoA thiolase (resp. +12, NS, dehydrogenase 3-hydroxyacyl-CoA sesamin), at 0.2% +32% +88%), enoyl-CoA hydratase (-3%, NSat 0.06% sesamin; and ACO (resp. +8, NS, and +31%), (resp.CPT +31 and PEX11 and thiolase, CoA octanoyltransferase, ACO, bifunctional enzyme, 3-ketoacyl- +140%), enoyl-CoA hydratase ( hydratase enoyl-CoA +140%), +211%), 3-hydroxyacyl-CoA dehydrogenase( +10% at 0.06% sesamin for trifunctional enzyme subunit kinase (-45%) activities activities reductase (+101%) 2,4-dienoyl-CoA (+139%) and thiolase hydroxyacyl-CoA dehydrogenase (+156%), 3-ketoacyl-CoA (+99%), CPT (+130%), enoyl-CoA hydratase (+76%), 3- activities (resp. -51 and -68%) and pyruvate kinase (resp. -20 and -51%) activities +157%) and +57 (resp. reductase 2,4-dienoyl-CoA and +249%) and (resp. +64 thiolase CoA dehydrogenase (resp. +68 and +228%), 3-ketoacyl-CoA enoyl-CoA hydratase (resp. +24 and +100%), 3-hydroxyacyl- and +279%), +64 +220%), CPT(resp. and ACO(resp.+59 and , 3-ketoacyl-CoA thiolase, 3-hydroxy-3-methylglutaryl-CoA ↑ ↑ PLlevel (resp. +6%, NS, and +37%) NS) PLlevel(resp.0and +6%, : : Critical ReviewsinFoodScienceandNutrition ≈ ≈ +188%) and 3-ketoacyl-CoA thiolase ( +141%) and 3-ketoacyl-CoA thiolase ( ≈

+151%) α idation enzymes: peroxisomal idation enzymes: peroxisomal idation enzymes: peroxisomal ) and of mitochondrial enzymes ≈ ≈ +420%), ACO( +500%), ACO( ≈ +300%), ACO ( ACO +300%), olesterol (resp. -17 and-30%) olesterol (resp. -25 and-25%) ≈ ≈ ≈ +146 and +242%) +73%), 3-hydroxyacyl-CoA +48%), 3-hydroxyacyl-CoA ≈ ↑ +175 and 263%) and +175 PL level (+42%) ≈ ≈ +540%), CPT ( +575%), CPT ( ≈ +300%), CPT ( ≈

+183%) and3- +183%) α ≈ ≈

β and to ≈ ≈

≈

(Lim etal., 2007) 41 Page 208of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 209of267 Secoisolariciresinol Secoisolariciresinol Stilbenes containing B5 - Stilbenes 1-Crui Curcumin - C1 Curcumin C -Phenolic-derived A and C longistylin cajanin, and diglucoside (SDG) (SDG) l diglucoside secoisolariciresino or (SECO) cajan (from extract-fraction compounds

L.), L.), Cajanus Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), i.e.

Mice fed hypercholesterolemic (2% cholesterol Hypertriacylglycerolaemic rats (10% fructose in Rats fed high-cholesterol (1%) diet Rats fed high-cholesterol (1%) diet

Rats fed high-cholesterol (1% +0.15% bile salts) and 0.5% cholic acid) diet acid) 0.5%cholic and drinking water) diet 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

3 and 6 mg/kg 1.6 or 3.2 mg 3 or 6 mg 0.15% ofdiet 100 and 200 b.w. b.w. SECO/kg SDG/kg b.w. mg/kg b.w.

7 weeks 4 weeks 2 weeks 4 weeks 4 weeks For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] - histological observations: SDG -

- ↓ ↓ ↑ ↓ ↓ ↑ - - - mitochondrial- CPT II, rifunctional enzyme subunits SECO - peroxisomalcarnitine octanoyltransferase, ACO, bifunctional - histological observations: NS) - - ↓ ↑ ↓ mRNA abundance of proteins involved in lipogenesis in almost TC (-16%), PL TG(-22%) TC and CE (-22%), (-18%, NS); HMG-CoA reductase (resp. -9%, (resp. - and TG NS, (resp. -23%)and -10%,NS,and TC SREBP-1c mRNA expression level (resp. -9 and -38%) PPAR ↓ ↑ median percentage fat accumulation at 1.6 mg/kg (+7%, NS) and LI(resp. -103%, NS, and -15%, NS) LI(resp. -10%, NS,and -12%, NS) ↑ median percentage fat accumulation (resp. -8%, NS, and -24%, ACAT2 (resp. +54 and +66%), CYP7A1 (+10%, NS, at 6 ApoE(+35%, NS,at 1.6 mg/kg), HMG-CoA reductase (resp. content (+6%, NS) (resp. 14%) contents and ketoacyl-CoA thiolase, 1a and -1c -1c and 1a dehydrogenase, DGAT 1 and 2, spot 14, adiponutrin, SREBP- glycerol3-phosphate mitochondrial pyruvate kinase, G6PDH, at 0.2% sesamolin for pyruvate kinase): ACC, FAS, ATPCL, -69% to sesamin+sesamolin for mixture of 0% all cases(from (-32%, NS,atmg/kg), 3 PPAR and -21%, NS), CYP7A1 (-7%,NSat 3 mg/kg), LDLreceptor 6 mg/kg) mRNA expression levels; and -22%, NS) mRNA expression levels (resp. -6%, NS, and-24%, NS) andSREBP-2 (resp. -15%, NS, HMG-CoA reductase (-6%, NS, at 3.2 mg/kg), LDL receptor 0.6%, NS at 3.2 mg/kg), CYP7A1 (resp. -36%, NS, and -71%), ↓ 1.6 mg/kg) and PPA and+35%,+28, NS, HMG-CoANS), reductase (+8%, NS, at expression levels; dienoyl-CoA reductase SREBP-2 (-27%, NS, and -19%, NS) mRNA expression levels enzyme, 3-ketoacyl-CoA thiolase and P11 octanoyltransferase): carnitine peroxisomal for at0.2%sesamolin +544% LDL receptor (+6%, NS,at 6 mg/kg) and PPAR mg/kg), HMG-CoA reductase (resp. +28, NS, and +35%, NS), median percentage fat accumulation at 3.2 mg/kg (-24%, NS) : :

≈ α +84%) mRNA expressions mRNA expression level (resp. +36 and +31%) ≈ +20%, NS, and Critical ReviewsinFoodScienceandNutrition ↓

ACAT2 (resp. 0 and -7%, NS), ApoE (- γ (resp.+17%, NS, and +17%, NS)mRNA ≈ Δ +48%) andLDL-receptor (resp. ↓ ↓ 3 amount of lipids amount of lipids , Δ ≈ +14%, NS, and 2

-enoyl-CoA isomerase and 2,4- γ (-14%, NS, at 3mg/kg) and ↓

ApoE (resp. -35%, NS, α

≈

+61%), CYP7A1 γ

(+2%, NS, at α and ↑

FC FC β ≈ , +28 3- (Felmlee 2009) etal., (Luo et al., 2008)

(Seetharamaiah and Chandrasekhara, 1993) 42 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Steroid saponins Saponins (purified) Commercial white Commercial white saponosides Purified Changkil saponins saponins Changkil Changkil saponins saponins Changkil Soy saponins Mixture of ucmn asfd1%ftde 02 fde 4 weeks 0.2% of diet Rats fed 10%-fat diet Ginsenosides (Rb C2 - Saponins Curcumin

Rc, Rg (from officinalis Saponaria Soapwort, European from (probably saponins officinalis Saponaria Soapwort, European from (probably saponins oleanosides) (mixture of 9 mandshurica from ginseng ginseng ( Re) prufied from grandiflorum Platycodon (from root of grandiflorum Platycodon (from root of meal) and B (from oat avecanosides A acidified ethanol washed with citrus pectin plant roots) +

Aralia Gypsophila Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), 1 ) and , Rd Panax Panax ) )

) )

1 ,

Rats injected with with injected Rats Rats chronically fed with ethanol (enteral administration (5 g/kg b.w.) for around 36 hours Mice fed saponins for 7 days before ethanol HepG2 cells and6.5% (40%) fed high-fat gerbils and Rats Rats fed standard diet fedstandard Rats fed Leghorn) white and (brown hens Laying Rats fed standard diet containing methionine- Rats fed normal or high-cholesterol (1%) diet and 2% margarine fedfatty(40% Rats

ethanol-extracted oatmealdiet with acidified ethanol standard diet casein (25%energy) supplemented sodium isolates of soybean or cholesterol) diet (with 0.01% methylthiouracil) min before killing feeding)for 4weeks 535-590. DOI :10.1080/10408398.2010.549596

Comment citercedocument : C-acetate from 30to 120 ± citrus pectin washed citrus pectin washed

5 mg injected i.p. 0.5,mg/kg 1or 2 b.w. 0.5,mg/kg 1or 2 10 ng/L 0.07% ofdiet 0.2% + 10% of 0.1, 0.2 or 0.4% 0.1, 0.2 or 0.4% 0.1 or 0.5% of 1% ofdiet 1% ofdiet 0.005 or 0.01 before killing before b.w. diet of diet of diet diet g/kg b.w.

Last 2 weeks 7 days hours 24 (gerbils) 21 5 weeks 18 weeks 8, 7or 6 5 or 8 weeks 56 days 3 weeks 12 weeks 4 hours (rats) days days (rats) 19 and Only weeks Review Peer For

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Histopathological observations: observations: Histopathological 0.01 g/kg 0.005 g/kg

Histologic observations: Compared to standard diet without citrus pectin effectNo oncholesterol content (resp.-3%, NS, and+8%, NS) Soybean-based diet Casein-based diet ↑ ↓ ↓ ↑ ↓ ↓ ↑ ↓ ↓ ↓ ↓ At 90 min. before killing: Rats Taking 100% as rate of cholesterol synthesis at 5 mg Rb Gerbils

Compared to standard diet with 10% citrus pectin Rb

rate of cholesterol synthesis from and (-4%, NS)contents lipid (-37%) and TC phosphorylated-AMPK level (resp. +16%, NS, +59 and +93%) content TL (resp. dose-dependently TG content (-7%, NS, -22 and -36%) PPAR lipid content (resp. -15%, NS, -21 and -29%) lipid content (resp. 0, -11%, NS, and -19%, NS) lipid content (resp. -16%, NS, and -26%) cholesterol (resp. -7%,NS, and 1 macrovesicular fat droplets contents acetate (resp. +209,+55, ≈ 39%) concentrations -21, -4%, NS, +23 and -53%) amounts, and FC/TC ratio at before killing (max. at 90 min: +73%) and TC(+13%, NS) contents TC (-65%)TC contents : +12% at : ≈ ↓ ↑ 0.5 mg and mg and 0.5 TL (-31%), and TC (resp. -10, -19,-14, -5%, NS, and +8%) and FC (resp. 0,

: α ↓ ( : TL(-4%, NS), TC NS)and FC (-6%, (-6%, contents NS) ≈ : ↓ +60%) and PPAR

↑ TL (-35%), TG (-35%) and TC (-11%) contents and and ≈ 10 mg, Critical ReviewsinFoodScienceandNutrition : ↓

≈ ↓ TL (+8%), TG(-40%) and TC(+14%) contents ≈ : -68% at 0mg injected

-15%, NS,-32 and -45%) cholesterol content (-4%) ↑ cholesterol content (+41%) ≈ -24% at ↑ ↓ TC (+2%, NS) and (+6%,FC NS) fat deposition and micro-faint and ↑ rate of cholesterol synthesis from

+32, +11%, NS, and +76%) and +32, +11%,NS, γ ( ≈ ↓ +80%) ≈ -52%) and TG (resp. -20 and - steatosis score (-49%) 3 mg, 14 C-acetate from 30to 120 min ≈ -65% at : ↓ :

TL (-68%) and ≈ ↑ 1.5 mg, 1.5 TL(+6%,NS)

1 injected: ≈ -68% 14 C-

(Pathirana et al., 1980) (Oakenfull et al., 1979) (Wojcicki etal., 1977) (Sakakibara et al., 1975) (Khanal et al., 2009a) (Khanal et al., 2009b) (Ricketts etal., 2005) 1995) Asp, and (Onning (Rotenberg and Eggum, 1986) (Whitehead et al., 1981) (Kamal-Eldin etal., 2000)

43 Page 210of267

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 211of267

β β β Saponins (from Phytosterol mixture Sitosterol Sitosterol and Sterols (from soy) Phytosterols from Phytosterols

C3 -Phyto- C3 -sitosterol -sitosterol -sitosterol -sitosterol Platycodi radix (57% spinasterol sterols/stanols maize (72.5% campesterol) 35% and 7% stigmasterol) and campesterol sitosterol, 20.5%

β Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human

Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

-sitosterol β ) - Mice fed diet containing safflower oil (0.5%) 90% pancreatectomized diabetic rats fed high-fat mg for 24 (12 diets daily) or fedcholesterol Rats Rats fed high-cholesterol (1%) diet Hamsters fed standard chow Mice fed ordinary powder diet

Rats fed diet containing combination of Male (M) andfemale (F)mice fed cholesterol Normal and hypothyroid rats fed high- Mice fed high-cholesterol (1%) diet with 0.25, (0.5%) diet (0.5%) cholesterol (1%) diet 0.5 or 1.0% of cholic acid or 10% containing fat andbutter (9.5 (0 or 0.5%) safflower oil 0.005% and butter fat (9.5containing (40% as energy) diet 4 weeks 0.28% cholesterol) campesterol,

535-590. DOI :10.1080/10408398.2010.549596 β -sitosterol and

≈ 0.005% Comment citercedocument :

≈

0.004% campesterol, β -sitosterol and and -sitosterol ≈ 0.28% cholesterol) ≈ 0.004% 0.004%

≈

0.2 g/kg b.w. 24,or 48mg 96 12,or 24mg 48 3% ofdiet 2% ofdiet 1% ofdiet 0.5% ofdiet 0.1, 0.5 or 2.0% 1% ofdiet 1% ofdiet 1% ofdiet 5% ofdiet 2.5% ofdiet of diet

8 weeks last weeks 3 last weeks 3 7 days 7 weeks 15 days 40 days 33 days 35 days 31 days 5 days and1, 3 5days 12 days 13 days 3 weeks For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

10% butter fat, 0% safflower oil and 0.5% No significant effect onACC (0 and -3%), ME ( Prevented the increase in st 12 mg cholesterol daily 24 mg cholesterol daily 2.0% No significant effect onFA content (resp. +13, +16 and -3%);

Campesterol ↓ ↓ ↓ ↓ ↓ ↓ ↓ 10% butter fat and 0% safflower oil 9.5% butter fat, 0.5% safflower oil and 0.5% 0.5% 0.1% Steryl glucoside Ergosterol Stigmasterol β ↓ ↓ ↓ ↑

cholesterol level (-52%)

TG content ( phosphorylated-ACC level (resp. +10%, NS, +40 and +70%) ACC (resp. -68, -70 and -69%), ME (resp. -63, -63 and -63%) and cholesterol concentration (-32%) and steroid 12 cholesterol (resp. -26 and -22%) and PL (resp. -4%, NS, and -3%, cholesterol (-54%) and TG(-44%) contents cholesterol content (resp. -23%, NS,-50 and -65%) - F: NS; (M:-7%, lipid neutral -sitosterol TC contentTC (-76% for normal rats and-83% for hypothyroid rats) with -7% and -47 -27, (resp. TC

NS) contents contents; no effect on PL content; observations) observations) activity (-30%) cholesterol content (resp. +1%, NS,and -3 and -8%) NS)serum concentrations ApoB (-9%, cholesterol content (-27%), and (+38%) serum concentrations (-31%), TG(-9%, NS) and PL (-2%, NS) contents; phytosterol daily (+23%) (resp. 0,-5 and +11%)activities except for ACC at 48 mg G6PDH (resp. -81, -76 and -74%) activities NS) levels -68%) contents serum concentration (+40%) (+7%, NS) serum concentrations and PL (+4%, NS) contents; contents; (+4%, NS) and PL NS) and PL (+6%, NS)contents;

β β β -sitosterol -sitosterol -sitosterol : : ↓ : :

↓ cholesterol content (-53%, n = 2 experiments)

↓ ↓ cholesterol content (-67%, n = 2 experiments) ≈

cholesterol content (-53%, n = 2experiments) cholesterol content (-57%, n = 2experiments) -17%, NS) : : : : ↓ Critical ReviewsinFoodScienceandNutrition ↓ ↓ ↓

cholesterol content (-18%, NS)

cholesterol content (-32%), and cholesterol content (-23%), and TG(-7%, and NS) NS) (-18%, cholesterol : : ainable lipids (microscopic ↑ 53%) and cholesterol (M: -48%; F: (M:-48%; cholesterol and 53%)

ApoA-I (+7%, NS) and ApoB ApoB NS)and (+7%, ApoA-I p ↑

TG (+6%, NS) and PL (+2%, PL and (+6%, NS) TG ↑ : ≅ ↑

ApoA-I (+19%, ApoA-I (+19%, NS) and 0.05 at 1.0% cholic acid)

ApoA-I (+22%) and ApoB and ApoB (+22%) ApoA-I β

-sitosterol β -sitosterol

≈ α 0)and G6PDH -hydroxylase -hydroxylase ↑ ↑

TG (+4%, NS) TG (+4%, (+16%, TG ↑

ApoA-I ApoA-I ↓

: cholesterol ↓

↓ ↓

(Kwon et(Kwon al., 2009) (Laraki etal., 1993) (Katagiri and Shimizu, 1992) (Kuroki etal., 1983) (Uchida et al., 1983) etal., 1982) (Sugano (Katz et al., 1970) (Best and Duncan, 1956) 1955) Anthony, and (Beher 44 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Phytosterol mixture (from Phytosterols Plant sterol mixtures Plant sterol mixtures Sitostanol Phytosterol mixtures Plant sterol mixture Free phytosterol from Free phytosterol (free) Nonesterified (free) Nonesterified Free phytosterol, (69% tall oil or soybean) pure sitostanol sitostanol), and and tall oil (0.2% (0.01% sitostanol) from soybean sitostanol) 0.8% and and tall oil (0.2 (0.01% sitostanol) from soybean material phytosterol soybean sitostanol-free and tall-oil) sitostanol containing naturally campesterol) 6% and 12% sitostanol sitosterol, (82% stanols) from and (sterols phytosterols esterified tall oil and (20%) from talloil (80%)/stanols phytosterols (20%) from talloil (80%)/stanols phytosterols or stanols esterified sterols campesterol) 15% and 16%, sitostanol

β Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), -sitosterol, r (from 0.15% cholesterol Gerbils fed high-fat (13.7%) diet containing Gerbils fed high-fat (13.7%) diet containing Gerbils fed high-fat (13.7%) diet containing Gerbils fed 0.15%-cholesterol diet ApoE-KO mice (model of atherogenesis) fed Hamsters fedcholesterol-enriched (0.25%) diet Rabbits fed cholesterol- Rabbits fed atherogenic diet (0.5% cholesterol) Hamsters fed 0.25% cholesterol standard diet Rats fed high-cholesterol (1%) diet liposomes with injected i.v. Rats diet fedstandard Rats 0.15% cholesterol 0.05, 0.10or 0.5%cholesterol mouse diet 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : enriched (0.25%)diet

0.75% ofdiet 0.75% ofdiet 0.5% ofdiet 0.75% ofdiet 2% ofdiet 0.51% or 1% ofdiet 1% ofdiet 0.001, 0.2 or 1% 1% ofdiet 1% ofliposomes 2% ofdiet of diet humans) in as found sisterolemia mimick (to

5 weeks 4 weeks 4-5 weeks - 20 weeks 90 days 45 days 50 days 45 days 10 days hours 42 7 days For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Soybean phytosterols Tall oil sterols Tall oil phytosterols oil Tall

Phytosterol consumed in a way alternated between diet without No significant effect onHMG-Co Stanol esters: Sterol esters: Tall oil sterols Phytosterols consumed with each dietary serving of cholesterol Soybean sterols

↑ ↓ ↑ ↓ ↓ ↓ ↑ ↓ ↓ ↑ Free phytosterols:

CYP7A1 activity (-26%) (-26%) activity CYP7A1 - and -30 -20, (resp. (resp. cholesterol -62%) -64,-65 FA and and TC (resp. -57, -71 and -39%), FC(resp.0,-38 and -11%, -71 and -57, NS) and TC (resp. -76%) and -88%) and CE (resp. -76 and -80, -91,-88 TC (resp. HMG-CoA reductase (+184%), cholesterol 7 cholesterol level (-54%) cholesterol ( hepatic cholesterol fractional synthetic rate (2-fold at 1%; no serum HDL cholesterol (+49%) for phytosterol mixtures naturally HMG-CoA reductase activity (+148%) and mRNA level ( (in % per day) (resp. +41%, NS, and +35%, NS) 10%, NS) in % per day (resp. -39%, NS, and -16%, NS) oil sterols and pure sitostanol) content NS) 32%) contents days phytosterolsand dietwith 0.15% of freephytosterol every other TC (-78%), FC (-19%, NS) and CE (-89%) concentrations level mRNA HMG-CoA ( +150%) concentrations concentrations NS) CE (resp. -72, -82 and -40%, NS) concentrations contents significant with both 0.001 and 0.2% levels) containing sitostanol ( phytosterols) sitostanol-free soybean phytosterol material (only unsaturated (+18%, NS) and sterol 27-hydroxylase :

↓

TC (-66%), FC (-19%, NS) and CE (-74%) concentrations and (-66%), concentrations CE (-74%) FC(-19%, NS) TC

↓ ≈ ↓ (0.8% sitostanol): (0.8% sitostanol): (0.2%

-74%, NS, for soybean sterols, and

TC (-77%), FC (-11%, NS) and CE (-88%) TC (-76%), FC (0) and CE (-88%) concentrations (0.01% sitostanol): Critical ReviewsinFoodScienceandNutrition ↓

TC (-80%), FC(-11%, NS) and CE (-91%) : : ↑

hepatic cholesterol fractionalsynthetic rate ↓

hepatic cholesterol fractional synthetic rate ≈

16 or 20% content); no effect with ≈

+160%)

↓ ↑ A reductase activity (-3%), and

median cholesterol level (-31%, median cholesterol level (+24%, ↓

median cholesterol level (- 11

(+3%, NS)activities α -hydroxylase ≈ -92% for tall ≈

: ↓

↑

et(Hayes al., 2002) (Wijendran et al., 2002) (Moghadasian et al.,2001) (Ntanios et al., 1998b) (Ntanios and Jones, 1998b) (Ntanios et al., 1998a) (Ntanios and Jones, 1998a) (Ling and Jones, 1995) (Shefer etal.,1994) 45 Page 212of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 213of267 diacylglycerol and in peroxisomal enzyme rate-limiting (ACO1, Oxidase ABBREVIATIONS t s r q p o n m l k j i h g f e d c b a MethylGlutaryl-Coenzyme A Synthase 2; i.p., intraperitoneally; IC intraperitoneally; i.p., 2; Synthase A MethylGlutaryl-Coenzyme comparsions and further relevant interpretations interpretations relevant further and comparsions oxidation of of oxidation Cholesterol; FFA, Free Fatty Acids; GAPDH, GlycerAldheyde-3-Phosphate DeHydrogenase (involved in glycolysis); G6PDH, Glucose-6- G6PDH, in glycolysis); (involved DeHydrogenase GAPDH,GlycerAldheyde-3-Phosphate Acids; FreeFatty FFA, Cholesterol; Coenzyme A; CPT, Carnitine PalmytoylTransferase (allows transfer of long-chain FA across mitonchondrial membrane membrane mitonchondrial FA across oflong-chain transfer (allows PalmytoylTransferase Carnitine CPT, A; Coenzyme Cardol: natural mixture of unsaturated C15 alkylresorcinol congeners, Cardanol: natural mixture of unsaturated C15 alkylphenol alkylphenol C15 unsaturated of mixture natural Cardanol: congeners, C15 alkylresorcinol of unsaturated mixture natural Cardol: daidzein and glycitein genistein, of respectively 18% and 1 40, Contains No inthereference given data ofhesperetin Metabolites Provinol 5- Phytosterols are composed of 22% of brassicasterol, 31.9% campesterol, 43.2% 43.2% campesterol, 31.9% brassicasterol, of 22% of composed are Phytosterols Catechins from greentea extract are composed of48% EGCG, 31%EGC, 13% ECG and8% EC oil) bran rice from (isolated sterols and alcohols triterpene of esters acid ferulic of Mixture Allterms used in the Table are precisely thoseof the article considered: for exemple,the hepatic contentinTG was named “co Isolated from fermented Koreansoybean paste Contains 48% EGCG, 31% EGC, 13% 13% 31% and8%EC ECG EGC, 48% EGCG, Contains Mainly contains quercetin-3- (isorhamneti flavonols and - LU7Glu) luteolin-7-glucoside - AP7Glu, apigenin-7-glucoside luteolin, (apigenin, Contains flavones isoflavones or unconjugated conjugated of mixtures respectively are U-iso C-iso and contains extract water 2.5% flavonoids; and acids phenolic respectively of mL mg/100 29.9 and 51.3 contains extract water 1.25% Contains protocatechuic acid (24.24%), catechin (2.67%),gallocatechins (2.44%), caffeic acid (19.85%) andgallocatechin gallat Polyphenon-100 tothe control, compared lipotrope by the induced percentage increased or thedecreased Indicates Δ

Conjugated linoleyl Cardol, Cardanoland 5- -C4 Alkylresorcinols Alkylresorcinols Alkylresorcinols Phytosterol mixture Phytosterols and α FA su unsaturated required ofhighly synthesis for 6 desaturase,

-saturated derivative of sitosterol of sitosterol derivative -saturated n Anacardic acid brans) rye from and wheat homologues lipid l (resorcinolic alk(en)ylresorcino β (from rye (from rye bran) ± margarines commercial phytostanols - soy lecithinsoy -sitosterol -sitosterol ® contains min. 95% of total polyphenols (proanthocyanidols 46%, prodelphinidol 21%, total anthocyanes 6.1%, catechin 3.8%, epic catechin 6.1%, anthocyanes total 21%, prodelphinidol 46%, (proanthocyanidols min. 95%of polyphenols total contains

fatty acids acids fatty Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), ® : ABCA, ATP-Binding CAssette transporter (also known as the cholesterol efflux regulatory protein that is encodes gene by ABCA1 is that encodes protein regulatory efflux the cholesterol as known (also transporter CAssette : ATP-Binding ABCA, contains more than 80% than catechin, more contains Acyl-CoA); EC,EpiCatechin; ECG, EpiCatechin Gallate; ECH1, Enoyl-CoAHydratase/3-hydroxyacyl-CoA dehydrogenase ( s

via t

phosphorylation of its substrates and control of gene transcription; has an ability to react to fluctuations in the AMP:ATP ra inAMP:ATP the to fluctuations react to anability has of transcription; gene and control of its substrates phosphorylation β - D

Rats fedstandardRats diet(0.2% cholesterol) 3T3-L1 cells (model tostudy adipocyte 3T3-L1 cells (model tostudy adipocyte Enzyme assays:methanolic solutions of Inbread Mice fed 2 weeks with hyperlipidemic diet then Rats fed high-cholesterol (1%) diet -galactoside (2.9%), quercetin-3- (2.9%), -galactoside differentiation) differentiation) (2 U/mL) enzyme with lipids resorcinolic 2 weeks with basal diet diet basal with weeks 2 ( phytostanols) i.e. overabsorb ph rats with amutation in the 535-590. DOI :10.1080/10408398.2010.549596 i.e. i.e.

β -oxidation of long-chain and saturated FA; ACO2, oxidizes branched-chain FA); ADH, Alcohol DeHydrogenase (NADH DeHydrogenase FA); ADH, Alcohol branched-chain oxidizes FA; ACO2, andsaturated long-chain of -oxidation 9.4% EC, 13.4% EGC, 53.9% EGCG, 1.7% ECG, 2.9% GCG and 0% CG 0% and GCG 2.9% ECG, 1.7% 53.9% EGCG, EGC, 13.4% EC, 9.4% Comment citercedocument :

ytosterols and and ytosterols β ch as EPA, DHA and AA, e.g. rate-limiting enzyme conversion e.g. for EPA, DHAand AA, ch as 50 - D , concentration required for 50% inhibition; ICR, Imprinting Control Region; IDH, Isocitrate DeHydrogenase; i.v., intravaneousl i.v., DeHydrogenase; Isocitrate IDH, Region; Control Imprinting ICR, inhibition; for 50% required , concentration -glucoside (3.4%), kaempferol-3- (3.4%), -glucoside Abcg5

β -sitosterol and 2.9% others; phytostanols are composed of 54.7% campestanol and 44.8% sitostanol sitostanol 44.8% and campestanol 54.7% of composed are phytostanols others; 2.9% and -sitosterol gene 0.2% ofdiet 0.04% ofdiet 0.1, 0.2 or 0.4% From 2.5 to 12.5 From 4 to 50 From 2.5 to 12.5 0.25

i.e.

μ of diet μ diet

steatogen diet (NS - Not Significant - means absence of significativity for the change observed; in other cases, the effect w the effect cases, other in observed; the change for of significativity absence means - Significant Not (NS- diet steatogen

M M β ± - 0.15% of 0.15%

-glucoside (13.4%), kaempferol-3- (13.4%), -glucoside μ M

5 weeks weeks last 2 5 weeks 4 weeks 7 days in Changes via For Peer Review Only Review Peer For mic diet hyperlipide with for 15 min 15 for absorbance carnitine binding); CYP7A1, CYtochrome P450 or Cholesterol 7 Cholesterol or P450 CYtochrome CYP7A1, binding); carnitine es (27.98%) congeners, Anacardic acid: natural mixture of unsaturated C15 alkylphenolic acid congeners acid alkylphenolic C15 unsaturated of mixture natural acid: Anacardic congeners, n and quercetin) 97.1 and 58.9 mg/100 mL of respectively phenolic acids and flavonoids flavonoids and acids phenolic respectively of mL mg/100 58.9 and 97.1 ntent”, “concentration” or “level”, and in some case noterm was used; studies reportingboth lipotrope-like andnon-lipotropic of linoleic acid into arachidonic acid

Phosphate Dehydrogenase Dehydrogenase (NADPH,H Phosphate URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] β atechin gallate 3%, OH cinnamic acid 1.8%, flavanol 1.4%, resveratrol 0.15% and free anthocyane 0.095%) 0.095%) anthocyane andfree 0.15% resveratrol 1.4%, flavanol 1.8%, acid cinnamic OH 3%, gallate atechin - D

↓ ↓ ↓ -galactoside (4.5%), (2R,3S)-catechin (29.8%) and (2R,3R)-epicatechin (2.6%) - 0% inhibition from 4 - from - from 50 (4 - from 50 - from - from 0 (4 (4 - from 0 5- ↓ ↓ 0.4%: 0.1 - from - from

- intermediate- betweenand C15:0 C21:0 - from - from 0 (4 (4 - from 0

catalyses the

TGcontent/accumulation: LI (-14%), and TC (-44%) and TG TC(-44%) and (-40%) LI (-14%), levels and HMG-CoA reductase (-1%, NS, and -4%, NS, plus lecithin) and cholesterol (-22% and -8%, NS, plus lecithin) and TG (-12%, NS,

cholesterol levels (resp. -40 and -16%)

μ = 6.3 μ ACAT (-12% and -12% plus(-12%ACAT and lecithin)activities -43%and plus lecithin)concentrations activities activities n M) M)

35%) concentrations concentrations and 0.2%: no effect onTL, TCand cholesterol inliver lipids -pentadecylresorcinol ↓ ≈ ≈ ≈ ≈ ≈ ); ACAT, Acetyl/Acyl-CoA:Cholesterol Acetyl/AcylTransferase (forms CE from cholesterol); ACC/CBX, Acetyl-CoA Carboxylase (invol Carboxylase Acetyl-CoA ACC/CBX, CE from cholesterol); (forms Acetyl/AcylTransferase ACAT, Acetyl/Acyl-CoA:Cholesterol );

tio); ApoA/B/E, ApolipoproteinA/B/E; ATPCL/CCE, ATP Citrate Lyase/Citrate Cleavage Enzyme (an important step in fatty acid bio TL (-18%, NS), TC (-47%) and cholesterol in liver lipids (- -5 to to -5 -25 to -32 to μ -15 to

-35 to

M) and hepta-decylresorcinols (C 17:0, IC

second and and second μ M) to 20% (50 20% to M) (50 30% to M) μ ≈ M) to 100% (11 (11 100% M) to

≈ -50% for anacardic acid ≈ ≈ ≈

-93% for heneicosylresorcinol (C 21:0, IC (C heneicosylresorcinol 21:0, for -93% -70% for Cardol -80% for Cardanol -59% for pentadecylresorcinol (C 15:0, IC Critical ReviewsinFoodScienceandNutrition

third third μ M to50 : reactions of the of reactions + +

-generating enzyme involved in alcohol breakdown); AIN,American Instituteof Nutrition; AMPK

-generating enzyme); GPDH, Glycerol-3-Phosphate DeHydrogenase (key enzyme in TG synthesis); HMG-CoA, 3-Hydroxy-3-MethylGlutaryl HMG-CoA, in TG synthesis); (key enzyme DeHydrogenase GPDH, Glycerol-3-Phosphate enzyme); -generating

μ μ

M) inhibition for G6PDH activity M) inhibition for ADH and LDH μ

M) inhibition fro GPDH activity μ M for IDH M for IDH

fatty acid acid fatty α Hydroxylase (enzyme for the (enzyme for initialHydroxylase step of rate-limiting bi y; LDH, LDH, y; ↓

for nona- (C 19:0, IC 19:0, (C nona- for β - oxidation oxidation L -Lactate DeHydrogenase; LDL, Low-Density Lipoprotein; LDLR, Low-Density Lipoprotein Receptor (involved in transfer of lipids in of lipids transfer in (involved Receptor Lipoprotein Low-Density LDLR, Lipoprotein; Low-Density LDL, DeHydrogenase; -Lactate 50 = 8.2 cycle);EGC, EpiGalloCatechin;EGCG, EpiGalloCatechin Gallate; ER, (o)EstrogenReceptor; FA,FattyAcid;FattyFAS,Acid Syntha

50 μ =5.0 =10.7 M)

as either significant or no information was given in the article) article) the in given was information no or significant as either 50

(Ross et al., 2004) (Rejmanand Kozubek, 2003) (Chen et al., 2010b) (Li etal.,2010) (Shin etal., 2004) le acid synthesis from cholesterol); DGAT, DiacylGlycerol AcetylTr effects ( effects i.e.

an increase in hepatic lipid content and/or lipogenic enzyme activities) are also presented to allow to allow presented also are activities) enzyme lipogenic and/or lipid content hepatic in increase an α , AMP-activated protein Kinase Kinase protein , AMP-activated synthesis); ved in FA synthesis; is ihibited when phosphorylated); ACO/ACOX, Acyl-CoA Acyl-CoA ACO/ACOX, phosphorylated); when ihibited is synthesis; FA in ved

b.w., body weight; CE, Cholesteryl Esters; CG, Catechin Gallate; CoA, Gallate; CG,Catechin Esters; CE, Cholesteryl weight; body b.w., α (AMPK regulates several Coenzyme A; HMGCS2, HMG-CoA/3-Hydroxy-3- ansferase(catalyzes the formationof intracellular systems including including systems intracellular to hepatocytes); LI, Liver Index Index Liver LI, to hepatocytes); se/Synthetase; FC, Free Free FC, se/Synthetase; TG from

46 β - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 (i Dehydrogenase Acyl-CoA Medium-Chain MCAD, Lipase; LipoProtein LPL, LysoPhosphatidylCholine; LPC, weight); weight/body (liver mM); NS, Not Signficant; PC, PhosphatidylCholine; PE, PhosphatidylEthanolamine; PEX11 PE, PhosphatidylEthanolamine; PhosphatidylCholine; PC, Signficant; Not NS, mM); receptors); SRE, Sterol Regulatory Element; SREBP, Sterol Regulatory Element-Binding Proteins; Element-Binding Regulatory Sterol SREBP, Element; Regulatory SRE, Sterol receptors); respectively; SCD, Stearoyl-CoADesaturase (catalyzesthe rate-limiting step inthe biosynthesis of monounsaturated FAand its

, peroxisomal membrane protein; PL, PhosphoLipid; resp., respectively; PPAR, Peroxisone Proliferator-Activated Receptor (transc Receptor Proliferator-Activated Peroxisone PPAR, respectively; resp., PhosphoLipid; PL, protein; membrane , peroxisomal

TC,Total Cholesterol;TG, TriGlyceride; TL, Total Lipids; UCP2, mitochondrialUnCoupling Protein2 (participates in excess cal For Peer Review Only Review Peer For deficiency increases fatty acidoxidation byactivating hepatic AMP-activated proteinkinase); SDG, Secoisolariciresinol DiGluc

nvolved in FA URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] β -oxidation); MCD, Malonyl CoA Decarboxylase; ME, Malic Enzyme; mRNA,messenger RiboNucleic Acid;MTP, Microsomal Triglyceride Critical ReviewsinFoodScienceandNutrition orie burning; increased UCP2 level lead to increased toincreased lead level UCP2 increased burning; orie ription factor of genes involved in lipogenesis); PPAR lipogenesis); in involved of genes factor ription

oside; SECO, SECOisolariciresinol; Sph, Sphingomyelin; SR-B1, Scavenger Receptor class B type 1 (oxidized LDL LDL 1 (oxidized type B class Receptor Scavenger SR-B1, Sphingomyelin; Sph, SECOisolariciresinol; SECO, oside; β

-oxidation and energy expenditure, and decreased lipid levels) α -null KO (Knock Out) mice, homozygous mice for deletion ofPPAR for deletion mice homozygous mice, Out) (Knock KO -null Transfer protein (role in lipoprotein assembly); n.i., no inhibition (IC no n.i., inhibition assembly); inlipoprotein protein (role Transfer

α gene; resp., resp., gene; 50 > 1 > 47 Page 214of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 215of267 Supplemental Table 5 its or Oatmeal Cottonseed Corn oil Plant extract or plant- Rice bran,defatted branoil(RBO),Rice Menhaden fish oil Safflower or branoilRice Safflower oil Whole wheatbreads Liquid aged garlic and oatWheat brans, Arachis oil,3 ethanol extract (control) coconut oil hydrogenated based foods rice bran of rice brans 4levels and DRB, oil (DRB), RBO + defatted rice bran menhaden fish oil or rye breads butter extract (Kyolic barley malted and barley gum and wax and rice bran oil bran oils (n = 2), margarines coconut oils

vs Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

vs e , rice

c and

® ) Rats fed 10%-fat diet fed diet Rats 10%-fat Healthy male subjects fed Rats fed fat-free and high-fructose/glucose fat-free high-fructose/glucose Rats fed and Rats fed white breads Rabbits fed 20%-fat diet (no control group) Hepatocytes isolated from rat liver and incubated Rats fed AIN 76-based and high-cholesterol (1% Hypercholesterolemic hamsters (control diet Malehamsters fed 0.3%-cholesterol diets (all Rats traineddays 10with high-glucose (58.43%) Rats traineddays 10with high-glucose (58.43%) Rats fed high-cholesterol (1% +0.5% cholic acid) In vivo Rats and gerbils fed high-fat (40%)and 6.5% American type diet PUFA, injected with supplemented with then days 7 dietfor (72%) with 0.5 mM [1- + 0.1% cholic acid) diet fatand 3%nitrogen 9% corn oil): all diets contain 10% fiber, 9% contains 0.3% cholesterol, 10%cellulose and contains 10% fiber and 9% fat) (control) tripalmitin or oil PUFA-rich with and fat-free then diet, supplemented 7days with PUFA-rich oils ortripalmitin (control) and fat-free then diet, supplemented 7days diet after injection cellulose diet

In vivo In or 535-590. DOI :10.1080/10408398.2010.549596 in vitro and models 14 in vitro in C]acetate Comment citercedocument : ± 1% cholesterol cholesterol 1% 3 H

ad libitum 2 O andO killed 20 min studies effectsreporting lipidhepatic on metabolism follow

institutional 7.5% (NSP and Resp. 50.2, 41.3- 35+ 35, Resp. 9, 20% digestible 20% digestible 10%diet of 5% or 10% of daily dose Supplemented - 20%diet of 10%diet of (24- ounce One 6.5% of diet 0.01, 0.05, 0.1, d

mM 0.4 and 0.2 lignin)diet of of diet 0.2% and 0.9 41.5, 7.9-9.0, 10.9% 32.8, 21.8and 8.9, and 43.7, dietenergy of dietenergy of diet 33 g)

days (rats) 19 and 21 (gerbils) 4 hours 14 days 21 days 21 days 7 days - 8 weeks 3 or 4 days 16 weeks 42 weeks 7 weeks 1 month exposition exposition lipotrope Duration of For Peer Review Only Review Peer For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Glucose Fructose Gerbils Corn oil Corn Hepatic effect(s) Rye breads - defatted bran +rice branoil: resp. -2%, NS, and -14%, NS - defatted bran +rice bran oil-gum/wax: resp. -29 and -27%, NS - defatted bran +rice bran oil wax: resp. -8%, NS, and -30% - defatted bran +rice bran oil gum: resp. -1%, NS, and -24% - defatted bran: -12%, NS, and -26%, NS -33% and -37 resp. - bran: Hydrogenated coconut oil ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↓ ↓ Rats

Males

Whole breads wheat Females esterol pool (+15%, NS,for barley pool esterol Compared to 20%-butter group: ar

rate of[1- cholesterol pool(-23% cholesterol and TG contents: (resp. content TG cholesterol content (resp. -5%, NS,-18, -15, -24, -8%, NS, -12%, -7%) and -9 -9, -11, -9, NS, -4%, -11, (resp. LI transcription rate of FAS(-94%) and S FAS mRNA abundance ( TG NS)contents NS)and (-32%, TC (-22%, phosphofructokinase (-10%, NSat 5% fat level) activities; level), glucokinase (-19%, NS at10% fat level) and synthesis (-32% at5% fat level and -76% at 10% level) month dienoic acid content (resp. +85, +50, +14 and +152%) acid (resp. -59, -72, -72 and 51%) contents, and toenhanced 72%), cholesterol (resp. -66, -51, -71 and 51%) and tetraenoic +600%), FC (+95 +600%), FC +493%), FC (+93 +493%), FC M2 and M3)lead toreduced concentrations 0.2 (-76%) and 0.4 (-87%) mM; no significant changes at other NS, and-3%) 87% for n-3-rich menhaden fish oil) fat level) FC (resp. -10 and -24%) -24%) and FC (resp.-10 7%, NS at 5% fat level) activities; lipogenic protein,-79%) NS, +14%, NS, and and NS, +14%, NS, barley barley and FC (resp. -10 and -15%) and -10 FC(resp. and : ↓ : adding cholesterol TL (resp. -8%, NS, and -10%, NS), TC (-52 and -55%) and -55%) and and -8%, NS),TC TL(resp. -10%, (-52 and NS, : : : : adding cholesterol : ↓ ↓ TL (resp. -2%, NS, and -1%, NS), TC (-38 and -34%) -34%) (-38 and NS), -2%, TL(resp. NS, -1%, TC and ↓ ↓ vs vs

FAS (-71% at 5% fat level) and phosphofructokinase (-

liver cholesterol (-25%) : FAS (-50-64% at 5% fat level), ACC (-57% at 10% fat 14 malted barley) malted barley) wheatbran) ↓ C]acetate incorporation into

TG level (NS) (NS) level TG ing supplementation of plant ing supplementation orplant-basedfoods of extracts

Critical ReviewsinFoodScienceandNutrition

≈ 0,+17%, NS, +13%, NS, +11%, NS, +13%, vs vs : ↓ +27%) and PL (+227 +80%)PL and (+26

TG (NS) and cholesterol levels ≈ 3 0) for oat bran : ↑ ≈ -69% for n-6-rich safflower oil and for safflower oil and -69% n-6-rich ↓ TL (+475

liver cholesterol (+9%, NS) upon 1 ↑ TL (+218 (+218 TL

total FA (resp. -84, -81, -60 and -

achis oil and margarines (M1, b vs upon 1 upon month wheat bran; +31% for malted vs ↓ vs

FA synthesis (-53% at 5% for NS, -13%, wheat bran; 14 +110%) vs protein (putative cholesterol at0.1(-72%), +75%), TC (+2436 (+2436 TC +75%), vs vs +14%)contents -3%)contents 2 , TC (+1916 (+1916 , TC

↓

FA vs vs ≈ -

(Onning and Asp, 1995) Yeh,1994) and (Yeh (Jackson et al.,1994) (Kahlon etal., 1992b) (Kahlon etal., 1992a) (Blake and Clarke, 1990) (Clarke et al., 1990) (Sharma and Rukmini, 1986) (Toussant et al., 1981) (Yacowitz etal., 1976) etal.,1961) (Krogh (Okey et al., 1961) (Frantzand Carey, 1961) References

48 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Soy proteinenriched Tangerine-peel Olive (oleic acid- Sesame seedpowders Whole flours of tea dryGreen solvent 10% (w/v) brewed starchRice Platycodi with isoflavones with extract rich), sunflower sunflower rich), 0732) and sesamolin - 0730 sesamin and and lines rich in (Masekin cultivar, mL/g) triticale (8.07 mL/g)and (5.15 2 wheat mL/g), wheat(1.44 1 different viscosity: extracts green tea extract radix levels) (lowhigh or

aqueous Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), f

Rats fed 10%fat (mixture of64%tripalmitin, Rats fed high-sucrose (61.7%) diet Rats fed semi-purified diet (75.3% starch) HepG2 cells HepG2 cells Rats fed high-cholesterol (1%) diet with Female ICR mice fed high-fat (40%) diet Rats fed atherogenic diet (9% fat, 1.2% Rats fed standard AIN-76-based diet Lean andobese( Rats fed high-cholesterol (1%) diet 16% tristearin and20% corn oil; 1.80%) contents and 1.39, 1.52, 1.65 (1.26, resistantstarch and and 63%, completed with corn starch to 63%) increasing contents inrice starch (0, 15, 30, 45 cholesterol and 0.2% cholic acid) AIN-76-based diet 535-590. DOI :10.1080/10408398.2010.549596 fa Comment citercedocument : / fa ) Zucker rats fed standard) Zucker rats i.e.

≈

80% 80%

0-200 0-200 2% of diet (in 20%diet of 70%diet of 50 or 100 - 2 or 5% of diet 20% ofdiet 20% ofdiet 20% ofdiet 16.7% ofdiet

place of corn EGC equivalence of μ

μ M

2 weeks 16 days 21 days hours 24 4 weeks 8 weeks 63 days 42 days 70 days 6 weeks hours 24 For Peer Review Only Review Peer For

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Lean Zucker Obese Zucker No effect on TG concentration ↓ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↓ ↑ ↓ ↑ ↓ ↓ ↑ ↓ ↓ ↓ ↓ Ethyl acetateEthyl extract

and TG(resp. -15%, NS,-26%, NS, and -14%, NS) and cholesterol mitochondrial (resp. FAsynthesis enzyme activities: FAS (resp. -71, -66 and -71%), FA oxidation enzyme activities: ACO(resp. +59%, NS, +366 and LDLR bindingactivity ( extracellular media cholesterol concentration at200 ( transcription factor form of SREBP-1 (+62-65% at 200 LDLR bindingactivity ( serum propionate (resp. nondetectable, +40, +47and +60 (-32%) and TG TG -17%, and -6%, - NS), and (resp. NS,and NS, -7%, LI(resp. ACATactivities and (-38%) (-36%) reductase HMG-CoA LI (resp. -12 and -14%) and TG concentration (-17%, NS, - (-17%, and NS, TGconcentration and -14%) and -12 LI (resp. cholesterol concentration (resp. -54, -61 and -66%) cholesterol ( to compared 0%- -10, -7and-7% -1, NS, (resp. TC concentrations TG concentrations (resp. -17, NS,-21, NS, -24, NS, and -28% compared to0%-ricestarch content) compared to0%-ricestarch content) ≈ unesterified cholesterol (+14%) concentrations 23%); no effect on TC concentration rice starch content) +9%, NS, +56 and +52%) +52%) NS,+56 and +9%, +50%, NS, for water extract) at100 +20%, NS, for chloroform,for NS, +20%, +3%, NS, and +11%) ≈ ≈ ≈ NS), TC (resp. (resp. +9%, NS, -25, -34 and -53%) and PL (resp. concentrations 100 (resp. -10%, NS, -3%, NS, and 0%) levels; pyruvate kinase (resp. -56, -60 and -63%) and ATPCL NS, for cultivar), Masekin G6PDH, ME(-32%, and +176%) (resp. +226 +69, thiolase ketoacyl-CoA CoA dehydrogenase (resp. +235, +504 and +490%) and 3- +442%), CPT (resp. +124, +333 and +262%), 3-hydroxyacyl- NS, and -24%) concentrations; -8%, (resp. CE and NS) -2%, and NS, -1%, (resp. TC NS), 27%, +33%, NS, +261 and +356%) FA oxidation rate and tended to tended and (+2166%), and HMG-CoA reductase mRNA (+1335%) -29% at 50 -77%) concentrations -49%, NS), TC(resp. -88%) concentrations ↑

TC(resp. +15, -10%, NS, -23%, NS, and-3%, NS), TG μ M equivalence of EGC), protein (+2100%) and mRNA : noeffect onLI; ≈ : -30%at at 200

↓ μ LI (resp. L) and ↓ ↑ media chenodeoxycholic acid concentration (NS) Critical ReviewsinFoodScienceandNutrition ≈ TC (+12%, NS), (+12%,CE and NS) -18%, NS, and : ↑ ≈ dose-dependently LDLR activity (+312% at +44, +83 and +61%) and peroxisomal (resp. ↑ ( ≈ ≈ ≈ ≈ -26 and and -26 ≈ +145% for methanol, at 200 +80% +107% at200 +107% -34 and and -34

↓ μ ≈ TG (resp. TG L) andFC ( +167%forethyl acetate and ↑ ≈ ≈ unesterified cholesterol (resp. -35%) and (resp.CE -43%), and TG (resp. TG (resp. and -43%), ≈ -48%) and CE(resp.

M equivalence of EGC μ μ L) ≈ -54%, NS, and L) cholesterol synthesis ≈ -25%at 200 ↑ PL levels (resp. ≈ 0for hexane,

≈ μ 0,-3%, NS, -

L ( μ ≈ ≈ L)

-51 and ≈ ≈

≈ +25%)

μ -54%, -33 and and -33 -46 and μ M ≈ L)

≈

(Takeuchi etal., 2001) (Sirato-Yasumoto etal., 2001) (Adam etal.,2001) (Bursill etal., 2001) (Cheng and Lai, 2000) (Han et al., 2000) (Peluso et al., 2000) (Bok et al., 1999) 49 Page 216of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 217of267 Diluted beverages Green and black tea Dried apricot Olive oil,fish oilor Olivesunflower or Soy proteinenriched flourWhole wheat White wheat flour flourWhole wheat Wheat bran Sea buckhorn Sea buckhorn paprika and tomato from fat butter oil with isoflavones with bread and whole wheat PUFA-rich) (n-3 acid) or sardine oil levels) (lowhigh or ± with linseed (enriched PUFA-rich), (n-6 geraniol

α -linolenic Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

Micefedfor 7days control dietand i.v.injected diet AIN-93-based fed rats Zucker Obese Rats fed semi-purified diet (71.75% starch) Rats fed semi-purified diet (76% starch) Specific-pathogen-free female mice fed standard Rats fed high-fat ( CCl Rats fed methionine-choline deficient diet Rats fed 1 month with high-fat (14% olive or with Triton WR1339 diet FA) saturated commercial diet months) rats rats months) subcutaneouslyfor 3daysat theendthe of 5 (5%) diet (5%) sunflower oil) then 1 month with normal-fat 4 -treated (1 mL/kg b.w.injected 535-590. DOI :10.1080/10408398.2010.549596 ≈ 15%) diet Comment citercedocument : j 3 hours before killing

2.79 20%diet of 70%diet of 48.6%diet of 70.0%diet of 21.4%diet of 100% of fluid 100% of fluid or10 20% ofdiet 0.45 mg/g rat 14% then 5% of oil) intake intake diet b.w. ± 0.067 g/kg

6 weeks 26 weeks 5 months 2 months 1 month + 1 7 days 11 weeks 8 weeks 21 days 21 days For Peer Review Only Review Peer month For (females) (males)

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] - up-regulation of genes involved in FA synthesis (ME, FAS, Tomato No effect on TG content - down-regulation of genes involved in FA synthesis (elongation of - up-regulation of genes involved infatty acid degradation Hepatic cholesterol ( Light micrography Paprika ↑ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↓ Histology

Ultrastructural observations (transmission electrommicroscopy)

PPAR AST (resp. and ACC(resp.

liver weight (resp. -12%, NS, and -26%), and cholesterol (resp. - TG (resp. -39 and -32%) and ch TG (-32%) and cholesterol (-54%) concentrations TG (-45%) and cholesterol (-30%) concentrations TG (-40%) and cholesterol (-23%) concentrations and newly synthesized cholesterol (resp. -44 and -45% with geraniol) -27 (resp. cholesterol and -1%, (resp. NS, -28%), weight and liver 2%, NS, and -39%) and TG (-5%, NS,and -47%) concentrations β and -350%) and TG ( NS, +156, activities oil and less important effect with sunflower oil droplets): apparent complete steatosis disappearance with olive ≈ volume and number of lipid globules PCDGT (resp. PCDGT (resp. +480 and ACO (resp. 8%, NS, and +1%, NS) concentrations expressions affected) 17% had mild-moderate fatty infiltration (<60% hepatocytes olive oil, fish oil and butter fat diet, resp.; resp.93, 90, 67 and (>60% hepatocytes affected) with methionine-choline deficient, with MDA (resp. concentrations +400%), MCD (resp. SREBP-1, ATPCLand ACC long-chain fatty acid,FAS, steroyl-CoA desaturase 1, ME, reductase) (HMG-CoA synthesis cholesterol and member) family (cytochrome P450, CPT-1a, acyl-CoA synthetase long-chain synthesis (acetoacetyl-CoA synthetase) and lipid circulation long-chain family member and CPT-1a), and in cholesterol cholesterol synthesis and catabolism dehydrogense and acyl-CoA oxidase 2 branchedchain), and in dehydrogenase, enoyl-CoA hydratase/3-hydroxyacyl-CoA ATPCL and ACC -oxidation (resp. ↑ ↑ TG content (resp. G6PDH (resp.

≈ : α : -14%,NS, ( ≈ ≈ : +12%, NS, +167, ≈ ≈ +400 and 3, ≈ ≈ ≈ +46, +260%) and ACC (resp. 0,

≈ ≈ 3,33 and 88% of rats had severe fatty infiltration +1950 and and +1950 ≈ ≈ +222 and ≈ -50, Critical ReviewsinFoodScienceandNutrition : -4%,NS, ≈ ↓ ≈ +64, r -16%, NS, and

degree of liver steatosis (accumulation of fat ≈

=-0.8) and TG ( α ≈ +100, ≈ ≈ +400%), CPT-1 (resp. (resp. CPT-1 +400%), +11%, NS, +16%, NS, ) and degradation (acyl-CoA synthetase ≈ -64 and

≈ ≈

0 and -38%) concentrations -29%, ≈ ≈ +90and +1100 and and +1100 ≈ +1300%), SREBP-1 (resp. SREBP-1 +1300%), ≈ ≈ ≈ +222%) activities, and peroxisomal

+367,

+46%, NS, α -54%) -48 and (resp. olesterol ≈ ≈ -70%) and DGAT (resp. +12%, NS, and ) and degradation (acyl-CoA ≈ ≈ -31, -2%, NS, and ≈ ≈ ≈ +95%) and CPT (resp. CPT(resp. and +95%) -23%)activities +633 and r ≈ ≈ = -0.4) contents correlated correlated contents =-0.4) +1230%), FAS (resp. FAS(resp. +1230%),

+400 and ≈ -23 and ≈ +35%, NS, and ≈ +150and ≈ +567%) ≈ ≈ ≈

≈ +6%) -65%), PAP -65%), +570%) gene -16%) and ≈ +770 and ≈ +650%), ≈ ≈ -14%, 0) ≈

≈

: ↓

et(Aizawa al., 2009) (Chen et al., 2009) (Ozturk etal., 2009) (Hussein et al., 2007) (Hernandez et al., 2005) (Wu etal., 2005) (Mezei et al.,2003) (Adam etal.,2003) (Adam etal.,2002) 50 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Ziziphus Mauritania Garlic aqueous Cinnamon bark Cauliflower

Monascus Mulberry extract Ginkgo biloba Sophora japonica butter oil, Coconut Freezed-dried coffee Freezed dried melon extract (20%, w/v) alcoholic extract extract mushroom water sylimarin sylimarin extract aqueous leaf soybean unfermented soybean or deoxynojirimycin) (0.53% of 1- extract and seed) including pericarp dried mature fruits powder (from and flaxseed oil coffee decaffeinated or caffeine) (3% juice extract extracts

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

-fermented vs k ethanol

leaf L.

Chronic alcohol (40% ethanol Rabbits fed high-cholesterol (0.5 g/kg b.w. i.g.) Mice fed standard diet for 4 days, and killed on Genetically obese ( obese Genetically Rats fed high-fat (8% lard, 7% egg yolk powder Mice fed high-fat (30%) diet Hamsters fed standard diet Mice fed high-fat (30%) diet Male hamsters fed high-fat (24%) diet Rats fed hypelipidemic (10% pig oil, 10% diet standard fed Rats for 6 weeks weeks 6 for gb. mL/100 1 intubation, months (GII)months diet for 4months (GI), then standard diet for 3 b.w.) g/kg day 5 12 hours after i.g.ethanol injection (6 and 0.5% sodium chocolate) powdered egg yolk and 1% cholesterol) diet 535-590. DOI :10.1080/10408398.2010.549596 ob Comment citercedocument :

/ ob ) mice fedstandard diet w.) administered rats via gastric

100 or 200 400 mg/kg b.w. 1.5 mL/kg b.w. 0.5 mL/kg b.w. 100 or 300 0.2%diet of 1 or 5% of diet diet7% of 1.1%diet of 0.7, 2.8 or 5.6 200 or 400 intubation) stomach (direct mg/kg b.w. water) water) (in drinking mg/kg b.w. gavage) by solution mg (aqueous mg/kg b.w.

6 or 2 weeks 3 last months 4 days before 10 weeks 19 weeks 1 month 6 weeks 8 weeks 12 weeks 40 days 4 weeks injection ethanol Only Review Peer For

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] Co-administrationalcohol with Pre-administration Histopathological detection Fermented - blunted ethanol-induced hepatic steatosis by Unfermented

↓ ↓ ↓ ↓ ↓ ↑ ↑ ↓ ↓ ↓ ↑ ↑ ↓ Histological examinations - Microscopic and image analyses Histological analysis Down- and up-regulation of gene involved in lipid metabolism: lipid in ofinvolved gene and up-regulation Down- - down-regulation of genes involved in cholesterol synthesis and

cholesterol (-86% (-86% cholesterol mean steatosis grade (only 1/8 rat with steatosis of grade 1: <33% -42%) -28%) -43 ,TG(resp. and and -28 weight(resp. liver content TC (-20%, NS) TGcontent (resp. -37 and -61%); no effect on cholesterol content +56 TG(resp. +37, +123%) and and +373 +193, (resp. cholesterol LI(resp. +21, +15and +15%) lipid content (resp. -42, -71 and -73%) (resp; TC -16%, NS, -23 and -35%) and TG (resp. -16, -29 and – CPTI (resp. FAS (resp. TG level (resp. -10%, NS, and -23%); no effect on TC and PL TG content (resp. -38%, NS, and -10%, NS); noeffect on TC ↓ and -27% FA and cholesterol biosynthesis, 21%) and TG (resp. -16%, NS, and -44%) contents contents -43%) -47 and (resp. cholesterol bile acids, and bile acids, of hepatocytres were involved) compared to GI and GII -38%) contents (resp. and -35 TC occupied asmaller area) 58%, NS)accumulation fat( oil levels levels content activities; 8%, NS, at 100 mg/kg b.w.) activities 200 mg/kg b.w. and +39%) (resp. mRNA expression ( +85%), PPAR ( +45%)and ACO and +26%)contents: lower increases ( 32%) levels catabolism (bile acid biosynthesis) 5.6 mg) hepatocellular ballooning degeneration (LDL receptor)(LDL ≈ -36%, measured as % of microscopic field) and TG ( ≈

+60%, NS,and : ↑ vs HMG-CoA reductase/mevalonate ratio (+8%, NS, at ≈ : ↓

≈ +31%, NS, and and NS, +31%, GII) levels GII)levels

↓

ME (resp.ME +50 and HMG-CoA reductase/mevalonate ratio (-16%)

↑ α FAmetabolism Critical ReviewsinFoodScienceandNutrition ( via vs ≈ : improved (at 2.8 mg) and disappearance (at

+15%, NS, at 100 mg/kg b.w.) and AMPK ≈ GI and -78% gastric intubation (30 min before alcohol)

+36% at200 mg/kg b.w. at 100 mg/kg b.w.) ≈ ≈

-15%, NS, at 200 mg/kg b.w.)

+60%), ACO (resp. ACO +60%), ≈ :

≈ -25%, NS,and

: +145%) mRNA expressions; ↓ lipid accumulation (lipid droplets ≈

: +19%, NS), CPT (resp. ↓ : cholesterol (resp. -9%, NS, and - NS,and -9%, (resp. cholesterol and TG (resp. -42 and-38%) ↓ conversion of cholesterol into vs TG and (-46% GII) vs ≈

-2%, NS) and ACO ( ACO and NS) -2%, control) with flaxseed ≈

+5%, NS, and ≈ 45% 45% ≈

+45% and ↓

PPAR vs GI ≈ ≈

- ↓ ≈

: α

- ↓

≈

2009) Obidoa, and (Dahiru al.,(Arhan et2009) (Kanuri etal., 2009) (Park etal., 2009a) (Gu et al., 2009) (Park etal., 2009b) (Yang et al.,2009) (Fukushima etal., 2009) (Décordé etal., 2009) 2009) Seong, and (Pyo etal.,2009) (Tsuduki 51 Page 218of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 219of267

Commercial low- Codonopsis Platycodi radix Safflower oil or Refined rice bran oil, Garlic +medicinal Fermented ginseng rich/low- trans water extract lanceolata extract cocoa butter oil (1:1) w/w) or cod liver linseed oil(3:2, with refined alone or blended plant extracts extract radix ethanol stearin) palm and butterfat anhydrous oil, from flaxseed (synthesizeed structured fat

fatorn-3- Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), trans root root l

Apo E diet of (36% energy) fedethanol liquid Rats 90% pancreatectomized diabetic rats fed high-fat db HepG2 cells fat) (4% chow standard fed Rats Rats fed 10%-fat (refined groundnut oil) diet ethanol/kg 20% mL (10 of fed ethanol Rats (40% as energy) diet shortening, 53.4% b.w./day) diet / db mice fedstandard chow diet -/- mice fed a mice 10%-fat fed (commercial 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument : trans FA) diet

29.5or 29% of 10%diet of (0.5+ 1.%) or 100 or 200 100, 250 or 500 500 10%diet of 0.5%liquid of 2 g/kg b.w. diet of diet (1.0 + 1.0)% mg/kg b.w. μ diet

g/mL μ g/mL l

3 days 60 days 4 weeks 10 weeks hours 24 From 1 to 24 12 weeks 8 weeks 8 weeks For Peer Review Only Review Peer hours For URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] ↑ Cocoa butter Post-administration (2weeks without alcohol) after 6weeks ↓ ↑ ↓ ↓ ↑ ↓ ↓ ↑ ↑ ↓ ↓ ↑ ↑ ↓ ↓ ↓ Liver histology

Hepatic tissue morphology

ATPCL (4.00-fold), ME 1 (1.81-fold), pyruvate kinase (1.59- kinase ME1(1.81-fold), pyruvate (4.00-fold), ATPCL

SCD-1 mRNA expression (resp. (resp. TG (resp. -37%), -14,-27 TC and TL(resp. -14 and -28%), TC(resp. -17 and -23%) and TG (resp. - gene expression of pAMPK and pACC ( TGaccumulation (resp. time-dependently SREBP1c, SCD1 and FAS gene expression; phosphorylation of AMPK (max.: HMG-CoA reductase (resp. -12%, NS, and -51%), ACAT (resp. - -41%) cholesterol -31 (resp. and and -44%), and -34 and LI(resp. phosphorylated/total ratio of AMPK ( AMPK TNF ( TG content TG ( β (max.: and FAD 3 (1.69-fold) mRNA expression; FAD2(1.57-fold) FAD 1(1.71-fold), 1 (1.63-fold), ACAT fold), (2.00- 2 ACAT ligase (1.63-fold), acid-CoA bile (1.66-fold), lanosterol synthase (1.72-fold), farnesyl diphosphate synthase (1.72-fold), reductase 7-dehydrocholesterol (1.87-fold), epoxidase ligase (2.01-fold), HMG-CoA synthase (1.89-fold), squalene cholate-CoA (2.12-fold), decarboxylase (diphospho) mevalonate farn diphosphate farnesyl fold), and number of lipid droplets were normalized -38%) contents +26%) AMPK and ACC), and of CD36 and PPAR and +88%) activity activity +88%) and alcohol time-dependently PPAR reductase ( accumulation ofhepatic lipid droplets (0.22-fold) mRNA expression (0.22-fold) SCD (0.27-fold)and 1 2 SCD (0.48-fold), CPTpc (0.63-fold), thioesterase 1(0.63-fold), peroxisomal thioesterase acyl-CoA 2B subfamilyABC A (0.46-fold), mitochondrial acyl-CoA TG (resp. -9, -19 and -26%) contents contents -26%) and -19 -9, (resp. TG 9%, NS, and -30%) levels and -47%) and PAP (resp. 0 and -12%) activities -25 -18%),ME(resp. and -66%), NS, G6PDH (resp. and -52 6%, levels -16%) and -22 (resp. TG SREBP1a, SCD1 and FAS SREBP1a, SCD1 +10%, NS) mRNAlevels

-oxidation (resp. -4%, NS, and +96%) and CPT (resp. +17%, NS, ≈ α ≈ +71%) levels

-33%) and cholesterol (

( α ≈ ≈ : -37%), LXR 2.7-fold at 24 hours) ( ↓ cholesterol (resp. -15 and -35%) and TG(resp. -30 and ≈ ≈ +6%,NS +59 and : ≈ -41%) andLDLR( -41%) ≈ -44%) : enlargement of the hepatocytes and increase inthe Critical ReviewsinFoodScienceandNutrition

≈ ) +60%)andcholesterol (resp. α , ACC ( , ACC (

≈

≈ α -17%), SREBP-1c ( -80, : low- gene expression geneexpression ≈ ≈ +48%), FAS (+29%) and SCD1 ( PL (resp. -13, -35 and -40%) and -40%) (resp.-35 and and -13, PL ≈ -36%) levels -80 and trans ≈ esyl transferaseesyl 1(2.69-fold), -31%)mRNA levels ≈ -62 and ≈ 2.7-fold at 12 hours) and ACC and at hours) 12 2.7-fold structured fat importantly ≈ +133%) and ACC ( ≈ ↑ -95%) -95%) phosphorylation of ≈

-81%) ↓ α GPDH 1 (0.63-fold), ; ≈ -21%), HMG-CoA ↓ gene expression of ≈ +21%, NS, ↑

↑ ↓

≈

(Gustavsson et al., 2009) 2009) Sambaiah, and (Chopra etal., 2009) (Soo-Jung (Kim etal., 2009) etal.,2009b) (Cho (Cho et al., 2009a) (Kwon et al., 2009) 52 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 c l k j i h g f e d b a comparsions and further relevant interpretations interpretations relevant further and comparsions Safflower oil- and cocoa butter-enriched diet respectively contain 77 and 3% linoleic acid, 15 and 33% oleic acid, 6 and 25% pa 25% and 6 acid, oleic 33% and 15 acid, 3% linoleic and 77 contain respectively diet butter-enriched cocoa and oil- Safflower lipoproteins of TG-rich catabolism thus preventing and lipase lipoprotein by inhibiting hyperlipidemia WR1339 induces Triton Geraniolis monoterpenoid a alcohol Contains 0.6% hesperidin and 0.03% naringin naringin 0.03% and hesperidin 0.6% Contains Oil extracted at 54°C 54°C at extracted Oil Margarinesare made of different mixtures from whale/coconut/rapeseed/cottonseed oils:M1 (30/45/25/0), M2(75/0/25/0) andM3 ( Allterms used in the Table are precisely thoseof the article considered: for exemple,the hepatic contentinTG was named “co Enriched with bioactive mevinolins (natural statins) and aglycone isoflavones (daidzein, glycitein and genistein) genistein) and glycitein (daidzein, isoflavones aglycone and statins) (natural mevinolins bioactive with Enriched 0. respectively and soyisoflavones, of 0.0578% and 0.0038 contains respectively diet protein-based soy isoflavone high and Low Low- and high-isoflavone soy protein diets contains respectively <0.0009%, <0.0004%, <0.0005% and 0.116%, 0.0696%, 0.0754% oft 0.0754% 0.0696%, 0.116%, and <0.0005% <0.0004%, <0.0009%, respectively contains diets soyprotein high-isoflavone Low- and in thereference No given data tothe control, compared lipotrope by the induced percentage increased or thedecreased Indicates Hibiscus sabdariffa diet High-protein Dried chestnut inner Tomato powder Whole blueberry extract ( tuna ham, salami and providedeggs, by scoparone) scoparone) scopoletin and coumarins, contains 2 extract that shell (metahnol extraction blueberry peel residue from ethanol extract or blueberry peel fiber), 67.4% peels (pomace, polyphenols)

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), ≈ 2% i.e.

Malemice fed high-fat (21% lard + 0.15% diet AIN93M-based standard fed Rats Hamsters fed high-fat (37% energy) diet HepG2 cells HepG2 cells Male hamsters fed calorie-rich-fat (0.2% Healthy male fed high-fat (+30% of total energy cholesterol and 10% coconut oil) diet 674 Kcal)diet as fat compared to control normal diet: 1349 cholesterol) 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

150 mg/kg (i.g.) 10%diet of 8, 6or 2%ofdiet 0.11.0 or 0.1, 0.5 or 1.0 1 or 2% of diet Extra protein i.e. mg/mL mg/mL mg/mL Kcal) 784 high-fat diet: compared to (+77% energy steatogen diet (NS - Not Significant - means absence of significativity for the change observed; in other cases, the effect w the effect cases, other in observed; the change for of significativity absence means - Significant Not (NS- diet steatogen vs 337

77 days 5 weeks 3 weeks hours 18 6 hours 10 weeks 4 days lmitic acid,and 2 and 36% stearic acid Only Review Peer For 0024/0.0012/0.0002% and 0.0370/0.0178/0.0030% of genistein/daidzein/glycitein genistein/daidzein/glycitein of 0.0370/0.0178/0.0030% and 0024/0.0012/0.0002% ntent”, “concentration” or “level”, and in some case noterm was used; studies reporting bothlipotrope-like andnon-lipotropic 30/0/25/45) otal isoflavones, genistein equivalents and aglycone isoflavones isoflavones aglycone and equivalents genistein isoflavones, otal URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected]

↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↑ ↑ ↑ ↑ ↑ Liver histology: clear improvement of the microvesiular hepatic Safflower oil No effect on AMPK and ↑ ↑

SREBP1c ( ( TG cholesterol ( and FC(resp. dose-dependently FAS (resp. -10, -49 and -57%) and HMG-CoA (resp. cellular cholesterol cholesterol (resp. intrahepatocellular lipids ( relative SREBP-1 protein level ( AMPKphosphorylation ( rate( oxidation FA and CYP7A1 (2.34-fold) G ABCsubfamily (2.44-fold), ATPCL relative SREBP-1 protein level ( AMPKphosphorylation ( rate( oxidation FA LDL LDL uptake (resp. PPAR +24%), and (resp.+27 31, AMPKphosphorylated reductase (resp. -6, -7 an -7 (resp.-6, reductase mRNA expression; (3.64-fold) 0.4-, spectra protein expression +34, +30 and +37%) and LDLR (resp. +44, +47 and +51%) 83%), HMG-CoA reductase ( 34%) levels fold) 40, fold) mRNA expression thioesterase 1 (0.42-fold), SCD 2 (0.08-fold) and SCD 1 (0.10- steatosis expressions and (resp. (resp. fold), PPAR , and -38%) protein expression -3 and -26 (resp.-24, reductase ABCG5 (resp. ≈ 2.2- and ↑ ≈ ≈ ≈ mRNA levels of CYP51 (resp. -40 and -69%) and TC( -19%, NS) contents; no effect onTL content ≈ 0.7- and ≈ -30, ≈ -30%, NS, ≈ :

≈ -40%), FAS( -40%), ≈ α ≈ 2.5-fold), ABCB11 (resp. -36%) and TG ( -43 and and -43 ≈ (resp. (resp. -16%, NS) and TG (resp. ≈ ≈ 0.1-, 0.6-fold) and SCD1 (resp. andSCD1 0.6-fold) Critical ReviewsinFoodScienceandNutrition ≈ -25 and ≈ ≈ ≈ +175%) +75%, NS) +25 and 75%) ≈ 0.4-, ≈ ≈ ≈ ≈ -47%) contents

0.15- and and 0.15- -25%, NS, and -60%) contents β actin protein expression d 47%) protein expression; expression; d 47%)protein ≈ ≈ ≈ -21%, NS) NS) -21%, +11%, NS) ≈ ≈ -15%, NS, -22%) ascalculated from -50%), ACC1 ( ≈ ≈ -30%) and TG (resp. 1.8- and and 1.8- ≈ ≈ -22%) levels -95%) and ACAT ( 4%) and SREBP-1c (resp. 0,-25 (resp. SREBP-1c 4%) and ↓ ≈ ≈ mitochondrial acyl-CoA +23%) +62%) ≈ 0.4-fold), CYP7A1 (resp. ≈ 0.6-, ≈ ≈ 1.4-fold), ACO (resp. ≈ -34 and and -34 ≈ -25%, NS), TC (resp. 0.2-, ≈ -18%, NS, ≈ ≈ -83%), ACC2 ( ≈ 2.3- and 0.6-, ≈ 1.3- and ≈ -48%) and TG ≈ ≈ -27 and ≈ 0.8- and -89%) mRNA ↓ 1 ≈ ≈ HMG-CoA

H-MR

-26%, NS, 1.9-fold), 1.9-fold), α ≈ 1.7- (resp. (resp. ≈ ≈ - - ≈ ≈ ≈ 1.0- 2.4-

≈ - as either significant or no information was given in the article) the in given was information no or significant as either (Noh et al., 2010) (Alshatwi et al., 2010) (Kim etal., 2010) (Yang et al.,2010b) 2009) al., et (Bortolotti effects ( effects i.e. an increase in hepatic lipid content and/or lipogenic enzyme activities) are also presented to allow to allow presented also are activities) enzyme lipogenic and/or lipid content hepatic in increase an

53 Page 220of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Page 221of267 SynThetase; ATPCL/CCE, ATP Citrate Lyase/Citrate Cleavage Enzyme (an important step in fatty acid biosynthesis); acid in fatty step important (an Enzyme Cleavage Lyase/Citrate Citrate ATP ATPCL/CCE, SynThetase; when phosphorylated); ACO/ACOX, Acyl-CoA Oxidase; ACO/ACOX, when phosphorylated); ABBREVIATIONS FAD, Fatty Acid Desaturase; FAS, Fatty Acid Synthase; FC, Free FC, Synthase; Acid Fatty FAS, Desaturase; Acid FAD, Fatty Binding Proteins; Binding respectivel resp., PhosphoLipid; PL, Transferase; DiacylGlycerol PhosphoCholine PCDGT, Significant; Not NS, Acid; RiboNucleotic Lipoprotein; LDLR, Low-Density Lipoprotein Receptor (involved in transfer of lipids into hepatocytes); LI, Liver Index (liver w (liver LI, Liver Index into inhepatocytes); of lipids transfer (involved Receptor Lipoprotein Low-Density LDLR, Lipoprotein; Carnitine Palmitoyl Transferase; CPTpc, CTP:phosphocholine cytidylyltransferase; CYP51, Sterol 14 Sterol CYP51, cytidylyltransferase; CTP:phosphocholine CPTpc, Transferase; Palmitoyl Carnitine

Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

TC, Total Cholesterol; TG, TriGlyceride; TL, Total Lipids; TNF Lipids; Total TL, TG, TriGlyceride; Cholesterol; Total TC, : ABCA, ATP-Binding CAssette transporter (also known as the cholesterol efflux regulatory protein); ABCB11, ATP-Binding CAssett ATP-Binding ABCB11, protein); regulatory efflux asthe cholesterol known transporter (also CAssette : ABCA, ATP-Binding 535-590. DOI :10.1080/10408398.2010.549596 Comment citercedocument :

AIN, American Institute of Nutrition; AMPK, AMP- Cholesterol; G6PDH, Glucose-6-Phosphate (NADPH,H Dehydrogenase Cholesterol;

, Tumor Necrosis Factor alpha (involved in the development of fatty liver) fatty of development the in (involved alpha Factor Necrosis , Tumor α -demethylase (involvedin first step ofcholesterol synthesis);CYP7A1, Cholesterol 7

activated protein Kinase (AMPK regulates several several regulates (AMPK Kinase protein activated

b.w., body weight; CPT, Carnitine Palmitoyl Transferase (involved in long chain FA oxidation in mitochondria); CCl mitochondria); in FAoxidation chain in long (involved Transferase Palmitoyl Carnitine CPT, weight; body b.w., For Peer Review Only Review Peer For eight/body weight); weight); LXR eight/body y; PPAR, Peroxisone Proliferator-ActivatedReceptor; PUFA, Poly-UnsaturatedFatty Acid; SCD, Stearoyl-CoADesaturase (catalyzes + URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] -generating enzyme); GPDH, Glycerol-3-Phosphate DeHydrogenase (key enzyme in TG synthesis); HMG-CoA, 3-Hydroxy-3-MethylGlutaryl HMG-CoA, in TGsynthesis); enzyme (key DeHydrogenase Glycerol-3-Phosphate GPDH, enzyme); -generating e transporter also known as BSEP (Bile Salt Export Pump); ACAT, Acetyl/Acyl-CoA:Cholesterol Acetyl/AcylTransferase (forms fr (forms CE Acetyl/AcylTransferase Acetyl/Acyl-CoA:Cholesterol Pump);ACAT, Export Salt (Bile BSEP as known also transporter e

α , Liver X Receptor alpha (role in regulating expression of genes involved in hepatic FA synthesis); MCD, Malonyl CoADecarboxyl Malonyl MCD, in FA synthesis); hepatic involved genes of expression in (role regulating X, alpha Receptor Liver intracellular systems including including systems intracellular

Critical ReviewsinFoodScienceandNutrition α

Hydroxylase (enzyme for the initial rate-limiting step of bile acid synthesis from cholesterol); DGAT, DiacylGlycerol AcetylTr DiacylGlycerol DGAT, cholesterol); from synthesis acid of bile step rate-limiting initial the for (enzyme Hydroxylase β -oxidation of -oxidation fatty acids acids fatty via phosphorylation ofits substrates and control of gene transcription; has an abilityto react to fluctuationsin the AMP:ATP ra 4 , Carbon tetraChloride; CD36, , fatty acid translocase (long chain fatty acid transporter); CE, Cholesteryl Esters; CoA, Coenzy the rate-limiting step in the biosynthesis of monounsaturated FA); REBP, Sterol Regulatory Element- Regulatory Sterol REBP, FA); of monounsaturated in the biosynthesis step the rate-limiting Coenzyme A; ICR, Imprinting Control Region; i.g., intragastrically; LDL, Low-Density om cholesterol); ACC, Acetyl CoA Carboxylase (involved in FA synthesis; is ihibited is ihibited insynthesis; FA (involved CoACarboxylase ACC,Acetyl om cholesterol); ase; MDA, Malonyl DiAldehyde; ME, Malic Enzyme; mRNA, messenger messenger mRNA, Enzyme; ME, Malic DiAldehyde; Malonyl ase; MDA, ansferase; EGC, EpiGalloCatechin; FA, Fatty Acid; Acid; FA,Fatty EpiGalloCatechin; EGC, ansferase; tio); AST, Acyl-CoA Acyl-CoA AST, tio); me A; CPT, 54 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 A. Jorgensen, R. P., Angulo, F., M. Abdelmalek, REFERENCES Adam, A., Levrat-Verny, M. A., Lopez, H. W., Leuillet, M., Demigne, C. and Remesy, C. (2001). (2001). C. and Remesy, C. Demigne, M., Leuillet, W., H. Lopez, M.A., Levrat-Verny, A., Adam, Adam, A., Lopez, H. W., Leuillet, M., Demigne, M., Leuillet, W., H. Lopez, A., Adam, Adam, A., Lopez, H. W., Tressol, J. C., Leuillet, M., Demigne, C. and Remesy, C. (2002). Impact Aiyar, A. S., Sulebele, G. A.,Rege,S., Sulebele,and Aiyar, Sr A. D.V. S., Petitjean, Berni-Canani, M., Kabir, N., Aghelli, Aizawa, K., Matsumoto, T., Inakuma, T., Ishijima, Allmann, D. W. and Gibson, D. M. (1965). Fatty acid synthesis duringearly linoleic acid deficiency study. Betaine,aagent promising forpatients with new plasma and lipids and rats. hepatic in plasma wheatWhole andtriticaleflours withdiffering vi Chemistry in its rats in cholesterol-lowering exerts lipids in rats. rats. in lipids liver and plasma the and fermentations cecal the on fractions milling its and flour wheat whole of and ubiquinoneratin levels livermitochondria. 1288. chain fructo-oligosaccharides in and Rizkalla, S. W. (1998). Plasma lipids and fatty acid synthase activityare regulated short-by mice: a DNA microarray analysis. analysis. microarray a DNA mice: Administration of tomato and paprika beverages modifies hepatic glucose lipid and metabolism in in the mouse. the in Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), American Journal of Gastroenterology of Journal American

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ocellular lipid deposition in humans. lipid ocellular deposition Journal of Nutrition Comment citercedocument : For Peer Review Only Review Peer For Journal of Nutrition Faeh, D., Chetiveaux, M., ench, S.W.,Morgan, T.R.,Morgan, K. and Nutrition sulin resistance liver andfatty disease without tivities of 3-hydroxy-3-methyl-glutaryl-CoA of tivities 3-hydroxy-3-methyl-glutaryl-CoA

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120 : 1727-1729. Ith, M., Vermathen, P., L American Journal of of Journal American -carnitine therapy in in therapy -carnitine Critical ReviewsinFoodScienceandNutrition Journal of 59 Page 226of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 227of267 Wells, L.E.andCharacteriW. (1977). Burton, W. C. Bursill, A. and Roach, P. D. (2006). Modulation of cholesterol metabolism by the green tea Bottema P.D., C., Roach, Bursill, Buchman,A. L.,Dubin, M.D., Buchman, A. L.,Ament, M. E.,Sohel, M.,Dubin, Busserolles, J., Gueux, E., Rock, E., Demigne, E., Rock, E., Gueux, J., Busserolles, Caballero, Fernandez,Fernandez-Checa, F., A., and Garcia-Ruiz,C. (2008). J. C.Methionine Capanni, M.,Calella, F.,Biagin Agricultural and Food ChemistryAgricultural polyphenol(-)-epigallocatechin gallate in FoodChemistry and Journal ofAgricultural lipoprotein receptor through the sterol-regulated 1403. intravenous supplementation. reversed thatwith be choline can nutrition Ament,J. and M.E.(1995). Cho trial. controlled patients receiving parenteralproof nutrition: W., Awal,M. and Ahn, C.(2001). Cholinedeficien Oligofructose protects against the hypertriglycer the against protects Oligofructose myo steatohepatitis. steatohepatitis. nonalcoholic model anutritional of deficiency liveraccountsthedamage in for observed rats.fructose dietin polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non- G., Sofi,Milani, F., S.,Abbate,SurrenR., Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), -inositol deficient rats. rats. deficient -inositol Journal of HepatologyJournal of Journal of Parenteral and Enteral Nutrition Journal ofNutrition Journal of Nutrition Journal of 535-590. DOI :10.1080/10408398.2010.549596 Moukarzel, A.A.,Jenden, D. M., J., Rice, Roch, K.M.,Gornbein, i, M.R.,Genise,Raimondi, S., L.,Bedogni, G.,Svegliati-Baroni, , C. D. and C. D.and Pal,, (2001).Green S. teaupregulates low-densitythe

54 line deficiency:cause a ofhepatic steatosis duringparenteral

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: 1903-1908. 49

: 5639-5645. 107 ti, C. and Casini, A. C. andCasini, ti, of a human choline requirement: A A placebo- requirement: choline of ahuman M., Jenden, D. J., Roch, M., Pownall, H., Farley, Farley, H., M.,Pownall, J., Roch, D. Jenden, M., C., Mazur,Rayssiguier, A.and Y. (2003). element binding protein inHepG2 liver cells. zation zation of the lactation-dependent fatty liver in idemic and pro-oxidative effects of a high : 1871-1883. cy causescy reversible hepatic abnormalities in URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

25 : 260-268. (2006).Prolonged n-3 Hepatology Critical ReviewsinFoodScienceandNutrition Journal of Journal

22 : 1399- 60 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Catolla Cavalcanti, A.andLevis,(1950).Steatos F. Rubio,Casaschi, B.A., K., Maiyoh, Th G.K.and Choline defici (1982). Williams, L. and C. Carroll, Causi, N., Romano, A. and Galfano, G.(1958). Galfano, and A. Romano, N., Causi, Chahl, J. S. and Kratzing, C. C. (1966a).Kratzing, C. and Enviro J. S. Chahl, J.Cha, Y., Cho, Y. Kim,S., Chahl, J. S. and Kratzing, C. C. (1966b). andKratzing, J.S. C.Enviro Chahl, Chakrabarti, C. and Influenc C. (1969). B. Banerjee, Chakrabarti, Atherosclerosis flavonoid, taxifolin,in HepG2cells: potentialrole microsom and (DGAT) acyltransferase diacylglycerol sources. 1151. Mediche (Torino) action of pantothenic acid and of itscombination withmeso-inositol. pantothenic nicotinamide.and acid . 1. Choline deficiency in ra in deficiency Choline 1. . phosphohydrolasein orotic activity acid-fedrats. hesperetin,citrus flavonoid, a livertriacylglycerol onthe contentphosphatidate and 163-164. liver alcoholic fatty study. disease: a pilot Research Rats .2.Choline and Methionine Requirements forLipotropic Activity. Vitaminology hepatic biosynthesis ofcholesterol of albi Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Nutrition Reports International Reports Nutrition

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25 Comment citercedocument :

Alimentary Pharmacology Therapeutics and : 773-782. no rats kept on cholesterola high diet. Only Review Peer For nmental temperature and cho and temperature nmental nmental Temperatureand C Coenzyme A in rat liver during administration of of ratliver duringadministration A in Coenzyme Plant Foods forPlant HumanFoods Nutrition e of riboflavin, choline, inositol and niacin on is tophosphorus.of theliverdue I.Lipotropic in the regulation of apolipoproteinsecretion. theregulation of B in ency in rats as influenced by dietary energy- dietary by influenced as rats in ency eriault, A. G. (2004). Inhibitory activity of al triglyceride transfer protein (MTP) (MTP) by the transfer protein al triglyceride Journal of Lipid Research URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Yanagita,(2001). T. Effect of Archivio per le ArchivioScienze per holine Requirements in in holine Requirements line requirement in rats in line requirement Critical ReviewsinFoodScienceandNutrition Journal of Lipid Lipid of Journal

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34 61 : Page 228of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 229of267 (2008 K. C. Heng, M. Y.and Chan, Chan, T. Y. andTang, P. L. (1995).Effect of W.Chan, T.,Fong,P.,Cheung,P. Y. L., Huang, Chen, N., Bezzina, R.,Hinch, E., Lewandowski, P. A., Cameron-Smith, D., Mathai,M. L., Jois,M., Cheng, H. Cheng, H. and Lai,M. H.(2000). Fermentatio Chen, Q., Gruber, H.,Swist, E.,Coville, K.,Pakenham, C., Ratnayake, W.and Scoggan, K. Chen, H., Liu, L.-j., Zhu, J.-j., Xu, B.and Li, R. Chezem, J.,Colon,I.and Matheson, H. (1996). Di Chiba, H., Uehara, M., Wu, J., Wang, X. X., Masu X., X. Wang, Wu, J., M., Uehara, H., Chiba, the expression levels expression plasmahepaticthe and genes of lipids. homeostasis in the rat. inthe homeostasis Journal ofNutrition green tea epicatechins are hypolipidemic inhamsters ( differentially alter metabolic geneexpr metabolic alter differentially black tea, epigallocatechinand modify body composition, improve glucose tolerance, and tea, (2009). Green R. S. andWeisinger, S. H. Weisinger, D., Wark,J. D. P., J., Begg, A. Sinclair, reducing serum and hepatic cholesterol in in rats. cholesterol hepatic and serum reducing pressure WKY inbredratsin theabsence in salt-loading. of (2010b). Dietary phytosterols and phytostanols decreasecholesterol increase levels but blood 1633-1636. blood lipid, glucoseblood antioxidant lipid, and levels enzymes rats. fatactivity high in 784-793. acid synthesisexcretion inrats.acid and lipids in ovariectomized mice. mice. ovariectomized in lipids Y. (2003). Hesperidin, a citrusflavonoid, inhibits loss bone and decreases serumand hepatic Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

129 Endocrine Research : 1094-1101. 535-590. DOI :10.1080/10408398.2010.549596 Journal of Nutrition Journal of ). Sequential effects of a high-fiber diet with psyllium husks on on husks psyllium with high-fiber diet of a effectsSequential ). FASEB Journal

ession in ratsession inhigh-fat a fed diet. Comment citercedocument :

For Peer Review Only Review Peer 21 For : 681-696. Journal ofNutrition Y., Ho, W. K. K. and Chen, Z.-Y. (1999).Y., Ho,W.andJasmine Z.-Y. Chen, K. (2010a). Effectsoybean of oligosaccharides on melatonin on the on melatonin main yama, R., Suzuki, K., Kanazawa, K. and Ishimi, Ishimi, and K. Kanazawa, K., Suzuki, R., yama, n of resistantn ricestarch produces propionate

etary fiber source alters liver cholesterol, fiber livercholesterol, alters bile source etary 133

10 : 2940-2940. : 1892-1897. Mesocricetus auratus URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] Nutrition

Nutrition andMetabolism

130 : 57-66. : 57-66. : 1991-1995. Nutrition Research Nutrition tenance ofcholesterol Food Chemistry ) a fed highfat diet. Critical ReviewsinFoodScienceandNutrition

7 : 11.

119

29 62 : : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Cho, Y. Y., Kwon, E. Y., Kim, H.J., Park, Y. B Kim, K., Kim, S.J.,Park, H., Cho, S. Chopra, R. and Sambaiah, K. (2009). Effects of rice bran oil enriched with n-3 PUFA on liver and onliverPUFA n-3 with enriched oil rice bran K. (2009).and Sambaiah, Effectsof Chopra, R. W., S. Choi, H., T. Kim, R., Lee,H. S. H., Cho, Clark, R. M., Balakrishnan, A., Waters, D., Agga R. M.,Clark, Balakrishnan,A., Waters, D., Coudé, F. X., Grimber, G., Pelet, Grimber, A.and Coudé, F. Benoit,X., Clarke, S. D., Romsos, D. R. and Leveille, G. A. (1 Clarke, S.D.,Armstrong, M. K. Jump,and D. B. da Costa, da K.-A., Garner, S.C.,Chang,Effects J.andZeisel, S. H. (1995). of prolonged (1year) mice. improves oil flaxseed from fat structured trans 50 serum lipids in rats. in lipids serum ovariectomized rats fedhigh-cholesterol diets. safflowerseed extract and phenolic compounds indiet plasmaon and liver lipid in 1293-1301. lanceolata valproic acid, on fatty acid oxidat acid, valproic Journal ofNutrition of long-chain saturated and polyunsaturated fatty acids onrat liverand adipose tissue lipogenesis. acid synthase liverfatty suppressand mRNAS14 ratcontent. rats. ovariectomized carnitine increases liveralpha-tocopherol and lo protein kinaserat Cin liver. choline anddeficiency subsequent re-feeding of choline on 1,2- Research Communications : 32-37. : 32-37. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Food and Chemical Toxicology rootliver fatty extractin the alcoholic against rat.

Lipids 107 Journal of Nutritional Biochemistry ofNutritional Journal : 1170-1181.

44 115 Carcinogenesis 535-590. DOI :10.1080/10408398.2010.549596 : 37-46. : 730-736. ion in isolated rat hepatocytes. rat hepatocytes. isolated in ion

Comment citercedocument : : 1550-1555. and Park, T.(2009a). Protective effect of Only Review Peer For 16 ., Lee,., K.T.,Park, T.and(2009b).Choi, M.S. Low Lee, W.J. and Choi, Y.(2004). Effects ofdefatted : 327-334. Journal of Nutritional Journal ofNutritional plasma and plasma and hepatic lipid rwal,D., Owen,K. Q. and Koo,S.I. (2007).L- 977). Differential effects of dietary methyl esters methyl dietary of effects Differential 977). (1990). Dietary polyunsaturated fats uniquely Y.(1983). Action ofthe antiepileptic drug, wers liver and plasma triglycerides in aging in andplasma triglycerides wers liver URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

: 623-628. Journal ofNutrition sn Journal of Medicinal Food Medicinal of Journal -diradylglycerol, acidsfatty and BiochemicalBiophysical and Science andVitaminology metabolism in apo E-/- metabolism inapo Critical ReviewsinFoodScienceandNutrition

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12 63 :

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57 : 6461-6467. (2007). Regulation of lipid flux between liver and flux lipid between of (2007). Regulation L. D. and L.D. Delzenne, C., Moundras, C. and Rémésy, C. (1995). Effect C.(1995).C., Moundras,Rémésy, and C. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

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103 leaf on leafon Pakistan : 161- 64 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Doan Thi Thanh, H., Takahashi, Ide,Y. and T. (2006). Activity and mRNA levelsenzymes of Drill, V. A. (1954). Lipotropic effect Lipotropic V. A. (1954). Drill, Eckstein, H. C. (1952). Dietary essential amino essentialamino H. (1952). Dietary Eckstein, C. Cloarec, A., Toye, H., R. Barton, E., M. Dumas, Engel, R. R. W. (1942). relation a The Engel, B-vitaminsof Esfandiari, F., Villanueva, J.Esfandiari, Wong, D.H., F., A., Fr Failey, R.Failey, B. and Childress, R.H.(1962). Th Felmlee, M. A., Woo, G., Simko, E., Krol, E. S., S., E. Krol, E., Simko, G., Woo, M.A., Felmlee, Fouret, G., Ramos, Sutra,T., C., Feillet-Coudray, involved involved in hepatic fatty acid oxidation in mice fed citrus flavonoids. Academy ofSciences Academy rats. Academy of Sciences of the United States of America phenot liver to fatty microbiota Gauguier,D. and Nicholson, J.(2006). K. Me Tatoud, R., Blanc, V., Lindon, J. C.,Mitchell, Journal ofNutrition micropigs. micropigs. activate deficiency folate and feeding ethanol cholesterol level in man. in man. cholesterol level hyperlipidaemic rats. secoisolariciresinol lignans diglucoside flaxseed RadicalBiology and Medicine effect of polyphenols: Involvement ofmitochondrial NAD(P)H and oxidase systems. and preventive a high-fatfed ratsdiet and high-sucrose C.(2009). Coudray, P. stress in Oxidative Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Journal ofBiological Chemistry American Journal of Ph

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46 : 624-632. ype in insulin-resistant mice. in insulin-resistant ype ysiology-Gastrointestinal and LiverPhysiology and ysiology-Gastrointestinal s of vitamin-B12 ands otherfactors.of

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Comment citercedocument : : 167-174. Clinical Nutrition Clinical Only Review Peer For e effect of para-aminobenzoic acid on serumthe acids and the liver lipide content youngwhite of lipide content theliver and acids hepatic endoplasmic reticulum stresspathway in Muir, Alcorn, A.D.and (2009). J. Effectsthe of J., Wrutnialc-Cabello, C., Cabello, G., Cristol, J. Cristol, G., Cabello, C., Wrutnialc-Cabello, J., nd dietary fat to the lipotropic action of choline. ench, S.W. Halsted, and C.H. (2005). Chronic

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. Pantothenic acid deficiency in cats. Pantothenic. aciddeficiency Comment citercedocument : not DGAT1 activity in HepG2 cells. For Peer Review Only Review Peer For research on the lipotropic and hepatoprotective Rivista Critica di Clinica Medica diClinica Medica Rivista Critica Nutrition Research (2009). Antiobesityaction ofa daidzein derivative

276 ct upon ofbiotin fat synthesis metabolism.and fatty liver in rats fed a fat-free ethanol and diet, liverin ethanol fatty fed rats a fat-free ruya, K., Nagai, T., Mizobe, H., Ichioka, K., K., Ichioka, H., Mizobe, T., Nagai, K., ruya, bitory effectsbitory organosulfurof garlic-derived : 1450-1458. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] Lipids

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360 in choline deficiency. deficiency. choline in CanadianJournal ofBiochemistry : 134-145. Archiv furGeflugelkunde , I.(1973).The importance ofnicotinic acidand itseffect the on liver fat tion oflipid-metabolismin tion 535-590. DOI :10.1080/10408398.2010.549596 fat diet-induced obesity. obesity. diet-induced fat

Canadian Journalof Biochemistry

Comment citercedocument : 209 : 171-177. Only Review Peer For ed labelling of liver phosphatidylethanolamine from from of liver phosphatidylethanolamine ed labelling Journal ofNutrition Journal Niemelä, O.,Parkkila, S. X., Zhang, X.F., Zheng,

vehjem, C. (1954).On C. A. vehjem, 37 Butter and Safflower Oil Elicit Different Effects Different OilElicit Safflower Butter and Effect of myoinositol Effect deficiency of onlipid- irment of triglyceride transport from liver in liver from transport oftriglyceride irment : 114-117. Hu, J., Zadjali, F., Tahir, F., Brismar, K., K., Brismar, F., Hu, Tahir, F., J., Zadjali,

43 Journal of Nutrition Journal of URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] myoinositol deficient rats. : 507-520.

Lipids

99 : 10072-10077.

129 44 : 1011-1027. Platycodi radix : 942-948. , Garrow, T. A., Wallock, Wallock, Garrow, T.A., , Y. N., Okuda, H.and thelipotropicaction of

Phytotherapy Research 48

130 Critical ReviewsinFoodScienceandNutrition : 885-892. Proceedingsthe of : 2760-2764. Biochimica et affects Lipid Lipid affects 68

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Hayes, K. C., Pronczuk, A., Wijendran, V. and B and V. Wijendran, A., Pronczuk, C., K. Hayes, del A., Canuelo, E., Martinez-Lara, R., Hernandez, Hayes, K.C.,Pronczuk, M.A., Cook, and W. Robbins,M. C.(2003). Betaine in sub-acuteand sub- Hayashi, E., Maeda, T.and Tomita,T. (1974b). Effect of myoinositol deficiency on lipid- Hong, S. Hong, Y., Kim, Y.J.and Kim, M. K.(2007) Hood, R.Hood, L. and Sidhu, G. S. (1992). Effect ofguar gum and tocotrienols on cholesterol metabolism Hotta, K., Kuwajima, M., Ono, A., Uenaka, R., R., Na Uenaka, Ono, M., A., Kuwajima, K., Hotta, E. B. (1975). Bexton, A.and Hosein, Protective ac Hou, Z., Qin, P.and Ren, G.(2010). Effect sunflower or olive diet:involvemeoil-based Pedrosa, J. A.and Peinado, M. A. (2005). Stea 1988. cholestero liver and plasma reduce ratstudies. chronic rats. metabolism inrats. 2. Me weight and lipidprofilein rats fe Gastroenterology on the Japanese quail. A1055. sativa steatosis. visceral juvenile with mouse strain of and heart IIin expression liver, muscle, carnitine palmitoyltransferase of Altered T., Horiuchi, M., Nikaido, H., Hayakawa, J.,Ko torats. administration ethanol and Food Chemistry Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Biochimica et Biophysica Acta et Biophysica Biochimica L.Japonica) on chronically alcohol-induced liver damagein rats.

11 Food and Chemical Toxicology . : 7480-7485. Nutrition Research Nutrition chanism of triacylglycerol accumulatio triacylglycerol of chanism 535-590. DOI :10.1080/10408398.2010.549596 Biochemical Pharmacology Biochimica etBiophysicaBiochimica Acta-GeneralSubjects d a high-carbohydrated a or high-fat diet.

l in gerbils fed cholesterol. cholesterol. l ingerbilsfed 360

: 146-155.

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12 For Peer Review Only : S117-S127. Review Peer For of anthocyanin-rich extract from black rice ( nt ofperisinusoidalstellate cells. kajima, H., Miyagawa, J., Namba, M., Hanafusa, M., Hanafusa, J., Namba, Miyagawa, H., kajima, . Effect ofhydroxycitric acid feeding on body Moral, M. L., Blanco, S., Siles, E., Jimenez, A., A., Jimenez, E., Siles, S., Blanco, L., M. Moral, tion tion of carnitine on liver lipid-metabolism after tosis recovery after treatmenta with balanced no, N.,Saheki,and T.Matsuzawa,(1996). Y.

eer, M.(2002). Free phytosterols effectively 41 : 1685-1700. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

24 : 1859-1863. n in liver ofmyoinositol-deficientn in Journal ofNutrition Faseb Journal Faseb Journal of Agricultural Agricultural of Journal Critical ReviewsinFoodScienceandNutrition

World Journal World 1289 : 131-135.

21 132 : A1055- : 1983- Oryza Oryza

69 of Page 236of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 237of267 Ikeda, M., Uno, H.,Y., Iwai,M.,Sato, Kawabe, H.and Sakakibara, B. (1992). Effects ofthe Ide, T. and Horii, M.(1989). Hepaticcarnitine and triglyceride lowering effect of dietary pectin in Hsu, C.-c., Yen, H.-f., Yin, M. Ide, T.,Hong, D.D.,Ranasinghe, P.,Takahash Itokawa, Y., Inoue, K., Sasagawa, S.and Fujiwara, Hu, M. C. C. (1975). Lipotropic action of carnitine in a low protein diet from plant sources. sources. plant from diet protein a low in ofcarnitine action Lipotropic (1975). C. C. M. Hu, Ide, T.,Ashakumary, L., Takahashi,Y., Kushiro, Hussein, O., Grosovski, M., Lasri, E.,Svalb, S Hurley, L.S., Volkert, Eichner,E. and N. J. T. lipid levels in germ-free and conventional mice. and conventional in germ-free levels lipid inositol-deficient dietthe on development offatty liver lipogenic enzyme activities and plasma rat. the compoundsin diabetic delay deterioration Balb/cA mice. BiophysicaActa-Molecular and of CellBiologyLipids fatand sesami types Interaction ofdietary s-allylcysteine sulfoxide and related sulfur-c related and sulfoxide s-allylcysteine Dissertation Abstracts International, B Biology ofLipids sterol regulatory elementprotein-1. binding sesamea lignan, decreases synthesis acid liver inrataccompanying fatty the down-regulation of Gastroenterology experimental hypercholesterolemic rats. 201-208. non-pregnant guinea pigs,withspecial reference effects to the on fetus. fat decreases hepatic lipid content inn content lipid hepatic fat decreases Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Nutrition ReportsInternational

1534 13 : 361-368. : 1-13. 535-590. DOI :10.1080/10408398.2010.549596 -c., Tsai, C.-m. and Hsieh, C.-h

39 36 on-alcoholic fatty liver fatty inrats.disease on-alcoholic Journal ofNutrition Journal Comment citercedocument :

: 861-865. : 655. n on hepatic fatty acid oxidation in rats. n on fattyacidoxidation hepatic For Peer Review Only Biochimica et Biophysica Acta-Molecular and Cell Review Peer For ., Ravid,U.and Assy, N. (2007). Monounsaturated (1965). Pantothenicacid inpregnant deficiency and M., Fukuda, (2001). N.andSugano, M. Sesamin, ontaining amino acids on Vitamins (Kyoto) M. (1973). Effect ofs-methylcysteine sulfoxide, i, Y., Kushiro, M. and Sugano, M. (2004).M. Sugano, i, Y.,Kushiro,M.and

1682 URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] Journal of Nutrition

: 80-91.

103 . (2004). cysteine-containing Five : 88-92. : 88-92.

66 : 43-49. : 43-49. Journal ofNutrition lipid metabolism of lipidmetabolism Critical ReviewsinFoodScienceandNutrition

134 World Journal of : 3245-3249. Biochimica et

86 70 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Ji, C.and Kaplowitz, N.(2003). Betaine decreases hyperhomocysteinemia, endoplasmic reticulum I. A. D. Suter, A., K. Jackson, Jin, F.Y.,Kamanna, V. S. and Kashyap, M. L. Kahlon, T. S., Saunders, R.M.,Sayre, R.N., C Jin, F.-Y., Kamanna, V. S. and Kashyap, M. L. Kamal-Eldin, A., Frank, J., Razdan, A., Tengblad, Tengblad, A., Razdan, Frank, J., A., Kamal-Eldin, Kahlon, T. S., Chow, F. I. Kahlon,Chow, F. T.S., Jonnalagadda,W. F.Robertson,S., Thye, and S. Kanuri, G., Weber,S.,Volynets, V., Spruss,A., Bi stress, and liver injury inalcohol-fedstress, liverand mice. injury diets withoutcholesterol. with and differ but bran wheat to relative plasma-cholesterol hypercholesterolemic hamsters. hamsters. hypercholesterolemic (1992b). Cholesterol-lowering effects ofrice bran andricein oilfractions bran 122 Cholesterol Transport. butnotcholesterol A-I apolipoprotein lipoprotein Arteriosclerosis ThrombosisVascular and Biology inhibitingdegradationby triacylglycerol synthesis human in hepatoblastoma (HepG2) cells. dietary phenoliccompounds tocopherol, on cholesterol,acids andfattyrats. in hamstersfed riceat bran various levels, defattedrice and branrice bran oil. Nutrition choles fecal and cholesterol liver cholesterol, 482-487. againstprotectsextract acutemice. alcohol-induced in liversteatosis 435. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human : 513-519. Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

123 : 1377-1382. Arteriosclerosis, ThrombosisArteriosclerosis, and Vascular Biology , Sayre, R. N.and Betschart,A. and Topping, D. L. (1994). Oat barley bran, and malted barley lower 535-590. DOI :10.1080/10408398.2010.549596 Cereal Chemistry Journal ofNutrition Journal

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Gastroenterology For Peer Review Only excretionterol inhamsters fedfiber diets. Review Peer For (1997). Niacin decreases removal ofhigh-density schoff, S. C. and Bergheim, I. (2009). Cinnamon(2009). C. andBergheim, schoff,I. S. how, F. I., Chiu, how, M. A. F.I., Chiu, A. Betschart, M. and

(1999). Niacinaccelerates intracellular apoB 69 ester by Hep G2 cells : Implication Implication for Reverse: G2cells Hep ester by

S., Basu, S. and Vessby, B. (2000). Effects of (2000). Effectsof B. Vessby, and S. Basu, S., 19 J. L. (1993). Plasma total and lipoprotein in their effects onliver cholesterol in rats fed : 485-489. : 1051-1059.

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17 : 2020-2028. Critical ReviewsinFoodScienceandNutrition Journal ofNutrition Lipids Journal of

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139 71 :

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17 -inositol: is phytic acid a vitamin-like substance? substance? avitamin-like isphytic -inositol: acid Journal of Nutritional Biochemistry : 721-728. hort-term experiments. Journal of Chemistry Biological Nutrition Research 535-590. DOI :10.1080/10408398.2010.549596 Journal of Nutrition of Journal

59 : 1159-1160.

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: 321-330. Comment citercedocument : myo

14 Journal of NutritionJournal of Only Review Peer For -inositol or phytic acid on -inositol acidon or phytic : 699-706. The lipotropic effect of folic acid on rats receiving onratsreceiving acid folic effect of lipotropic The Bulletin of IIDA Women's Junior College Women's IIDA of Bulletin

16 of dietary lipid,carnitineexerciseand on lipid hepatic lipid metabolism in a similar manner as manner asimilar in metabolism lipid hepatic etary phytosterols on cholesterol levelsin liver, ition of cholesterol deposition in livers of mice livers ofmice in deposition ofcholesterol ition : 205-212. myo

108 myo Osada, K. (2005). Comparison of regulative regulative of Osada, K. (2005). Comparison

187 -inositol onthemetabo -inositol : 630-639. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] -inositol on lipid metabolism in rats fed rats fed in metabolism lipid -inositol on

: 529-535. Nutrition Research Recent Research Developments in

100 : 1141-1147. hepatic concentrations of concentrationshepatic Critical ReviewsinFoodScienceandNutrition

lic changes in rats inrats lic changes 13 : 748-753. : 445-454. Bioscience, : 60-67. Nutrition Nutrition 72 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Hwang,Choi, J.H., Y.P.,Chung,T., Khanal, Y. T., Choi,Khanal,H., Hwang, J. Y. (1 andWolf,G. A. E. Khairallah, Khor, H. T., Chieng, D. Y. and Ong, K. K. (19 K. Ong, K. and D. Y. Chieng, T., Khor, H. Kharbanda, K. K., Rogers, D. D., Mailliard, M. E., M. E., Mailliard, K., Rogers, D.D., K. Kharbanda, Khor, H.T.and Ng, T. T. (2000). Kim, D. Y., Park, J. S., Yuan, H. D. and Chung, and D. H. Yuan, S., J. Park, Y., D. Kim, Kim, H. K., Jeong, T. S., Lee, M.K.,Park, Y. Kim, H., Bartley, G. E., Rima G.E., Bartley, Kim, H., mice. rootfrom theof Platycodon grandiflorum protect 2754. activationvia the ofAMP-dependentprotein kinase. saponins from the root of Platyc methionine. and dietslimitedfed protein in activity in the guinea pig. pig. intheguinea activity hepatocytes. adenosylmethionine on ethanol-induced changes in methioninemetabolism steatosis and rat in Sorrell, M.F. and Tuma, D.J. (2005). A comparisoneffects of the and of betaine Nutrition liverand lipids HMG reductaseactivity. serum CoA Biotechnology activation. AMPK through hyperglycemia and accumulation lipid peels and peel extract. extract. peel and peels related to plasmalower cholesterol in hamsters fed high-fat diets supplemented blueberrywith of hesperetin metabolites in high-cholesterol fed rats. high-cholesterol fed in metabolites hesperetin of Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Food and Chemical Toxicology

51 : S3-S11. : S3-S11. Journal of Nutrition of Journal

18 : 172-178. Journal of Agricultural Nutrition Research 535-590. DOI :10.1080/10408398.2010.549596 ndo, A. M. and Yokoyama, W.(2010). HHepatic gene expression 965). Growth-promoting and lipotrop and 965). Growth-promoting Effects ofadministration ofalpha-tocopherol and tocotrienols on odon odon grandiflorum liver against chronic ethanol fatty in feeding

P.,Chung,Jeong, Y.C.and H. 135

: 519-524.

47 Comment citercedocument : : 530-535. For Peer Review Only Review Peer For Journal ofNutrition

15 and Food Chemistry Food and 95). Tocotrienols inhibit inhibit 95). Tocotrienols B. and Choi, M. S.(2003) S. H.(2009). Fermented ginseng attenuates hepatic : 537-544. C. and Jeong, H. G. (2009b). Saponins isolated Siford, G. L., Barak, A. J., Beckenhauer, H. C., Beckenhauer, Siford, A.J., Barak, G. L., against acute ethanol-induced hepatotoxicity in Clinica Chimica Acta Chimica Clinica International Journal ofFood Sciences and Food and Chemical Toxicology andFood Chemical URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

87 G. (2009a). Protective effects of : 469-476. . ic effect of carnitine in rats carnitine ic effectof liver HMG CoA reductase reductase HMGCoA liver . Lipid-lowering efficacy

327 Food Science and Critical ReviewsinFoodScienceandNutrition : 129-137.

47 : 2749- 73 S - Page 240of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 241of267 J.,H. Kim, S.,Shin,Kim, S.Y.,Kim, J. H., Kok, N., M.,Roberfroid, Robert, A.and Delzenne (1996a). N. Delzenne, M.and Roberfroid, N., Kok, Kim, S.,Sohn, I.and Lee, Y.S. (2005). Hepatic Kok, N. N., Taper, H. S. and Delzenne, N.M. Klopfenstein, C. F. (1990). Nutritional properties fine ofcoarse and sugar-beethardand fiber red Kotaki, A.,Sakurai, T.,Kobayashi, Yagi, M.and K. Kondo, T., Kishi,M., Fushimi, T.and Kaga, T. (2 Kritchevsky, D. and Tepper, S. A. (2005). Influence of a fiber mixture on serum and liver lipids and and lipids liver and serum on mixture afiber of Influence (2005). A. S. Tepper, D.and Kritchevsky, Kritchevsky, D.,Tepper, S.A.,Satchithanandam, lower VLDLsecretioninducedlower byoligofructosein rats. fructose on hepatic triacylglycerol metabolism. supplementationin mice with diet-induced obesity. PPARalpha. Genistein enhances expression of genesinvolved Agricultural and Food ChemistryAgricultural genes for acid fatty oxidation enzymes in rats. in diet a by fat-rich induced alterations characteristics. wheat 1. bran. Effects onratserum andliver cholesterol triglycerides and and on fecal of Vitaminology(Kyoto) myoinositol onthe cholesterolmetabolism ofrats suffering from experimental fatty liver. on fecal fat excretion in rats. in rats. fatexcretion fecal on 318-321. Influence of a fiber mixture on serum and liver lipids and on fecal fatexcretion in rats. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Molecular Cereal Chemistry

and Cellular

14 . Nutrition Research Nutrition 535-590. DOI :10.1080/10408398.2010.549596

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Comment citercedocument : For Peer Review Only Journal of Applied Toxicology Review Peer For liver to suppress body fat accumulation. accumulation. fat body suppress to liver (1998). Oligofructose modulates lipid metabolism Lee, Y.S.,Kim, D.H.and Lee,M. O.(2004). Metabolism

S.,Cassidy,M. M.an 25 geneexpression profiles alteredare bygenistein , N.(1996b). Involvement oflipogenesisthe in 009). Acetic acid upregu : 485-489. Dietary modifies of oligofructose Dietary impact the in fatty acid catabolismthrough activation of (1968). myoinositol. StudiesEffect of IV. on Journal ofNutrition 220 URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] British Journal ofNutrition British : 51-58.

45 : 1547-1550.

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18 lates the expression of : 33-41. Critical ReviewsinFoodScienceandNutrition : 47-53.

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23 74 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Kumari,andAu K.,Mathew,B. C. Krogh, B., Funch, J. P. and Dam,H. (1961). Cholesterol and polyenoic acids fatty in liver,serum Kushiro, M., Masaoka, T., Hageshita, S., Taka Kuroki, S., Muramoto,S., Kuramoto,and Hosh Kuroki, T. Kumari, K. andAugusti, K. T. ( Kuzu, N., Bahcecioglu, H.,Me N.,Bahcecioglu, I. Kuzu, Kushiro, M.,Takahashi, Ide, Y.and (2004). T. Sp Kwon, Kwon, D. Y.,Kim, Y.S.,Hong, Laird, R. D. and Drill, V. A. (1971). Lipotropic activity of inositol and chlortetracycline alone and and alone chlortetracycline and inositol of activity Lipotropic (1971). A. V. Drill, D.and R. Laird, Allium cepa Journal ofNutrition and aorta ofrabbits given dietspurified some withbutter, margarines and arachis oil. Journal ofNutrition and oxidation acid fatty an sesamin of effect Comparative Biophysics methyl cysteine sulfoxide isolated from Pharmacobio-Dynamics sitosterol on hepatic-steroid 12-alpha-hydroxylase activity in female hamsters. high fat diet. K.(2007).Sahin, Role ofmelatonin in treatment of nonalcoholic steatohepatitis inrats induced bu (sesamindietary lignan episesamin) and in derived from Platycodi radix (22 years radix old)e derived fromPlatycodi in various combinations of choline, vitamin B vitamin choline, of combinations various in Journal ofNutrition stimulated 90 % pancreatectomizedhigh-fat diet. a in fed insulinsecretion diabeticrats Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

32 Linn in high cholesterol dietfed rats. Journal of Hepatology : 49-54.

15 91 101 : 481-488. : 377-386. synthesis in rat liver. liver. rat in synthesis

: 358-366. 6 : 551-557. 535-590. DOI :10.1080/10408398.2010.549596 2007). Lipidlowering effectof tin, K., Ozercan, I.tin, K.,Ozercan, H., M., Tuzcu, Yalniz,M., Ustundag, B. and S. M.and Park, S. (2009). L gusti, K. T.(1995). Antidiabetic and hypolipidemic effectsof d episesamin on the activity andge episesamin ontheactivity d

: S263.

Comment citercedocument : Allium cepa Allium For Peer Review Only Biochemistry ofNutritional Journal Review Peer For affecting hepatic fatty acid metabolism. metabolism. acid fatty hepatic affecting 12 nhances hepatic insulin insulin hepatic nhances and folic acid - activity acid andfolic ecies differences in the physiological activity of of activity physiological the in differences ecies ita, T. (1983). Effect of feeding cholesteroland Effectita,of T.(1983). Journal of Ethnopharmacology hashi, Y.,Ide,Sugano, T.and M. (2002). linn. linn. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Indian Journal of Biochemistry and ong-term consumption of saponins S -methyl cysteine sulfoxide from from sulfoxide cysteine -methyl ne expression of enzymes in in enzymes of expression ne sensitivity andglucose- sensitivity of 3 liver extracts with extracts 3liver of Critical ReviewsinFoodScienceandNutrition

109 13 : 289-295. : 367-371. Journal of British British British British British British 75 S - Page 242of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 243of267 Lamon-Fava, S., Diffenderfer, Barrett,P.H. M. R., Diffenderfer, Lamon-Fava, S., Laird,D., McCormick, R. V. A. Drill, H.M.and Laraki, L.,Pelletier, X.,Mourot, Debry, J.and Effects G.(1993). of dietary phytosterols liver on Leclerc, J. and Miller, M. L. (1989). J. andMiller, Inositolandch M.L. Leclerc, Lee, S. H., Park, H. J., Cho, S. Y., Jung, J.,C H. J., Park, H. Cho, Jung, S. Y., S.H., Lee, Lee, Park, S.-H., H.-J.,Chun, H.-K.,Cho, S.-Y., Lee, Y. H.and Yeh, Y. Y. (2003).Inhibitory effe Li, B. H.and Tian,W. InhibitoryX. (2004). effects flavonoids of animal on synthase.acidfatty apolipoprotein (Apo) A-I and A-I and apolipoprotein (Apo) and Schaefer,(2008).E. J.Extended-releas Otokozawa,Asztalos,Matthan, B.F., Ai,M., N. S., Pharmacology choline, vitamins B choline, vitamins 103-116. substances. these for assays Vascular Biology lipids and lipid metabolism enzymes. enzymes. metabolism lipid and lipids Research rat. oflactating content Effects ofdietary phytic acidonserum andhe ICR mice feda high-cholesterol diet. and Lillehoj,S.(2007).Dietary H. phyticimproves acid serum levelsaged hepatic and lipid in Journal ofBiochemistry compounds of garlic on cholestergenesis inHepG-2 cells. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

25 : 869-876.

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28 : 1672-1678. 12 and B and International Journal Research for VitaminandNutrition Journal International

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Comment citercedocument : cts of garlic extractcts ofgarlicand water-soluble organosulfur Only Review Peer For Jung, H.-J., Cho, S.-M., Kim, Kang,D.-Y., M.-S. patic lipid levels in diabetic KK mice. diabetic KK in levels lipid patic ho, ho, S. M., Cho, Y. S.a R., Buchsbaum, A., Nyaku, M., Horvath, K. V., K. V., Horvath, M., Nyaku, A., Buchsbaum, R., (1965). Lipotropic activity of combinations of e niacin alters the metabolism of plasma of plasma metabolism e altersniacin the oline levels in thediet levels oline A.R., Lichtenstein, H.,Dolnikowski, G.G. n and Metabolism n and URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

FASEB Journal : 505-510. Arteriosclerosis Thrombosis and nd Lillehoj, H. S. (2005). S. H. nd Lillehoj, Toxicology and Applied and neutral lip and neutral

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59 : 180-183. id hepatic id hepatic Nutrition Nutrition

194 76 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Lim,J. S.,Adachi, Y.,Takahashi, Lin, C. and Yin, M.C. (2008). Effects of J.,Liang, X. Yin, L. Li, R.,Jia, C.-S., Yue, L., Zhang, X.-M., Xia, Q.-Y., Zhao, S.-L., Feng, B., Zhong, F. and Chen, Lin, C. C., Yin, M. C., Lin, M., Kao, S.,Chung, P., Chan,K., Yang, M. Liu, C. and M. Yin, C.C., Lin, Ling, W. Jones, H.and P. J. H.(1995). Enhanced Liu, Liu, L. and Inhibition c Y.-Y.of (2000). Yeh, fat diet. fat diet. triacylglycerol cholesterol and anti-oxidativeandliver protection in consuming frommice a high- he sesamolin) and inaffecting (sesamin WorldGastroenterology Journalof ameliorating effects ofcarnitine hepaticon steatosis induced parenteralby total rats. in nutrition Nutrition mice. in properties lowering W.-J. (2010). Lipase-catalyzedsynthesis of conjugated linoleyl Lipids compounds onthree lipogenic enzymes in Balb/cAconsuming mice a highsaturated fat diet. nucifera diet-induced hepatic injuriesand flavonoid-enrichedoxidative stress by extractfrom 3406. cysteine onMCD diet-induced hepatotoxicity inmice. Atherosclerosis free phytosterolmixtureslipoprotei inaltering derived from garlic. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

39 British British Journal of Nutrition leaf.

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5 99 : 312-315.

: 37-43.

Comment citercedocument : patic fatty acid metabolism in rats. rats. in acidmetabolism fatty patic holesterol organosulfur compounds biosynthesisby Only Review Peer For cysteine-containing compounds on biosynthesis of efficacy of sitostanol-conta and Wang, C. (2009).Improvement forhighfat P.(2004). Effectof five cysteine-containing n cholesterollevelsn synthesis and in rats. Food andFood ChemicalToxicology URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

and Huang, J.F. (1999). Astudy theof

: 5925-5932. β -Sitosterol and its cholesterol- and -Sitosterol

58 ining versus sitostanol- : 1898-1902. Critical ReviewsinFoodScienceandNutrition British Journal of

46 Nelumbo : 3401- 77 Page 244of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 245of267 Looney, M. A. and Lei, K. Y. Looney,and Lei, M.A. Lombardi, P. and B.,Pani,Schlunk, F. F. (1968). Choline-deficiencyfatty liver:impaired releaseof Lowenstein, J. M. (1971). (1971). Effect (-)-hydroxy M. J. of Lowenstein, Luo, Q.-F., Sun, L., Si, J.-Y. and Chen, D.-H. (2008). Hypocholesterolemic effect of stilbenes of effect Hypocholesterolemic (2008). Chen, D.-H. and Si,J.-Y. L., Sun, Q.-F., Luo, Mahboob, S. (1975). Effectpantothenic-acid of McHenry, E.W.and Patterson, J. J.McGarry, Foster, D. and D.W.In(1979). support oftherolesmalonyl-CoA of carnitine and McNeil,Hay,J., S.M.,Rucklidge,C. J.,Reid G. Menendez, R.,Amor, A.M.,Gonzalez, R.M.,Fraga, Menendez, R., Arruzazabala, L., Mas, R., DelRio, A., Amor, A. M., Gonzalez, R. M., Carbajal, D., D., Carbajal, R. M., M., Gonzalez, A. A., Amor, DelRio, R., Mas, L., Arruzazabala, R., Menendez, cholesterol levels in rat. in cholesterol levels triglycerides. hepatic containing extract-fraction from extract-fraction containing Journal ofBiological Chemistry of Nutrition andMetabolism of Nutrition Phytomedicine Biological Chemistry acyltransferaseI intheregulation hepaticof acidfatty oxidation and ketogenesis. with lipid metabolism in the fetal liver of the rat. rat. the of liver fetal the in metabolism lipid with associated mechanisms modify donors methyl related and acid folic in deficient diets Maternal 167. on theon hepaticcholesterol biosynthesisof normocholesterolemic rats. 923-932. diet. starch-casein a wheat by induced hypercholesterolaemia with Chol (1997). J. Illnait, V. and Molina, V., Fraga, 253-257. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

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246 Cajanus cajan Cajanus M.(1944). Lipotropic factors. : 629-632.

Comment citercedocument : For Peer Review Only Review deficiency on microsomal rat-liver. of lipids Peer For citrate on fatty acid synthesis by rat liver liver rat by synthesis acid fatty on citrate

L. ondiet-induced hypercholesterolemiamice.in 9 , M. D., Duncan, G. J. and Rees, W. D.(2009). British Journal ofNutrition British : 437-446. esterol-lowering effect of policosanol on rabbits rabbits on policosanol effect of esterol-lowering V. and Mas, R. (1996). Effect of policosanol

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102 Critical ReviewsinFoodScienceandNutrition : 1445-1452. Journal of

24 in vivo Annals : 128-

77 29 78 : : . 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 M. W., Peluso, R. Steger, J., W. Banz, Mezei, O., Merrill,M. andLemley-Stone,J. J.(1957). serumandtissuecholesterol Effects on acid ofnicotinic Moghadasian, M.H.,Nguyen, L. B.,Shefer, S.,Salen, Nagiel-Ostaszewski, I. and Lau-Cam, C.A.(1990) Mullen,R. M.,OsborneE., Brown, Moiseenok, A. G., Sheibak, V. M. andMoiseenok,A. G.,Sheibak, Gurinovich,V. M. V.A.Hepatic(1987). CoA,s-acyl-CoA, Moon, Y. S., Latasa, M. J., Griffin, M. J. and Sul, and M. J. Latasa,J.,Moon, Y.S., Griffin, M. Morise, A., Thomas, C., Landrier,J.-F., Besnar Am N., Combe, Boué,C., J., Mourot, A., Morise, mice. Zucker rats murine and RAW 264.7 cells. exertantidiabeticisoflavones hypolipidemicand inPPAR pathwaysobese effectsthroughthe rabbits. in treatment. treatment. and fecal sterollevelsin mice: Effectsapo of Hepatic cholesterol and bile acid synthesis, low- Communications inChemicalandPathology Pharmacology cystamine againstcarbon tetrachloride-induced inrat.the hepatotoxicity Journal ofNutrition elementregulatory binding proteins (SREBPs) pantothenic-acid deficiency. biosynthetic precursorsof thecoenzyme and pantothenate-protein complexes indietary promoteracids. bypolyunsaturated fatty metabolismresponse todietary fattyis acids modulated differently by PPAR fatty metabolism todietary Yvan-Charvet,L., Fénart, and E.,Weill,P.Herm Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), European Journal ofNutrition Circulation Research Metabolism-Clinical and Experimental and Metabolism-Clinical

134 : 2942-2947. acids inthehamster. International JournalInternational forVi 535-590. DOI :10.1080/10408398.2010.549596

5 : 617-619. , T.F. and Shay, N. F. (2004). isoflavonesSoy affect sterol

: 465-473.

Comment citercedocument : Journal of Lipid Research ofLipid Journal Journal of Nutrition Journal of For Peer Review Only Review Peer lipoprotein E deficiency and probucol or phytosterol For British Journal ofNutrition British density lipoproteinreceptordensity function, and plasma and and SREBP-regulated genes HepG2 cells.in

H. S. (2002). Suppression fattyof acid synthase . Protection by pantethine,Protection by . pantothenic-acid and d, P.andHermier,(2009).D. Hepatic lipid ier, D. (2006). Gender-related response of lipid 50 R.,Winters, T.A. andShay, N.(2003). Soy sler, G., Gripois, D., Quignard-Boulangé, A., A., Quignard-Boulangé, D., Gripois, sler, G., : 708-714. G., Batta, A.K.and Frohlich, J. (2001). URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] tamin andResearch Nutrition

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43 : 691-698.

95 α Critical ReviewsinFoodScienceandNutrition in male and female female and male in : 709-720.

57 Research : 71-77. 79 Page 246of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 247of267 Nakamura,Y., Kaihara,K., Tsumura, A., Yoshii, Noda, S.,Haratake, J.,Sasaki Nieminen, P.,Kakela,R., Mustonen, A. M.,Hyvarinen, H.and Asikainen, J. (2001). Exogenous Naruta, E. and Buko, V.(2001). Hypolipidemic effect pantothenic of acid micederivatives in with Noh, J.-R., Kim, Y.-H., Gang, G.-T., Yang, K.-J., Lee, H.-S., Nguyen, P. H., Oh, W.-K., Song, K.- Song, W.-K., Oh, P. H., Nguyen, Lee,H.-S., K.-J., G.-T., Yang, Gang, Kim, Y.-H., J.-R., Noh, Nakamura, Y.and Tonogai, Y.(2002). Effects Nakamura, Y., Kanazawa, M., Liyanage, R., Iijima Ntanios, F. Y. and Jones, P. J. contents and fecal steroid excretion in rats. oral the of administration of green tea andpolyphenol tannic serum on acid and hepaticlipid hopantenate, in dogs. hepaticencephalopathysteatosis with pantothenic-acidby induced antagonist, calcium Biochemistry and Physiology C-Toxicology and Pharmacology ( in mink activities and enzyme affectslipids melatonin 393-398. hypothalamic induced obesity by aurothioglucose. S. and Lee, C.-H. (2010). Chestnut ( Chestnut (2010). C.-H. Lee, and S. Health Science contents fecallipid and excretion steroid in normal hypercholesterolemic and rats. diet. beetfiber onserumlipids and sugar containing Yamauchi, A.,Hashimoto, N.,Ohba, Fukushima, K.and M.(2009). Effect ofwhite wheatbread hepaticsteatosisC57BL/6 in mice fedahigh-fat diet. increases cholesterol synthesis in male hamsters. hamsters. male in synthesis cholesterol increases Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Bioscience, BiotechnologyBiochemistry and

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11 535-590. DOI :10.1080/10408398.2010.549596 H.(1998a). Dietary sitostanol reduces cholesterol absorption and : 134-142. , A.,Ishii,N., Umezaki, H. Castanea crenata

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Journal of Health Science For Peer Review Only Review Peer For of grape seed polyphenols on serum and hepatic Y., Ishimitsu, S. and S. and Y., Ishimitsu,Tonogai, Y. (2001). Effects FASEB Journal FASEB

hepatic mRNA in rats fed fed inon acholesterol-free rats mRNA hepatic 73 , S., Han, K. H., Shimada, K., Sekikawa, M., M., Sekikawa, Shimada,K., H., K. Han, S., , Experimental and Toxicologic Pathology : 1280-1285. Food Chemistry ) inner shell extract in extract shell ) inner URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

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128 andHorie,A. (1991). Acute

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121 : 107-117. : 437-442. ) liver. ) liver. hibits development of Critical ReviewsinFoodScienceandNutrition Comparative Comparative Journal of

53 80 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Okazaki, Katayama, Y.and T.(2003). Effects carbohydrate of dietary and Odbayar, T. O.,Badamhand, D., Kimura,Ta T., Oda, T.,Aoe, Sanada,S., H.and Ayano, Y. (1993). Effects ofsoluble and insoluble fiber L., R. Hood, E., D. Fenwick, G., D. Oakenfull, S. Nunn, L., Tauxe, W.N. Juergens, and J. L. (1961). Effect of nicotinicacid human on cholesterol Ntanios, MacDougall, F. Y., Jones, D.E.and J. H.(1998b). P. Gender effects oftalloil versus Ntanios, F. Y. and Jones, P.J. Okazaki, Y. Katayama,and T.(2008).myositol Dietary hexakisphosphate, but not Ntanios, F. Y., Jones,Ntanios,F. andFrohlich, P.J. H. J. of NutritionalBiochemistry hepatic fatty acid synthesis in mice. Comparative studies ofsome phenolic compounds (quercetin, rutin, and ferulicacid) affecting rats. fed preparations isolated fromoat, and barley, whea 42 (1979). Effects ofsaponins on bile-acids and plasma-lipids in the rat. biosynthesis. and Pharmacology soybean phytosterolscholesterol-lowering as agentsin hamsters. 101-110. phytos and lipid profile plasma trichloro-2,2-bis (p-chlorophenyl) ethane. clearly improves hypercholesterolemiain ratsfedcasein-type aminoacidmixtures and 1,1,1- metabolicchanges inrats fed 1,1,1-tric formation lecithinbut not cholesterol Lipids and Lipid Metabolism : 209-216. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), JournalofNutritional and Science Vitaminology Circulation

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hloro-2,2-bis (p-chlor

acyl transferase activity in rabbits. activity transferase acyl Comment citercedocument : Nutrition Research Nutrition For Peer Review Only Review Peer For t accu on cholesterol liver Topping, D. L., Illman,R. L. and Storer, G. B. J. (1998a). Dietary sitostanol reduces plaque kahashi, Y.,Tsushida,andIde, T. T.(2006). URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

39 : 73-79. : 73-79. ophenyl) ethane (DDT).

28 : 714-721. Biochimica etBiophysica Acta- Canadianof Journal Physiology British JournalofNutrition British mulation in cholesterol- in mulation Atherosclerosis Critical ReviewsinFoodScienceandNutrition

54 myo : 8261-8265. myo -inositol on The Journal -inositol, -inositol,

138 81 :

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L 1

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Comment citercedocument : For Peer Review Only Review Peer For the hepatic to reference with and Ostwald, R. (1961). Fatty acid components of of components acid R. (1961). Fatty and Ostwald, dietary protein, fat,and choline theupon serum

23 American Journal of Clinical Nutrition Clinical Journal of American : 1089-1096. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] myo

L -methionine

-inositol andphyticacid onhepatic 73 Nippon Eiyo Shokuryo Gakkaishi : 275-286.

50 Bioscience, Biotechnology,and

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33 L -cysteine pantethine and : 162-169. myo myo Critical ReviewsinFoodScienceandNutrition Journal ofNutrition -inositol, -inositol status in in status -inositol Federation D

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Comment citercedocument : B-Biochemistry and Molecular Biology Only Review Peer For 36 (2005). Dietarycarotenoid pigment supplementation (1980). Effects(1980). protein ofsoy saponins and serum on : 595-596. and Banz, J.(2000). W. Acooperative interaction L.) on andhepatic damagesteatosis induced by (2006). Melatonin ameliorates nonalcoholic fatty Circulation Nutrition Research , A., Vardi, N., Otlu, A. and Yilmaz, I. (2009). I.(2009). andYilmaz, Otlu,A. N., Vardi, A., , Journal of Biological Chemistry Journalof Biological URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

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Sophora japonica 29 : 819-824. Oncorhynchus mykiss Critical ReviewsinFoodScienceandNutrition

142

14 268 L. prevent prevent L. : 398-402. -acetate in in -acetate Journal of Annals of : 11230- 83 ). ). Page 250of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 251of267 Dormard,and Perrault, Y.(1966).M. Lipotropiceffect ofbetaineaspartate experimental on hepatic Preuss, H. G., Bagchi, D., Bagchi, M., Rao, C. V. V. C. Rao, M., Bagchi, D., Bagchi, G., H. Preuss, Perry,W. F. (1960). Effect of nicotinic acid and nicotinamide on incorporation of acetate into Rhew, T.H. and Sachan,Effects D.S.(1983). of Rejman, Kozubek, J.and A.(2003). Inhib D. M. Peterson, C., W. Burger, A., A. Qureshi, Pyo, Y.-H.andSeong,K.-S. V. C. Rao, M., Bagchi, D., Bagchi, G., H. Preuss, Rhew, T. H. and Sachan,Rhew, T.H.and D. S. (1984). Dose steatosis. Study using triolein-C using Study steatosis. plus niacin-bound chromium and (-)-hydroxycitri of a naturalextract Effects of 689. cholesterol, fatty acids and CO and acids fatty cholesterol, fatty liver. fatty and Food ChemistryAgricultural dependent dehydrogenases and on triglycerideaccumulation in 3T3-L1 cells inculture. 10544-10550. of cholesterolinhibitor biosynthesis isolated from barley. 57 extracts rats in fed a high-fat and-cholesterol diet. humanpilot study. volunteers: A HCA-SX, niacin-boundchromium and of combination a and (HCA-SX) acid (-)-hydroxycitric of extract natural a novel, of Efficacy and Metabolism hepatic steatosis. : 8617-8622. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Federation Proceedings

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52 Thérapie Gymnema sylvestre

42 : 246-250. : 1308-1308 (Abstract5960).

Comment citercedocument :

Gymnema sylvestre 43

For Peer Review Only Review Peer For 21 itory effect ofnatural phenolic uponNAD- lipids : 395-395 (abstract: 395-395 645). : 719-731. c acid (HCA-SX) and HCA-SX a combination of c acid(HCA-SX) and dependent effect of carnitineonethanol-induced andElson, C. E. (1986). The structure ofan carnitineits and precursors alcohol-inducedon S.,Satyanarayana, S.and Dey,D. K.(2004b). S., Dey, D. K. and Satyanarayana, S. (2004a). S. (2004a). Satyanarayana, and D.K. Dey, S., Metabolism-Clinical Experimental and

Journalof Agricultural Food Chemistry and 24 extract on weight loss. weight on extract : 45-58. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Journal of Biological Chemistry extract inweightmanagement in Critical ReviewsinFoodScienceandNutrition Diabetes, Obesity Journal of

9 : 686-

261 84 :

60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Roy, S.,Freake,Fernandez, H. C.and L. M. Rotenberg, S.andRotenberg, Eggum, B.O.(1986). The effect Rhew, T. H. and Sachan, D.S.(1986). Dose-dependentlipotropic effectcarnitine of in chronic- Ricketts, M.-L., Moore, D. D., Banz, W. J., Riggs, T. R. andHegsted,(1948).Theeffect D. M. Rikans, L. L.,Arata, D.and Cederq Rong, N., Ausman, L. and Nicolosi, R. (1997).L. andNicolosi,N., Ausman,Oryz R. Rong, Rosenfeld, B. (1973). Regulation by dietary choline choline bydietary Regulation (1973). B. Rosenfeld, Roongpisuthipong,C., Kantawan, Roongpiand R. Ross, A. B., Chen, Y., Frank, J., Swanson, J. E., J.E., J.,Swanson, Chen, Frank, A. B., Y., Ross, Scandinavica A298. A298. cholesterol (LDL-C)by modulating hepatic cholesterol 7-alpha hydroxylase. the diet on selected lipid parameters lipid selected dieton the alcoholic rats. A review. mechanisms ofaction of the isoflavonessoy include rats. niacin in niacin in high fat diets. II. Effect choline of supplements. fatty streaks in hamsters. hamsters. in streaks fatty Journal of Lipid Research 16 the short term treatment of obese women in Thailand. Thailand. in women obese of treatment term short the tissue body and weight: effect ofwater soluble ca in rats and inhibit and rats in Kamal-Eldin,Aman,P. and A. Cereal(2004). : 25-29. : 25-29. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Journal ofBiological Chemistry Journal of Nutritional Biochemistry Journal ofNutritional

36 Journal of Nutrition

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32 uist, D.C.(1965). livers Fatty produced inalbino rats byexcess

: 303-309. 116

172 : 2263-2269. in liverin andblood-plasma ofrats.

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in vitro For Peer Review Only Review Peer For (2000). Dietary solublefi 16 Parker, R. S., Kozubek, A., Lundh, T., Vessby, B., Vessby, T., A., Lundh, Kozubek, Parker, R. S., alkylresorcinols elevate gamma-tocopherol levels Mezei, O. and Shay, N. F. (2005). Shay,O. and Mezei, N.F. Molecular : 321-330. of purified pectins withand without saponins in of pantothenicdeficiencyacid onacetylation in anol decreases cholesterol absorption and aortic . lcium hydroxycitrate in Garciniaatroviridis on suthipong, W. (2007). Reduction of adipose Journal ofNutrition s activation ofpromiscuouss activation nuclearreceptors. of hepatic fatty acid synthetase in the rat. rat. the in acid synthetase of fatty hepatic Asia Nutrition Pacific Journal of Clinical URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected] Journal of Nutrition

134 ber lowers plasma LDL : 506-510.

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American Journal of Clinical Nutrition Journal ofClinical American Nutrition Reports International Nutrition 123 AnnalesAnim deBiologie : 1328-1337. Chemical and Pharmaceutical Bulletin andPharmaceutical Chemical Annals of Internal Medicine of Internal Annals synthesis in rat liver. liver. rat in synthesis 535-590. DOI :10.1080/10408398.2010.549596 d Ruark, R. A. (1984).Ameliorating effectscarnitine its and of ale Biochimie Biophysiqueale Biochimie

143 on the cholesterol contents of rat-livers. of rat-livers. contents the cholesterol on

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lipotropic factors on cholesterol metabolism in c effect of carnitine on alcohol-inducedon of carnitinec effect hepatic c effect of carnitine on alcohol-inducedon of carnitinec effect hepatic 35

d Borgis,d K.-J.(1979). Influence ofsilibin A. (1942). Pantothenic acid deficiency studies in and Shoji,(1975). J. Ef 21 s inplasma and hepatic lipids,small-intestinal Arzneimittelforschung : R32, page xx. : 848-862. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

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60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 M., Chen, Schwarz,T. W. J. Linfoot, and P. (199 Seetharamaiah, G. andS. Chandrasekhara, N.(1988). Hypocholesterolemic activity of oryzanol in Shils, M. E. and Stewart, W. B. (1954). Development of portal fatty liver in rats on corn diets - - diets on corn in rats liver of portal fatty Development (1954). B. W. Stewart, and E. M. Shils, Sekiya, M., Yahagi, N., Matsuzaka, T., Najima, Y Najima, T., N., Matsuzaka, M., Yahagi, Sekiya, Seetharamaiah, G.S.and Chandrasekhara, N.(1993).Comparative hypocholesterolemic activities Sharma,and R.Rukmini, C.(1986). Rice bran oiland hypocholesterolemiain rats. Sener, G., Balkan, J., Cevikbas, U., Keyer-Uysal, U., J.,Cevikbas, Balkan, G., Sener, Shieh, J., Wu, H., Cheng, K. and Cheng, J. (2 Cheng, and K. Cheng, H., J., Wu, Shieh, B. L. Bullock,J.,Nguyen, G., Salen, S., Shefer, 85 Circulation lipogenesis, gluconeogenesis and glucose production in obese hyperinsulinemic subjects. rats. response to lipotropic agents. agents. lipotropic to response Journal ofPineal Research in obesemice SREBP-1suppression.in by J.-i., Yamada, N.and Shimano, H.(2003). Polyuns 30 of oryzanol, curcumin and ferulic acid in rats. liverand probably the in aortaC57BL/6Jmice. of cholesterolaccumulationand prooxidant stateinduced high by cholesterolthe dietplasma, the in diabetes and stimulates glycogen synthesis via a PKC via synthesis glycogen stimulates and diabetes sitosterolemicand homozygotes.hydroxylase rat inthe on regulationsitosterol the of3-hydroxy-3-methylglutaryl-CoAreductasecholesterol and 7-alpha- Tint, K.and Batta, A. S., I.,Lerner, Chowdhary, 717. : 298-303. : 249-252. Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Nutrition Reports International

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: 927-935. Comment citercedocument : Hepatology 009). Melatonin ameliorates high fat diet-induced Only Review Peer For Journal ofFood Science and Technology-Mysore ., Nakakuki,., M.,Nagai, R.,Ishibashi,S.,Osuga, , Ness, G. C., Vhao, Z. H., Belamarich, P. P. F., , Vhao, H., Belamarich, Ness, G. C., Z. 9). Effect of hydroxycitrateon hepatic de novo M. and Uysal, M.(2004). M.and Uysal, Melatonin reduces Journal of Pineal Research Pineal of Journal aturated acidsamelioratefatty steatosis hepatic G. S. (1994). Theeffect ofincreased hepatic

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20 β pathway in hepatic cells. cells. inhepatic pathway : 213-219. Critical ReviewsinFoodScienceandNutrition

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: 173-175. Comment citercedocument : For Peer Review Only lipotropic action of some sulfur-containing amino Review Peer For on diet-induced hypertriglyceridemia inmice d Park,d T.(2004).Phytosterols and lecithindonot Journal ofVeterinary Medical Science M.-L.(2009). Dietary andKoo, green S.I. tea JournalChemistryFood ofAgricultural and a,Choline H.(1990).deficiency activates URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

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60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Sugatani,J., Wada, T., Osabe, M.,Yamakawa, K. B.J.,Song, Moon, K.H., Olsson, and U. N. Sale Spadaro, L., Magliocco, O.,SpampiSpadaro, L., Soo-Jung, Jung-Hye,L., Min-Jung, K., S., Jeong-Gyun, K., Shin-Kwon, Nak-Ju, and K. S.(2009). Spaniol, M., Kaufmann, P., Beier, K., Wuthrich K., Beier, P., M.,Kaufmann, Spaniol, Story, J. A., Baldino, A., Czarnecki, S. K. Czarnecki, A., Baldino, J. A., Story, Stewart, J. R., Fryer, E. B. and Fryer, H. C. (19 Subramanian, Pandi-Perumal,S. P.,Mirunalini, S., Sugano, M.,Ikeda, I.,Imaizumi, K., Wata Journal ofNutritionalScienceand Vitaminology concentrationsthe ofserumand livercholesterol serum and apolipoproteins rats inbutterfed fat. inulin alleviatesinulin hepatic steatosis and xenobiotics-induced liver injury inrats fed a high-fat and Hepatology and mitochondrial the dysfunctionin long-chain ratby poly unsaturated acids. fatty 561-568. nonalcoholic fatty liver disease. livernonalcoholic fatty A. M.and Purrello, F. (2008). Effects ofn-3 extr plants medicinal and garlic of effect The rats administered with alcohol. alcohol. with administered rats due to treatment withtrimethylhydraziniumpropionate. Krahenbuhl, S. (2003). Mechanisms ofliversteatosiscarnitinesystemic in ratswith deficiency cholesterol accumulation by cholesterol accumulation protein-levels on serum and liver lipids inrats. of rats. Melatonin treatment improves the antioxidant status and decreaseslipid content in brain and liver Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), European Journal ofPharmacology

49 : 262-273. dietary fiber in rats. rats. in fiber dietary 535-590. DOI :10.1080/10408398.2010.549596 Journal ofthe Korean Society Digestive andLiver Disease nato, D., Piro, S., O

nabe, M. and Andoh, M.and M.(1982).nabe, Effects of Comment citercedocument : Only Review Peer For 571 and Kritchevsky,Modificationand D.(1981). liver of 87). Effects87). of dietarycarbohydrate, fiber, lipidand acts on the liver function function theliver acts on Journal ofNutrition Journal : 116-119.

Nutrition Reports International m, N.(2008).Prevention ofalcoholic liver fatty 28 , J., Torok, M., Scharnagl, H., Marz, W. and W. H., Marz, Scharnagl, M., Torok, , J., , Yoshinari, K. and Miwa, M. (2006). Dietary polyunsaturated acids fatty subjects in with : 117-126. R., Trakht, I. and Cardinali, D. D. P. (2007). I.and Cardinali, R., Trakht, liveri,C.,Alagona, C.,Papa, G., Rabuazzo, Journal of Lipid Research URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

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68 H. andMoon, T. W.(2004). Isoflavones foundin Simonyi, A.,Rudeen, P.K. , O. and Wheatley, V. (1974b).of (-)- Effect V. and Wheatley, O. , : 1051-1058. O. (1974a). Effect of of Effect (1974a). O. Wheatley, V. R. (1972). Inhibition of lipogenesis lipogenesis (1972). of Inhibition R. V. Wheatley, Lee, H.G.(2005). Antioxidative activity of

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92 β - 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Wang, X., Song,and K.-S., Guo, Wang, Q.-X.Tian, Wang, W., Basinger, A., Neese,A., Shane,B., R. M.,J.-M.,Wang, Liu, J.-R.,Gao, Parry,J. W. Lu, W. M., Cheng, H., Y. Zou, J., Li, Q., J. Wang, van der Hoorn, J. W. A.,de Haan, W., Berbee, J. Vaishwanar, I.,Jiddewar,G., S G. Uchida, K.,Mizuno, H., Hirota, K.,Takeda, K.,Ta Ueshima, T., Shigata, Y., Wada, M., Oji, K.and Pharmacology synthase. fatty-acid inhibit to feature structural critical the is catechins E540-E547. triglyceride production. (2001).M. K. Effectnicotinicof acidadministration lowlipoprotein- onhepatic very density and Food ChemistryAgricultural buckwheattartary branextract itsand effect leve on hepaticsteatosis in X. W., Hu, C. M.and Liu, L. (2009a).P. Preventive effectsflavonoids total of of Thrombosisand Vascular Biology plasma levels of estercholesteryl transfer proteinin APOE*3Leiden.CETP mice. C. N. and Princen, H. M. G. (2008). Niacin increases HDL by reducing hepatic expression and Biology on serum and hepatic lipids in expe excretionsbile-acid inmice. ch liver and plasma on sitosterol and spinasterol liver diseases and its with diseases and liver correlation liver function. pantothenic acid in liver damage. I. Urinary excretion of pantothenic acid in patients with various Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

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66 : 2039-2047. American Journal of Physiology-Endocrinology and Metabolism rats fed with high fat diet. Japanese Journal ofPharmacology 535-590. DOI :10.1080/10408398.2010.549596 hukla, R. D. and Kowale,C. N.(1972). Effect of nicotinic-acid

28 rimentally induced fatty liver. inducedfatty rimentally

: 5106-5112. : 2016-2022.

Comment citercedocument : on the lipid profile of hyperlipidemic rats. on the profile ofhyperlipidemic lipid Only Review Peer For and Wei, Y.-M. (2009b). Antioxidantactivity of Yoshida, T. (1956). Studies onthe metabolism of W.-X. (2003). The galloyl moiety of green tea F. P., Havekes, L. M., Jukema, J. W., Rensen, P. P. W., Rensen, J. Jukema, M., L. Havekes, P., F. Myong, A., S. Christiansen,and M.Hellerstein, olesterol levels and biliary and fecal sterol sterol and fecal and and levels biliary olesterol C., Zhang, L., Ge, J. F., Huang, C., Jin, Y., Y., Lv, Jin, C., Huang, J. F., Ge, Zhang,L., C., keuchi, Ishikawa,Effectsand Y. (1983). N. of JournalVitaminology of Journal of Ethnopharmacology URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

33 Indian JournalIndian ofExperimental : 103-112.

2 Critical ReviewsinFoodScienceandNutrition : 299-306. Arteriosclerosis Litsea coreana

121 Biochemical Journal of : 54-60.

280 93 :

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22 : 281-288. Aralia mandshurica

16 : A242-A242. : A242-A242. 535-590. DOI :10.1080/10408398.2010.549596 JournalLipid of Research

Comment citercedocument :

Rupr. et Maxim. Part IV. Influence of saponosides on Only Review Peer For 17 Hincenbe.I (1968). Effects of dietary fat level on patocellularlipoid changes pantothenic in acid , H., Lundquist, M., Skattebol, L., Songstad, J.Skattebol,H., Lundquist, L.,Songstad, M., , : 115-134. Archives ofBiochemistryand Biophysics

10 K. C.(2002). Freephytosterolslower plasma techin gallate: a natural inhibitor of fatty-acid offatty-acid inhibitor anatural techin gallate: : 525-530. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

42 Journal ofNutrition : 725-734.

288 : 1200-1206. Herba Polonica Critical ReviewsinFoodScienceandNutrition

94 : 377-382.

23 British British : 285-

135 94 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Yang, D.-J., Chang, Y.-Y., Hsu, C.-L., Liu, C.-W., Lin, Y.-L., Lin, Y.-H., Liu, K.-C. and Chen, Y.- Yagi, K. and Kotaki, A.(1969). The effect of massive doses of Yacowitz,H., Fleischman, A.I.and Kritchevsky, D. (1976). Does fiberin bread affect and serum Wu, Z. M., Zhang, Y., Qi, Y., Lu, J. H., Tan, N. Z. R. S., W.Wright, Anderson, J. Yeh, Y. (1979). The opposing effects of nicotinic-acid and dibutyryl cyclicadenosine-3',5'- Yang, S., Tseng, J., Chang, Y. and Chen, Y.(20 Yeh, Y.-Y. Yeh,S.-M. and (1994). Garlicreduces Yeh, Y.-Y. and Liu, L.(2001). Cholesterol-lowering effect of extractsgarlic and organosulfur Yang, M.-Y.,Peng, C.-H., Chan, Y.-S K.-C., Yang, longans (2010a).C. Antiobesity and hypolipidemiceffects polyphenol-rich of longan ( phospholipid metabolism. liverlipids inrats. Chemistry lipids. serum policosanol, and SB formula: inhibitory discrepant expressions of livercholesterol synthesis and synthesis. monophosphateon ketogenesisisolated rathepatocytes. in of hyperlipidemic hamsters. and triacylglycerol synthesis. and triacylglycerol compounds: human and animal studies. hepatic lipid clearance. hypolipidemic effect of Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6), Lour.) flower water extract in hypercaloric-dietary rats. rats. hypercaloric-dietary in extract water flower Lour.)

Proceedingsofthe Societyfor ExperimentalBiology and Medicine 58 : 2020-2027. FASEB Journal Journal ofNutrition Journal of Agricultural andFoodJournal ofAgricultural Chemistry Hibiscus sabdariffa Hibiscus Annals oftheNewYorkAcademy ofSciences Journal Chemistryof AgriculturalFood and

535-590. DOI :10.1080/10408398.2010.549596 Lipids 19 and Bridges, R.(1990).Propionate S. lipid- inhibitshepatocyte : A972-A972.

: 189-193. 106 Journal of Nutrition Comment citercedocument :

: R26-R26. For Peer Review Only polyphenols promoting and inhibitinglipogenesis via Review Peer For 09). Flaxseed attenuatesoil nonalcoholic fatty liver plasma lipids byinhibiting hepaticplasma lipids cholesterol ., C.-N. andHuang, Wang, C.-J. (2010b). The , Yin, W. T. and Zhu, URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Journal of Journal Nutrition

131 : 989S-993. Journal ofAgricultural and Food

58 : 850-859.

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myo 57 J. S. (2005). Geraniol, : 710-725. . -inositol on hepatic

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109 : 26-29. : 110-118. Dimocarpus 95 Page 262of267 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Version16 15 14 13 preprint12 11 10 9 8 7 6 5 4 3 2 1 Page 263of267 Young, R. J., Lucas,Young, R.J., J.C. C.,Patterson, M. R. andSuzue, T., Takahash.S Esashi, F., Yokota, Zhang, Kamanna,L.-H., M.C.a V.S.,Zhang, Zeisel, S., Da Costa, K.,Franklin, P., Alexander, E., Lamont, J., Sheard, N. and Beiser,(1991). A. Youssef, J.,Cunningham, M. L.and Badr, M. (1994). Down-regulation of hepatic peroxisomal

Zhang, R., and Tian,Xiao,Wang,X. X.,Wu,W.W., (2006).Novel inhibitors offatty-acidsynthase 405-408. BiochemistryPhysiology and rats:studies in comparisons ofcholine, betaine,andmethionine. on incorporation of sodium acetate-1- Lipid Research Biotechnology expression of ATPsynthase Choline, an essential nutrient for humans. beta-oxidationto due pantothenic acid-deficiency. from greenfrom ( tea Fardet, A., Chardigny, J.-M. (2013). Plant-Based Foods asaSource of Lipotropes for Human Nutrition: A Survey ofInVivo Studies. Critical Reviews in Food Science andNutrition, 53(6),

and

49 Camellia sinensis : 1195-1201.

Applied Biochemistry

535-590. DOI :10.1080/10408398.2010.549596 β 34 chain in HepG2in chain cells: implications for raisingHDL. : 713. Xihu Longjing)a and withhighactivity new reacting site.

14 C into lipid of rat liver. liver. ofrat lipid into C

Comment citercedocument :

43 FASEB J FASEB For Peer Review Only : 1-7. Review Peer For and Best, C. H. (1965). Lipotropic dose-response nd Kashyap, M.L.(2008). Niacin inhibitssurface (1974). Effectsof excessmethionine and glycine FASEB Journal

5 : 2093-2098. URL: http://mc.manuscriptcentral.com/bfsn Email: [email protected]

Nutrition ReportsInternational

8 : A736-A736. : A736-A736. Canadian Journal of Critical ReviewsinFoodScienceandNutrition Journal of

10 96 : 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 Version33 32 31 30 preprint29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Fardet, A., Chardigny, J.-M.(2013).Plant-Based Foods asaSource ofLipotropes forHuman Nutrition: ASurveyof In VivoStudies. CriticalReviews inFoodScience andNutrition, 53(6),

URL: http://mc.manuscriptcentral.com/bfsn Email:[email protected] 535-590. DOI :10.1080/10408398.2010.549596 Only Review Peer For Comment citer cedocument: Critical ReviewsinFoodScienceandNutrition

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