Transcriptional control of physiological and pathological processes by the nuclear receptor PPAR beta/delta Nguan Soon Tan, Manuel Vázquez-Carrera, Alexandra Montagner, Ming Keat Sng, Hervé Guillou, Walter Wahli
To cite this version:
Nguan Soon Tan, Manuel Vázquez-Carrera, Alexandra Montagner, Ming Keat Sng, Hervé Guillou, et al.. Transcriptional control of physiological and pathological processes by the nuclear receptor PPAR beta/delta. Progress in Lipid Research, Elsevier, 2016, 64, pp.98-122. 10.1016/j.plipres.2016.09.001. hal-01594607
HAL Id: hal-01594607 https://hal.archives-ouvertes.fr/hal-01594607 Submitted on 26 Sep 2017
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. Ù×Ö ÔØ Version postprint ÅÒ Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : eoei spbihdi t nlfr.Pes oeta uigtepouto process production the during that th pertain. note manuscript. affect journal Please the the could of to form. which proof apply publication. version discovered final resulting for its be early the in may accepted this of errors published providing review been is and has are it typesetting, we that copyediting, before manuscript customers undergo will unedited our manuscript an to The of service file a PDF As a is This 10.1016/j.plipres.2016.09.001 V´ Soon, Nguan Tan as: article this cite Please 2016 September 20 2016 August 31 2016 April date: 1 Accepted date: Revised doi: date: Received S0163-7827(16)30013-3 925 JPLR in: appear To Reference: DOI: PII: Herv´ Sng, V´ Manuel Tan, Soon Nguan the by processes pathological and PPAR receptor physiological nuclear of control Transcriptional ÔØ lgcladptooia rcse ytencerrcpo PPAR receptor nuclear the by processes Herv´ pathological Guillou and Keat, ological Ming Sng dra, ulo,Wle Wahli Walter Guillou, e 10.1016/j.plipres.2016.09.001 Comment citer cedocument: β / δ 10.1016/j.plipres.2016.09.001 zuzCrea lxnr otge,Mn Keat Ming Montagner, Alexandra azquez-Carrera,
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by References Acknowledgements 10. Conclusion 9. 8 7 6 5 4 inearly3. PPARβ/δ 2. Molecular oftranscriptional mechanisms regulation Introduction1. Contents the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : . . . . . PPAR PPARβ/ ininsulin resistancePPARβ/δ and incardiovascularPPARβ/δ disease int PPARβ/δ PPARβ/δ 9.2 8.2 8.1 7.1 Adiposetissue 9.1 Neuroprotectivein neuro role 7.4 Pancreas 7.3. Liver 7.2 Skeletal muscle 6.3 Cardiacdisease 6.2 Atherosclerosis dysfunction6.1 Endothelial otherorgans repair5.3 Tissue in 5.2 Skin repair repair tissue 5.1 Inflammatory during response 2.3 Transrepression and 2.2 Transactivation localization 2.1 Cellular
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by superfamily. receptor nuclear the of members all among regions conserved most the are respectively) LBD, and (DBD structur metabolism, veryand challengingtarget attractive system, PPARβ to attributed been have functions syndrome al diseases pharmacological and catabolism overlapping isotype rang that extensivel been have family PPAR the of (NR1C2) 1990 in hepatocytes rodent in proliferation peroxisome ligands. respective their superfamily receptor hormone nuclear the to belong that 1. the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : though
Introduction - proliferator Peroxisome ally specific s s h cs fr all for case the is As
uterine implantation, implantation, uterine [6 e far e and PPARγ PPARγ and small ,7] [8
organized into function into organized
cell ,9] functions .
beyond beyond In contrast
. PPARβ/δ is expressed in numerous tissues tissues numerous in expressed is PPARβ/δ . or shar or ular
tde o hmn subjects human on studies
in agt of targets
differentiation and proliferation, ACCEPTED are both and respectively, storage, lipid and differentiation adipocyte MANUSCRIPT The DBD consists of of consists DBD The (NR1C3)
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, ic te icvr o PPARα of discovery the Since
tissue expression, all three PPAR three all expression, tissue no PPARβ/δ ligandsno PPARβ/δ .
PPARα and PPARγ have established roles roles established have PPARγ and PPARα FDA
the gut, the brain, and skin and brain, the gut, the mediati te member other - , activated receptors activated
were subsequently were - prvd drugs approved
al ,
ng modular domains. The DNA The domains. modular as it is involved in numerous key functions, such as energy suchas innumerous functions, isinvolved key it as /δ in skeletal muscle, adipose tissue, the cardiovascular the tissue, adipose muscle, skeletal in /δ peroxisome proliferation peroxisome y linked to numerous systemic and cellular activities cellular and systemic numerous to linked y α - s
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PR/ ligands PPARβ/δ [12] binding motifs together with two zinc zinc two with together motifs binding
and their activities are dependent on on dependent are activities their and s
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These factors make PPARβ/δ a PPARβ/δ make factors These [10 et of ment
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the treatment of the treatment and ligand and as a receptor that mediates mediates that receptor a as ,11] different or, in some cases, some in or, different cancer , erized
and ueos metabolic numerous
in
to treat metabolic metabolic treat to progression [4]
- binding domains domains binding many important important many at acid fatty
. [2
Dependent on Dependent ,3] any disease, disease, any PPARβ/ . Members . .
(FA) (FA) is δ 3
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by lipid they PPARβ/δ, 2.1 2. many metabolic ofthe caused diseases by thedysregulationof PPAR, the promote consequently and PPARβ/δ of LBD transcription ofdownstreamgenes target the to bind to molecules coactivator induces repress and bind to molecules corepressor for allows conformation open its in exists 12 helix present, is ligand no to When PPARβ/δ. of LBD able are Ligands corepressors. and coactivators allosterically with binding of levels the between of presence FA natural including pocket binding sheet is LBD The genes. target PPARβ/δ of domains receptor finger the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
Cellular localization Cellular Molecularmechanisms transcriptionaof - A a ebr f h PA fml, PR/ as psess rltvl lre ligand large relatively a possesses also PPARβ/δ family, PPAR the of member a As . binding protein binding - like In this review, we will will we review, this In As a nuclear receptor, PPARβ/δ is localized in the nucleus of cells. of nucleus the in localized is PPARβ/δ receptor, nuclear a As PPARβ/δ
( cnomtoa cag a hlx 12 helix at change conformational a RXR motifs a alter the conformation of the helical structure (helix 12) at the 12)atstructure the (helix helical conformation ofthe the alter ligand, transcriptional activity is dependent on and regulated by a tight balance balance tight a by regulated and on dependent is activity transcriptional ligand, )
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e structure of the DBD the of structure e FA be transported from the cytoplasm into the nucleus the into cytoplasm the from transported be ACCEPTED MANUSCRIPT s eicosanoids, , 10.1016/j.plipres.2016.09.001 Comment citer cedocument:
ACCEPTED MANUSCRIPT
- to 3 binding protein 5 (FABP5) selectively performs this transport function transport this performs selectively (FABP5) 5 protein binding )
, which allow which ,
peroxisome proliferator peroxisome
the status of this nuclear receptor as a potential therapeutic target for target therapeutic potential a as receptor nuclear this of status the discuss
n snhtc gnss r antagonists. or agonists synthetic and
tde rltd to related studies s [13]
PPARβ/δ to interact with a broad spectrum o spectrum broad a with interact to PPARβ/δ
allows .
l regulation ,
composed expos response elements (PPREs) in the regulatory the in (PPREs) elements response PPARβ/δ its its ing transcriptional acti transcriptional h functions the
by PPARby
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a
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f h less the of
[14] vities. vities. F C or ligands to bind to bind to ligands or
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- a well known known well stranded stranded
retinoid X X retinoid f ligands, f , which , β 4 - -
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by of sites PPRE the for competition PPARβ/δ the via transcription basal transcription transcription basal repress to able is PPARβ/δ 1) (Figure to acetyltransferases histone other and CBP/p300 as such PPARβ/δ 2.2 atherosclerosis and F between activities and differentiation, cell homeostasis, function many affect the and tissues, these of many in PPARβ/δ cell specific kidney brain, glands, mammary in FABP5 of expression FABP5 to the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
enhance the transcriptional activity of PPARβ/δ of activity transcriptional the enhance PPARα and PPARγ, PPARβ/δ functions as a transcriptional repressor in its unliganded state unliganded its in repressor transcriptional a as functions PPARβ/δ PPARγ, and PPARα
Transactivation and Transactivation in
T ahlgcl conditions pathological n keratinocytes in e t he
monomers or heterodimers or monomers This . induced
type ransactivation of PPARβ/δ involves the binding of an agonist to the LBD of of LBD the to agonist an of binding the involves PPARβ/δ of ransactivation [28]
[24] s such as macrophages as such s . function
In . isotype ABP5 and PPARβ/δ ha PPARβ/δ and ABP5
that ACCEPTED MANUSCRIPT s 10.1016/j.plipres.2016.09.001 Comment citer cedocument:
ACCEPTED MANUSCRIPT r f PR/, including PPARβ/δ, of
epression
report, the authors demonstrated that unliganded PPARβ/δ suppressed PPARβ/δ unliganded that demonstrated authors the report, nearly f PPARβ/δ of - many erimn o crpesr molecules corepressor of recruitment
specific s
, liver, lung liver, , w dcds g, ueos tde have studies numerous ago, decades two uh as such tissues those
ersin f PR ad PR tre genes target PPARγ and PPARα of repression with RXRs and RXRs with
genes [16] is
apoptotic n organs and trbtd o w itreae properties interrelated two to attributed ve cancer . interaction s
This expression pattern expression This . , heart, skeletal muscle skeletal heart, , been reported to be involved in neurogenesis in involved be to reported been
It
has
hs involving those [15] [20 s el as well as resistance also previously also , such as the epidermis, adipose tissue, tissue, adipose epidermis, the as such , the the ,21]
[25 (Figure 1) (Figure of FABP5 with PPARβ/δ PPARβ/δ with FABP5 of recruitment of coactivator molecules, coactivator of recruitment mtblc syndrome metabolic , - 27]
[15, (Figure 1) (Figure PPARα Te as demonstrated also They . .
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is [22 :
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that of of that and ,
[19] that the the
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by anti BCL [35 VCAM as such dissociation This triggered cells cells, cells endothelial and cells muscle smooth vascular repressor transcriptional certain perform to able is PPARβ/δ 2.3 the recruitment ofhistone deacetylases keratinocytes human in on effect repressive potent a exert to able another coactivators and [29 (SMRT) receptor hormone thyroid and retinoid for mediator silencing and (NCoR) corepressor rep mediated the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : ,30] ,36] - Transrepression atherosclero -
[29, 6 PPARβ/δ PPARβ/δ - , . Such anti Such . n diin to addition In mediated
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been shown that shown been - Interestingly, PPARβ/δ PPARβ/δ Interestingly, (BCL 6 - accelerated atherosclerosis accelerated PPARβ/δ
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[26] the anti the
promoter
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the dissociation of BCL of dissociation the -
only mediated transactivation of target genes target of transactivation mediated Fgr 1) (Figure - the inflammatory inflammatory
regions of pro of regions on PPARβ/δ bound to bound PPARβ/δ on the direct induction of target genes, genes, target of induction direct
have p65/RelA
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PPARβ/δ PPARβ/δ also been reported been also protecting the -
6 activity [37
[28, - s lo euae by regulated also is subunit PPARβ/δ inflammatory genes genes inflammatory ,38]
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and the vasculature the of PPARβ/δ PPARβ/δ of
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by of groups nucleophilic with bonds covalent form may unclear remains activatePPARβ/δ β pancreatic and polyunsaturated (4 hydroxydodecadienal of products peroxidation 8( product lipoxygenation eicosanoids, very of components and activity. by caused diseases metabolic the of many for target functions functions antagonist development the controversies, discrepancies diseases certain in PPARβ/δ of role the regarding and PPARβ/δ PPARβ/δ andsynthetic ligandsof 2.4 Natural in macrophages ne the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : phro their pathy As a member of the PPAR family, PPARβ/δ is responsive to naturally oc naturally to responsive is family,PPARβ/δ PPAR the of member a As groups independent many years, the Over
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. However, the mechanism by which these two 4 two these which by mechanism the However, . play a roleplay inregulating hdoyioaereoc cd [8( acid hydroxyeicosatetraenoic ) f syntheti of
. It has been proposed that these chemically reactive aldehydes aldehydes reactive chemically these that proposed been has It . h sau o ti ncer eetr s ptnil therapeutic potential a as receptor nuclear this of status the
to meeting to ligands c
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Across eotd aiu fnig rltd to related findings various reported dysregulat to related studies Arachidonic acid metabolites, or or metabolites, acid Arachidonic found ly
amino acids (i.e. histidine, lysine, histidine, (i.e. acids amino [40
understanding understanding
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ligand of simultaneous se transporters se
peuain f AP, iecn o CRABP of silencing FABP5, of upregulation
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ve it has also been reported that steric hindrance prevented hindrancesteric that reported been also has it
found to promote promote to found motn fntoa consequences. functional important
2
ratio, resulting in a pro a in resulting ratio,
[15, : expression in vivo in CRABP ir corresponding ir 17, - 50 and
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54 PPARβ/δ by RA is regulated by a a by regulated is RA by PPARβ/δ was uncertain was
receptor - critical apoptotic effect. On the other hand, hand, other the On effect. apoptotic ,55] .
RAR activation by RA occurs by RA activation RAR of to s to the to [51,
, in many human tumors human many in
their cognate receptors and theirand cognatereceptors enabling direct transfer of of transfer direct enabling cells with higher FABP5 FABP5 higher with cells FA o eape numerous example, For 53]
how RA could play could RA how efficient activation of of activation efficient transporters
[17, . uo types tumor
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by similar PPARβ/δ demonstrated for approved been have compounds these of none Although healthcare These development ligands ne hippocampal postnatal subjects obese of tissue adipose indirect undiscovered t possible also is as Intheir selectiveagonists. PPARβ/δ otherand between RA propositio this against argued oncogenic of expression oncogenic that FABP5 of d Bioscience Compedia cancer various in prognosis patient poor with associated are tumors in FABP5 esophagus and colon, skin, breast, prostate, bladder, pancreas, the of the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
shown by their reporter assays reporter their by shown
in line with line in
iad icue gnss and agonists include ligands ,
o ht ewe FB5 and FABP5 between that to Interestingly, h ne t dsoe therapeutic discover to need the could
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of
[58 [64] benefits against a divers synthetic ,
and t and
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in enabling the activation of of activation the enabling in [65]
antagonists but are upregulated in neural stem/progenitor cells during cells stem/progenitor neural in upregulated are but PPARβ/δ o recruit coactivator recruit o . Moreover, it has been documented that elevated levels elevated that documented been has it Moreover, . .
In addition to addition In
PR/ lgns a ligands PPARβ/δ
n metabolism in gns for agents
[17, ; has
the potential benefits benefits potential the PPARβ/δ and FABP5 are downregulated in in downregulated are FABP5 and PPARβ/δ
20, en prop been 49, and the desire to identify to desire the e range of metabolic disorders. metabolic e range of
60 eaoi dsae rsle i the in resulted diseases metabolic study, invasion and tumor development and and development tumor and invasion s to s S . clinical use, clinical – 62] ptnil yoiiei drugs hypolipidemic potential s osed based on based ial du therap drug uitable studies bind to PPARβ/δ to bind . PPARβ/δ RA failed to activatePPARβ/δ, to failed RA
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type .
ih ees of levels High [63] s (Oncomine s ies . Hence, it Hence, .
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by 3. differentiation expression demonstrated a hypothesis, suggests present expressed PPARβ/δ importance shuttling ofnucleocytoplasmic partitioning [69] 41 Ro example, For another. an Interestingly, antagonist for demonstrated been agonists PPAR determined antagonists. transport or agonists synthetic and including eicosanoids, ligands, of spectrum broad a with interacts PPARβ/δ ma studies, the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
PPAR I ti con this In .
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is uncertain is
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10.1016/j.plipres.2016.09.001 Comment citer cedocument: ACCEPTED MANUSCRIPT is various the among interplay he
of the e the of loss o expressed not
. d
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and .
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is strongly upregulated strongly is at this developmental stage developmental this at antagonist of RARα but is able to able is but RARα of antagonist
interest Using its its Using various . in
family member family hs results These
laevis uce ( muscle
that
sn a atsne opoio (MO) morpholino antisense an using PPARβ/δ iad to ligands oee, w However, relatively large ligand large relatively effectors
- embryo eitd niiin f PPARβ/δ. of inhibition mediated this this are cc, myod1 actc1,
[2,
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s
can , are 4 and FABP5, and 4 mlctd n the in implicated y obnn te loss the combining By
. vrey of variety a
in which in during gastrulation during PPARβ/δ PPARβ/δ key for development development for key The
ehr intracellular hether function as function supported supported
[38] and ) PPARβ/δ .
PPAR In support of this this of Insupport - activate binding pocket, pocket, binding
remains to be be to remains ri ( brain
for for natural an by α
agonist of agonist protein particular is weak is selec reduced reduced k , which , PPAR rox20 s
FA [70]
- tive FA the of
10 ly is s - ) , .
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by the PPARβ/δ ( significantly increased gene age with change (ED54 fro intestin by examined development. processes, pathological role important development ofthe duringtheformation placenta be develop pluripotencyof Importantly t stage pluripotent the at deposited and gastrulation During unveiled. was PPARβ/δ marks epigenetic between cooperation important an experiments, immunoprecipitation with approach function the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : between
m embryonic day (ED) 54 to 125, to 54 (ED) day embryonic m development. early during coordinated PPARβ/δ PPARβ/δ [75] – al ept is discovery its Despite ment of ment 120), , liver, lung, heart, kidney, adrenal, thymus, stomach and spleen and stomach thymus, adrenal, kidney, heart, lung, liver, ,
ED54 . protein ua ftl ie expressed liver fetal Human , PPARβ/δ is the first identified transcription factor transcription identified first the is PPARβ/δ ,
a few few a kidney The mRNA The s
protein in vivo in , a and of
as determined by real by determined as expression greater groups groups PPARβ/δ
125
(ED54 ACCEPTED MANUSCRIPT
10.1016/j.plipres.2016.09.001 during embryonic during Comment citer cedocument: across the age range age the across ACCEPTED MANUSCRIPT high level ) su
mechanistic understanding of how the activation of activation the how of understanding mechanistic and intestin and and protein expression of expression protein and r [74
prisingly – - 125), throughput RNA throughput decreased with fetal age, no age, fetal with decreased
n t in ,75] s eemnd by determined as s early as e rncitoa cnrl of control transcriptional he .
spleen ( spleen Based on an analysis of analysis an on Based
activate o PPARβ/δ al tissues al ite s nw aot t epeso during expression its about known is little - time PCR PCR time as PPARβ/δ development
In mammals, In
ED67 , 92 and 1992 ;
PPARβ/δ recognizes H3K27me3 marks H3K27me3 recognizes PPARβ/δ in contrast, in -
seq seq mRNA expression in fetal lung, adrenal, stomach adrenal, lung, fetal in expression mRNA ( the the ED54 , inwhich , –
125) using transcript expression analys expression transcript etr bo analysis blot western RA rm ED54 from mRNA rncito of transcription PPARβ/δ in human various fetal tissues was was tissues fetal various human in PPARβ/δ –
[70]
120) the
and thymus and PPARβ/δ also plays a major role later in in later role major a plays also PPARβ/δ
2 it tissue showed a showed tissue .
- s expression s PPAR
nine human nine ueos tde underscor studies numerous . Except for for Except . microglobulin as the internal control control internal the as microglobulin T h ese energy homeostasis homeostasis energy
to drive to
finding is alsoinvolved
tissues al dfeetain genes. differentiation early –
fetal tissues fetal
adrenal 125 decrease an epigenetic signature signature epigenetic an
s . tissues
significant change in change significant open ( The spatiotemporal spatiotemporal The , ED74
and its expression expression its and many e
s and chromatin chromatin and s tissue, in which in tissue, , ranging in age age in ranging , the doo the d
–
in [71
, 120) 120) ua fetal human genes genes and various various and specifi
previously fetal heart heart fetal – 73] r ing did not did for for might might . cally
the the the the 11
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by already test mouse in supported by the spermatocytes isfurther spermatocytes and spermatids is PPARβ/δ 4. playrole major and tissues fetal human various in detected barely was PPARβ/δ nuclei 8 at colon fetal human the of layers cells. villous differentiated the in than cells epithelial the 22WD, At studied. stages all intestine, small the marked cells epithelial esophageal stage developmental antibodies polyclonal was tract digestive fetal human the of of distribution the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
PPAR in ly All three PPAR isotypes are expressed in somatic and germ cells of the testis. In rat In testis. the of cells germ and somatic in expressed are isotypes PPAR three All detectable at by immunohistochemistry
epithel
decrease staining was observed in the crypt regions of the colon. However, colon. the of regions crypt the in observed was staining β/δ expressed in Leydig cells and Sertoli cells Sertoli and cells Leydig in expressed
in es PPARβ/δ PPARβ/δ s ial and mesenchymal cells. mesenchymalcells. and ial
in gametes [77] d tissue tissue stronger
at 20WD. At la At 20WD. at in these regions these in examined. s
ACCEPTED MANUSCRIPT Pemlnain os embryos mouse Preimplantation . [74] 10.1016/j.plipres.2016.09.001 Comment citer cedocument: ACCEPTED MANUSCRIPT during( development
morphogenesis, and/or development physiology and
. was detectable between 7WD and 14WD, and 7WD between detectable was
PPARβ/δ PPARβ/δ PPARβ/δ PPARβ/δ
preimplantation embryos in and
[10] PR/ epeso i the in expression PPARβ/δ regions of the fetal the of regions
ter stagester -
. PPARβ/δ at 14WD at 20WD. The 20WD.
further further a detected was h epeso of expression The staining was observed in the ileum than in the jejunum at jejunum the in than ileum the in observed was staining
o bserved Compared to Compared , examined
from
PPARβ/δ PPARβ/δ [74]
tiig inl a srne i te la crypt ileal the in stronger was signal staining the PPARβ/δ signal w signal PPARβ/δ
. expression ofexpression two 7
The throughout
to digestive tract suggest that suggest tract digestive - PPARβ/δ was expressed in expressed was PPARβ/δ via cell stagecell 22 staining was more restricted to nucl restrictedto more wasstaining [76] distinct PPARβ/δ PPARβ/δ show
weeks PPARβ/δ immunohistochemistry using specific specific using immunohistochemistry . I cytoplasm and nucleus of human human of nucleus and cytoplasm n
the gastric epithelium at all the the all at epithelium gastric the PPARβ/δ expression profi expression Ssm mice p [78] of gestation of lacentation staining in the in staining as
, a novel PPAR target gene, gene, target PPAR novel , a peak
n os semtd and spermatids mouse in , or primarily localized to localized primarily PPARβ/δ PPARβ/δ
the .
ed xrsin which expression,
eight
, WD; , WD; at 15WD, 15WD, at
PPARβ/δ staining PPARβ/δ les of of les is expressed in expressed is ileum, strongerileum, - PPARβ/δ cell stagecell the different different the ~ ED49 PPARβ/δ and then and - ei. In ei.
154 may [79]
the
12 is s ) ,
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by genotypeMendelian were found distributions PPAR of colony The background. genetic prod backcrosses Subsequent intrauterine of producedfewer Sv/129) x (C57BL/6N PPAR PPAR the species, mRNA these PPAR PPAR of skin transcript type PPAR liver and terminal in 1.14 PPAR of role the in discrepancy apparent an reveal groups these from observations The mice. knockout context play PPARβ/δ PPARβ/δ and the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
the genomic clone, herein referred referred herein clone, genomic the E10 - ean detectable remains kb phosphoribosyltransferase intheII same thelast direction into gene exon of transcription β/δ β/δ β/δ β/δ
o understand To embryos and and embryos in rodents in 60 amino acids amino 60
ex8 ex8 in placentation. In 2000, Peters et al. disrupted the mouse PPAR mouse the disrupted al. et Peters In2000, placentation. in in the inner cell mass and the trophectoderm the and mass cell inner the in tissue a udtcal i aut os skin mouse adult in undetectable was
mouse, development ie Te breeding The mice. s
β/δ in
an important rolein an important s
non ex8 eeld n mRNA an revealed , three , and the expression of this mutant transcript mutant this of expression the and
-
ACCEPTEDmice, MANUSCRIPT E18 E18 muta
10.1016/j.plipres.2016.09.001 Comment citer cedocument: h fntos of functions the ACCEPTED MANUSCRIPT
throug independent groups have used different strategies to generate PPAR generate to strategies different used have groups independent , of PPAR of
fetuses nt and n ti result this and
mice. Neither the larger nor nor larger the Neither mice. uce ot h pemlnain eid Mue lsoyt as express also blastocysts Mouse period. preimplantation the hout h gross the β/δ d
β/δ PPAR of absence the that revealed
of PPAR early development.
prote
[81] eeoyos fsrn o mxd eei background genetic mixed of offspring heterozygous homozygous homozygous transcript to
PPARβ/δ β/δ n a nt eetd n eai ncer xrcs from extracts nuclear hepatic in detected not was in as . Northern blot analysis of R of analysis blot Northern . morphology
a epand y a by explained was
β/δ ex8 in PPAR
ex8 subsequent heterozygous matings.subsequent mice k lre ta te wild the than larger kb 1 cells
mice reproduced successfully, and normal normal and successfully, reproduced mice β/δ n an in PPAR ,
~75%
ex8
[79 [82] f h concepti the of Ti isrin truncate insertion This . a β/δ n vivo in ,80] truncated mRNA was detected in the the in detected was mRNA truncated Hwvr dsie h peec of presence the despite However, . ex8 of which were in the the in were which of .
was was mice than expected. An analysisAn expected. than mice These observations suggest that suggest observations These
later study study later n physiological and lower than lower β/δ NA from brain, adipose brain, from NA perd normal appeared
β/δ was not lethal lethal not was - type mRNA in the the in mRNA type
gene by inser by gene that that
that of that
d revealed that that revealed
only only y relevant ly C57BL/6N C57BL/6N
the wild the the the during
ti [81] ng β/δ C 13
a s - - .
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by differentiation cell trophoblast promoting in PPARβ/δ plac death animals mutant background (mixed mating 4 exon delete E9.5 morphogen proper undergo to placenta the of failure extensivemajor E10.5lethalityexhibited maternal point placent loose counterpart markedly background genetic specific a or res backcrosses PPAR lethal that suggesting crosses, heterozygous eliminated PPARβ/δ which gene, PPARβ/δ the the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : ult indicates that indicates ult enta was the most most the was enta ity and β/δ were ar e al et Nadra al et Barak
ex4 ex4 to stun E10.5
nearly s
observed. Further investigation revealed that the trophoblast giant cell layer of the of layer cell giant trophoblast the that revealed investigation Further observed. Hsooia eaiain f PPAR of examination Histological . embryos of [72] embryos al ted
- n ms of most and the original knockout original the decidual connections. By E12.5, three of four PPAR four of three E12.5, By connections. decidual ,
I cnrs to contrast In .
n lv PPARβ/δ live and [73] the entire PPAR entire the growth .
.
(2002) used a Cre/lo a used (2002) the lethality of PPARβ/δ of lethality the 20) ofre ta dlto of deletion that confirmed (2006) ,
. ACCEPTED MANUSCRIPT
showed no increase in survival rate survival in increase no showed 10.1016/j.plipres.2016.09.001 Comment citer cedocument: hs needn gop used group independent This hc appeared which severely ACCEPTED MANUSCRIPT at term at ,
xn 5 exon harbors C57BL6/Sv129) did not produce the expected Mendelian ratio of of ratio Mendelian expected the produce not did C57BL6/Sv129) affected , the
β/δ and most most and
ex4
from
approach h N the [72, strain gene product. PPAR product. gene
the fsrn wr rare were offspring
o cu a E10.5. at occur to x by this mutation this by 81]
- homozygous loss of PPAR of loss homozygous the the mediated recombination strategy to delete exon 4 of of 4 exon delete to strategy recombination mediated
- (129 PPARβ/δ emnl af f the of half terminal ex4 Sriig PPAR Surviving . PR/ gn ( gene PPARβ/δ
by is not alleviated by alleviated not is s v/Jae) v/Jae)
β/δ ees t al et Peters esis, leading to embryonic lethality embryonic to leading esis, ex4 ex4 a
hemorrhages
with homologous recombination strategy to to strategy recombination homologous the concepti at E9.5 revealed abnormally abnormally revealed E9.5 at concepti pups towards . The authors showed a direct a showed authors The .
β/δ despite ,
PR/ gn result gene PPARβ/δ although
ex4 isogenic C57BL/6J breeders C57BL/6J isogenic n otat to contrast In were smaller than their wild their than smaller were .
i.e., i.e.,
20) ti dsuto strategy disruption this (2000), β/δ pups were rarely obtained from from obtained rarely were pups
in cls This cells. giant the performance of performance the DBD either a heritable component component heritable a either β/δ - eiin progeny deficient PPARβ/δ
into thelabyrinthineinto zone.
β/δ no ex4 herein ,
embryos surviving the the surviving embryos ntne of instances frequently resulted in in resulted frequently
ex4 PPAR
. Heterozygote ). eerd o as to referred s
β/δ n severe a in function of of function
up to six to up ex8 perinatal perinatal between showed role . mice,
- This type type
14 of
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by have Investigators also 85% and 100% with compared stage blastocyst two of harvest after after hours 48 as early as delay developmental hampered development embryo affected adversely postimplantation and implantation, preimplantation, fertilization, and placentation PPAR that evidence further stage of finding which factor inhibitory between relationship reciprocal a showed (2007) al. et Wang decidu and implantation subfamily of expression PDPK1 activation, Akt in and B) kinase PPARβ/δ the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : exhibit
ev a cl lnae sensor lineage cell as serve In fact, In ad integrin and )
depended implantation implantation that
I was erae ebync el rlfrto cmae wt wild with compared proliferation cell embryonic decreased -
PPARβ/δ mfa, mfa, - , all s novd in involved is - ,
pcfc nerto o mtra ad mroi PPAR embryonic and maternal of integration specific s
specifically
n 2% subsequently 28% and proposed that activation of PPARβ/δ of activation that proposed ignal at least partly least at
-
on phosphatidylinositol3 on of which areof which cell embryos, only 65% of PPARβ/δ of 65% only embryos, cell ACCEPTED MANUSCRIPTnon a - ikd iae (ILK) kinase linked 10.1016/j.plipres.2016.09.001 Comment citer cedocument: alization, and embryonic PPARβ/δ is PPARβ/δ embryonic and alization, ACCEPTED MANUSCRIPT t [79] ex4 ransducer - helix
β/δ
embryos Cmae wt wild with Compared .
3
is a molecular link that coord that link molecular a is - - phosphoinositide h dfeetain rcs. aenl PR/ i ciia to critical is PPARβ/δ Maternal process. differentiation the loop of associated with associated crucial to
a s wild nd
- can be lost lost be can helix (HLH) inhibitor of the myogenic basic HLH (bHLH) (bHLH) HLH basicmyogenic the of inhibitor (HLH) helix o iet rpols cl fts uig lcnain This placentation. during fates cell trophoblast direct to a - ctivator ye embryos type
uig h pemlnain stage preimplantation the during a successful I adto, PR/ caused PPARβ/δ addition, In . un - kinase (PI3K) and(PI3K)kinase der
harvest of harvest
prior to E9.5 at any stage any at E9.5 to prior o - high expression levels of two kinases involved involved kinases two of levels expression high dependent kinase 1 (PDK1 1 kinase dependent went f t - ranscription 3 (STAT3) 3 ranscription ye embr type respectively ,
pregnancy by an by acig or hatching ex4
two
inates implantation, decidualization, implantation, inates embryos ha embryos
crucial endogenous PPAR ligand, such as as such ligand, PPAR endogenous the the - o, PPARβ/δ yos, cell stage embryos. At 96 hours 96 At embryos. stage cell
Akt1 (also (also Akt1
PPAR [83]
for placentation. for [80] [79] had had .
d β/δ . β/δ PPARβ/δ .
reached or passed the the passed or reached , PPARβ/δ
ace completely hatched referred to as referredto
- including ovulation, including
signaling AKT and AKT ; also ;
an signaling ex4 n consequently and
- increase ye embryos. type embryos show show embryos referred to referred ex4 ex4
Moreover, pathways
leukemia provide embryos ablation
protein n the in
15 as s , ,
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by might the of acids amino 60 last product gene by performed strategies PPAR underlying PPAR investigation. the toxicity developmental cells glycogen of lysis with associated degeneration Histopatho placenta. GW501516 agonist PPARβ/δ carriers gestational to transferred when rates manner concentration a in embryos cultured of implantation and development the enhanced by activation PPARβ/δ ap pharmacological biological processes in pro the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : sta activity glandin I2 (also known as pro as known (also I2 glandin β/δ β/δ not This role of PPARβ/δ in preimplantation and placentation clearly warrants further further warrants clearly placentation and preimplantation in PPARβ/δ of role This placentation, in PPARβ/δ of role beneficial a support approaches genetic Although [85 ex8
disruption in a congenic background. It has been proposed that the different disruption disruption different the that proposed been has It background. congenic a in disruption employed employed completely
– of PPARβ/δ duringof PPARβ/δ development.
hs differences these [81] 87]
[72 The reason for the stark contrast in the role of PPAR of role the in contrast stark the for reason The Barak et al. al. et Barak . Embryos preconditioned with L with preconditioned Embryos .
,73] and PPAR rahs ae yield have proaches , oial, snl oa amnsrto o G511 idcd cystic induced GW501516 of administration oral single a logically, may be responsible for these discrepancies. discrepancies. these for responsible be may
ACCEPTED MANUSCRIPT whereas the whereas abolish PPAR abolish . 10.1016/j.plipres.2016.09.001 embryos Comment citer cedocument:
ACCEPTED MANUSCRIPT T the hese results suggest that a transrepression mechanism may dominate dominate may mechanism transrepression a that suggest results hese (200 β/δ
LBD of LBD
ytei aoit L agonist synthetic
to pregnant rats resulted in malformation in resulted rats pregnant to ex4 ol require would 2 during ) and )
[72 approach employed approach
β/δ ,73] sta PPARβ/δ Nadra pre cyclin) activity ed
mice implantation andsubsequent implantation
varying
et al et
remain [81] oprtv aayi o tee w mdl of models two these of analysis comparative [84]
[79, and - - . 165041 or iloprost showed higher implantation implantation higher showed iloprost or 165041 165041
(2006), eliminated (2006), . In the latter approach, the limited deletion deletion limited the approach, latter the In .
86] or retinoic acid retinoic or outcomes could theoretically produce theoretically could s
[88] by Peters et al. (2000) dis (2000) al. et Peters by unclear . diitain of Administration or uepcel leading unexpectedly ,
lpot a tbe G2 analog PGI2 stable (a iloprost
,
t ifrn sae o gestation of stages different at and and determining themechanisms
D β/δ [17] suto o the of isruption nearly s stages of development.stages of
in placentation between between placentation in of ,
may be necessary for for necessary be may the endometrium and and endometrium the
the entire PPAR entire the the
rupted a hypomorph a oe selective more
o significant to - dependent dependent DBD only only as , ue β/δ the the 16
ic ) .
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by inflammation of modulation the in PPARβ/δ of role pro effects inflammatory transiently related to infections microbial external against protection from range that purposes serve processes inflammatory These reactions. inflammatory several healing. support cannot that the of mechanisms protective site wound 5.1 repairtissue process. repair have We 5. independent laboratories the of PPAR of roles opposing review, this of sections subsequent in elaborated As diseases. neurological PPAR allele the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
- Inflammatory response during tissue repair tissue Inflammatory during response repairTissue inflammatory cytokine inflammatory
se β/δ β/δ [91]
that A cardinal feature of poor of feature cardinal A disorders such as such disorders
studies ex previously have been have . Below, we focus on recent findings related to related findings recent on focus we Below, . 8 elevated
retain mice [92]
. This can lead to unbalanced proteolytic activity, which overwhelms the the overwhelms which activity, proteolytic unbalanced to lead can This . ae been have
s may
oe prcpo functio aporeceptor some after
reported
ACCEPTED MANUSCRIPTthe reviewed [82, 10.1016/j.plipres.2016.09.001 Comment citer cedocument: be ACCEPTED MANUSCRIPT
[72 94] atherosclerosis and type 2 type and atherosclerosis adult mouse adult
applicable to applicable s
, including TNFα, IL TNFα, including , ,73] roughly concordant when using using when concordant roughly , .
PR ae centr are PPARs local tissue and leads to a to leads and tissue local particularly in particularly In comparison, PPARγ activation leads to leads activation PPARγ comparison, In .
ly involvement of all three PPARs in tissue injury and wound wound and injury tissue in PPARs three all of involvement
healing wounds is a persistent inflammatory response at the the at response inflammatory persistent a is wounds healing injury
tde o studies relation to relation and has been implicated been has and
al n - f [88 effectors 6 and nitric oxide nitric and 6
aiu iess sc as such diseases, various
diabetes – during wound repair repair wound during rmto of promotion 90] tumorigenesis dysfunctional Importantly, .
the n the in
[93] PPARβ/δ
specific . induction The expression of PPARα is PPARα of expression The
ahlgcl inflammation pathological (NO) ;
wound microenvironment wound
in the the in however, ex4 roles of PPARβ/δ in the in PPARβ/δ of roles
ihr PPAR either reduced productio reduced
mice is poorly understood. understood. poorly is [95]
n mdlto of modulation and promot tumorigenesis . derived the In contrast, the contrast, In conclu ion of ion β/δ by ex
sions anti
4 n two two
and and
17 or of - -
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by manner regulated spatially and par and epithelialization), compos dehydration tissue ba epidermal effective and new a reconstruct injuries. skin repair has been 5.2 Skin repair inflammatory thewoundactivities closes as and heal healing wound of phases inflammatory of recruitment early the in important is PPARα While has crosstalk ( synthase lipopolysaccharide downregulate to reports other observations, these with agreement B of ligand the involves function macrophage of switching exists model current one However, the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : tially CL
(Figure Of all the Of all the ed -
t rpes h tasrpinl ciiis f pro of activities transcriptional the repress to 6 overlapping pattern via the production of cytokines and growth factors in a in factors growth and cytokines of production the via pattern overlapping particularly
iNOS f he mjr phases major three of
also been implicated in the maintenance of tissue homeostasis, particularly homeostasis, tissue of maintenance the in implicated been also
pn omto of formation Upon 2 immune cells to the wound bed, PPARβ/δ plays a crucial role in role crucial a plays PPARβ/δ bed, wound the to cells immune ) )
Ctnos on rpi i casfe a a high a as classified is repair wound Cutaneous . human n COX2 and - and mediated activation of PPARβ/δ and PPARβ/δ of activation mediated
ACCEPTED studied well MANUSCRIPT 10.1016/j.plipres.2016.09.001 xrclua mti ( matrix extracellular Comment citer cedocument: any opportunistic microbial infections microbial opportunistic any ACCEPTED MANUSCRIPT tissues tissues ,
i NF via in which in
[98]
in terms of thefunctions of s
; ctnos on, h piay ol f h bd i to is body the of goal primary the wound, cutaneous a -
from pro from nue pro induced this model this Te inflammat The . - – κB
inflammation the role of PPARβ/δ role of the
[96 ECM - ,97]
to anti to re ta cvr te on, hrb preventing thereby wound, the covers that rrier
suggests that that suggests have - Itrsigy PPAR Interestingly, . nlmaoy ee, including genes, inflammatory )
remodeling s . -
ion inflammator , suggested that PPARβ/δ agonists PPARβ/δ that suggested the cell
phase begins immediately after skin skin after immediately begins phase - inflammatory
subsequent promot subsequent
PPARβ/δ
has been studied rlfrto and proliferation [98 the role of PPARβ/δ PPARβ/δ of role the Tee he pae ocr in occur phases three These . ,99] y - roiy uvvl epne to response survival priority . This switching mechanism mechanism switching This . . Normal wound healing is healing wound Normal .
at various stages of tissue - eitd inflammatory mediated
genes ,
ion of ion skin skin
migration Fgr 1) (Figure reducing inducible involves tissue repairtissue
temporally the release release the are for the the for in these
skin. able able In . NO (re the 18 a -
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by manner. temporal a in types cell different among the regulation healing migration ofkeratinocyte during wound production upregulate tissues shown have re for edge wound the pathways death the both modulating by apoptosis keratinocyte activities These (PTEN). 10 chromosome on deleted homologue tensin and phosphatase of expression the of downregulation PPARβ/δ of PDK1 and ILK of production SAPK/AP havecytokines,as TNFα, such injury, skin during cells inflammatory of influx the at epidermis injury, cutaneous upon However, adulthood. to the as declines epidermis interfollicular the in PPARβ/δ of ofinflammatoryblood clotting and cells. influx signals release injury the of vicinity the in vessels blood Damaged injury. the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
W subtype PPAR dominant the is PPARβ/δ [100] . This process This . ound repair involves epithelial involves repair ound - s
ptwy Consequently, pathway. 1
[100] the activity of NF activityof the that PPARβ/δ activation PPARβ/δ that I adto to addition In . - mediated
. This increased production production increased This . ACCEPTED MANUSCRIPT edges wound 10.1016/j.plipres.2016.09.001 Comment citer cedocument: -
ensures ACCEPTED MANUSCRIPT pteilzto to epithelialization
ciain I adto, PR/ atvto coordinate activation PPARβ/δ addition, In activation.
- (
κB, which κB, or or been ,
the recruitment of recruitment the lead and its PDPK1)
found to anti exerts PPARβ/δ o n nrae n K1 activation AKT1 in increase an to nuto of induction
- - leads mesenchymal interactions mesenchymal ppoi eff apoptotic , both ,
an anti an occur of MMP of be associated with associated be
- to increased matrix metalloproteinase matrix increased to PPARβ/δ PPARβ/δ ciaig iad ae produced are ligands activating
of in the human epidermis. In mice, the expression the mice, In epidermis. human the in
The signals that are communicated within the within communicated are that signals The
a - [82, which have have which apoptotic effect on keratinocytes in wound in keratinocytes on effect apoptotic the sufficient
- 9 was subsequently found to found subsequently was 9 PPARβ/δ 99] ects during wound healing, PPARβ/δ PPARβ/δ healing, wound during ects expression - expression is expression eetr n mitochondrial and receptor Furthermore, . animal
[101] quantity of viable keratinocytes at keratinocytes viable of quantity
been
P expression par
develops from develops
(Figure 2) level that require that reported to be direct targets targets direct be to reported β/δ rapidly
gene stimulation o pro of s n vivo in that
which , le . upregulated in the the in upregulated a
initiate localized initiate
d
[82] communication s on studies wound -
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beneficial role beneficial production through the integrin/JAK/ production through the 110 Inaddition to In addition – 112] α accelerat with - protein wound. SMA SMA participates
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by vascular the In effects. indirect and direct through vessels blood protect may activation diseases cardiovascular of progression and development the to leading rupture, dyslipidemia 6.1 its 6. administration beneficial this Interestingly, responsiveness. insulin restoring by ethanol of severity reducesthe attenuatedinsulin These end products bilirubin H against effect vasculoprotective to shown been GW501516 of presence appearance of of myofibroblasts, into transdifferentiation proliferation and activation the the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
role incardiovasculardisease Endothelial dysfunctionEndothelial PPAR Several reports have shown that shown have reports Several Perturbation of endothelial function due to conditions such as hypertension or or hypertension as such conditions to due function endothelial of Perturbation of result a as regeneration liver impair can consumption alcohol chronic liver, the In I homeostasis. endothelial maintaining in role a play to known also is PPARβ/δ and β/δ
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by protein G oxidase NADPH reduced antio levels, protein eNOS increased with associated were changes reduce activation ( (PKC) C kinase protein mitochondrial FA β (CPT 1 palmitoyltransferase carnitine upregulating bioavailability NO a through dysfunction endothelial cause Lipids genes. antioxidant ROS vascular of levels reduced high a fed mice aortaefrom in study recent more a oxidase NADPH 1 to contribute agonist PPARβ/δ of effects indirect and direct the Both disease. vascular of progression which of prevention the endothelium causes and phosphorylation, eNOS increased directly activation PPARβ/δ endothelium, the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : eNOS [127]
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by the FAO in involved genes of expression PPAR 2011) (2008, dysfun FAO of expression MHC in promoter chain heavy myosin hypertrophy. conditional the in decrease a with together decreased, [152] antioxidants, attenuated and oxidation glucose and lipid in reduction survival failure, heart congestive and hypertrophy cardiac dysfunction, cardiac by FAO, myocardial PPAR Cre/ 6.3 [29, anti the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : Cardiac disease - 35, iohnra DA oy number copy DNA mitochondrial loxP inflammatory effects in macrophages due to to due macrophages in effects inflammatory . In addition, expression of t of expression Inaddition, . β/δ ction 148] Genes involved in FAO are transcriptional are FAO in involved Genes /δ
[151] -
ex4 eitd cardiomyocyte mediated upon tamoxifentissue administration ina . ; )
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contrasted with contrasted
progressive myocardial lipid accumulation. This is accompanied is This accumulation. lipid myocardial progressive constitutive expression of key FAO genes and decreases basal basal decreases and genes FAO key of expression constitutive he key mitochondrial biogenesi keymitochondrial he -
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by in healing cardiac on GW610742 of effects therapeutic potential the investigating While expression effect fibrosis early on that showed study alleviate upregulati and of attenuation ischemia induced and reduction levels was rats diabetic induced streptozotocin in cardiomyopathy Moreover, failure. heart of onset the at metabolism glucose from PPAR th of expression the in increase an provokes dysfunction. to contribute might activity or development of impeded and function cardiac improved heart adult the in PPARβ/δ of activation Moreover, the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : reduces s of GW610742 might not be be not might GW610742 of s reliance predominant a
β/δ [157] Given the important role important the Given
- ada hypertrophy cardiac lipid s reperfusion injury in Zucker in injury reperfusion protein levels and mitochondrial FAO mitochondrial and levels protein
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ACCEPTED MANUSCRIPT nace myocardium infarcted
on t be to found
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[155] after myocardial infarction andafter beg myocardial infarction signaling the of FAO in the healthy myocardium myocardium healthy the in FAO β/δ exacerbat
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β/δ activation in the adult heart adult the in activation sustained PPARβ/δ agonist GW610742 GW610742 agonist PPARβ/δ diabetic diabetic
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in cardiac FAO, a reduction in reductioncardiacain FAO, e miRNA cluster miR cluster miRNA e
fatty rats through several mechanisms, including mechanisms, several through rats fatty [160] n ta the that and
[156] conditions - reperfusion injury by increasing cardiac FAO FAO cardiac increasing by injury reperfusion
[155] Pr e a. (201 al. et Park .
. These changes facilitate a metabolic shift metabolic a facilitate changes These . pathological processes involved in cardiac cardiac in involved processes pathological certain . Similarly
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by inflammation grade 7.1. Adiposetissue organs year the Over 7. PPAR drugs of functions on focused have CVD a over develop may CVD of disease. original the of complications onset after period considerable that established well is It disease. kidney as events infarction B factor growth derived in recruitment cell stem mesenchymal d 7 TGF and differentiation myofibroblast increased GW610742 observed was fibrosis or angiogenesis untreated GW610742 the in higher significantly were infarction myocardial after the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : y atr ycril infarction. myocardial after ays myocardial infarction, the authors showed that the degrees theauthors that ofangiogen showed myocardial infarction, targeting targeting
such as such and tissues As adipose tissue expands during obesity, there is an increase in chronic in increase an is there obesity, during expands tissue adipose As vessels, blood and heart the of disorders of group a are diseases Cardiovascular β rats rats [160] / δ
PPARβ/δ in insulin resistance insulin in and s
, at 1 week following myocardial infarction, myocardial following week 1 at hypertension, hypertension, PPARβ/δ. PPARβ/δ. . PPARβ/δ PPARβ/δ
. Its insuch organs. roles
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mainly due to greater macrophage infiltration and polarization towards the towards polarization and infiltration macrophage greater to due mainly ACCEPTED MANUSCRIPT
in CVD in 10.1016/j.plipres.2016.09.001 Comment citer cedocument: ACCEPTED MANUSCRIPT , stromal , the the has been has
relative heart att heart
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stroke W172 lo nrae bn marrow bone increased also GW610742 are t week 2 at -
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f the therapeutic potential of of potential therapeutic the
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rae rt ta i the in than rats treated significant difference significant oee, h long the however, esis and fibrosis after insulin ,
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by IRS degradationof (IRS) substrate receptor SOCS3 PPAR (SOCS)3 and phosphorylation STAT3 increased displayed mice gain weight to prone were tissue adipose white in metabolism th be might effects These in reduction HFD both to resistant accompanied these changes sensitivity. insulin of specific which on site binding (STAT6) 6 transcription of activator and transducer and al. et target drug potential a diabe and resistance insulin of development the in role pro the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
akr o te lentv anti alternative the of markers - , inflammatory M1 phenotype. This chronic inflammatory process is thought to play a major major a play to thought is process inflammatory chronic This phenotype. M1 inflammatory
o lse extent lesser a to (2008) β/δ rges alternative triggers oevr specific Moreover,
PPAR expression
protein levels levels protein ciain ih peet h atvto o SA3 n te usqet nrae in increase subsequent the and STAT3 of activation the prevent might activation
triglyceride accumul triglyceride demonstrated demonstrated β/δ ex4 - , 1
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- nue ad eeial peipsd obesity, predisposed genetically and induced 1 to the insulin receptor and by promoting promoting by and receptor insulin the to 1 IL
than
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4, induce induce 4,
mice showed increased showed mice overexpressi their their reover, adipose tissue inflammation and glucose intolerance were were intoleranceglucose and inflammation reover,tissue adipose activation . In a different study, the adipose tissue of PPAR of tissue adipose the study, different a In . dipose ation - ing nlmaoy 2 hntp, hc i blee t improve to believed is which phenotype, M2 inflammatory
that Th2 cytokines secreted by adipocytes, including IL including adipocytes, by secreted cytokines Th2 that
[164] wild
insulin insulin
tissue macrophage activation and insulin sensitivity. Kang Kang sensitivity. insulin and activation macrophage tissue in in PR/ expressi PPARβ/δ ise nlmain lipolysis inflammation, tissue adipocyte -
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and and
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[162] elevated by preventing preventing by
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in white adipose tissue renders mice mice renders tissue adipose white in [161] n in on
[165] Consequently . β/δ
M1 markers and decreasedand markers M1 . PPAR . suppressor of cytokine of suppressor macrophage ex4 Tee idns sugg findings These .
knockout β/δ t he he the the PPARβ/δ PPARβ/δ the and insulin resistance resistance insulin and n association in
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[163] levels levels - 33 13 d a - , .
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by for responsible are myocytes 7. metabolic alterations. PPAR reduced that suggest findings PPAR and findings These expression. SP reabsorption. sodium and (SGLT2) 2 cotransporter Adipose production. PPAR natriuresis enhancesand glucose tolerance Fabp4 with compared high PPAR specific diabetes. in unclear remains homeostasis glucose relationship and the intake sodium Furthermore, between debatable. remain reduction sodium of benefits potential the factor a 2(Nrf2), transcription be to shown the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : 2 - 1 Skeletal muscle - the salt diet (HSD, high sodium) sodium) high (HSD, diet salt bound to bound β/δ Lipid sa dietary in reduction A /δ in perirenal fat fat perirenal in /δ kidney
s lower is exacerbated - induced insulin insulin induced
the promoter of promoter the /δ knockout mice (Fabp4 mice knockout /δ ht links that
n obdy bs patients obese morbidly in -
ACCEPTED the suppressed adiponectin derived MANUSCRIPT - 10.1016/j.plipres.2016.09.001 Comment citer cedocument: PPAR ACCEPTED MANUSCRIPT
, which plays a crucial role in the regulation of renal glucose transport transport glucose renal of regulation the in role crucial a plays which , in fructose in Adiponectin reducedAdiponectin by
reveal oim intake sodium
increasing osmotic pressure, leading to an increase an to leading pressure, osmotic increasing approximately 80% approximately resistance in skeletal muscle is of paramount interest interest paramount of is muscle skeletal in resistance
/δ the gene encoding gene the lt intake is recommended for many diabetic patients, patients, diabetic many for recommended is intake lt ex4
an interesting an reduced
- fed PPAR fed ie sgetn ta PPAR that suggesting mice, that has been that has been β/δ - PPAR
[167] fasting blood glucose level glucose blood fasting to xrsin n dps tsu mgt otiue to contribute might tissue adipose in expression
lcs homeostasis. glucose β/δ the levels of the of levels the
t . mode of mode a i non in han /δ The
ex4 SGLT2 of reported toimpairinsulin ex4
knockout insulin ), HSD selectively elevated the expression of expression the selectivelyelevated HSD Zhao et al. et Zhao
communication between adipose tissue tissue adipose between communication
kidney kidney ( SLC5A2 - - bs subjects obese stimulated glucose uptake and thus thus and uptake glucose stimulated
mice via nuclear factor E2 factor nuclear via mice transcription factorstranscription xrsin f sodium of expression
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in showed that that showed HNF
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by which ceramides, accumulated be to availability their reducing endogenous ligand PPAR hepatic diurnal PPAR that indicate liver the as such FA evidence This pyruvate the PPARβ/δ inhibits which (PDK4), 4 oxidation FA to leading complex, dehydrogenase kinase dehydrogenase pyruvate of expression s oxidation, mitochondrial (ACS); in involved FA in involved genes The type PPAR selective reduction a to leading metabolism, oxidative in circuit oxidative more muscle and FAs, of consumer important affect greatly the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : O rdcn te viaiiy f FA of availability the reducing , towards
[170] Altogether, these findings su Altogether, findings these appears c a hydroxyacyl as uch cellular . This .
muscle fibers muscle the
eel ta PAβδ n kltl uce rmts mtblc switch metabolic a promotes muscle skeletal in PPARβ/δ that reveals β/δ fibers utmtl prev ultimately ,
whole to be dependent on PGC dependenton be to
ex4 alteration of β/δ rmt ifamto ad nui rssac. hs PPAR This resistance. insulin and inflammation promote FA uptake, such as FAT/CD36; FA activation, such as acyl as such activation, FA FAT/CD36; as such uptake, FA
ACCEPTED MANUSCRIPT ablation in ablation β/δ PPARα PPARα
[169] 10.1016/j.plipres.2016.09.001 - Comment citer cedocument: FA FA eitd increase mediated - ACCEPTED MANUSCRIPT body
activity through the synthesis of the phosphatidylcholine 18:0/18:1 phosphatidylcholine the of synthesis the through activity
pae sc a criie amty taseae CT; n F β FA and (CPT); transferase palmitoyl carnitine as such uptake, metabolism with
poal truh an through probably , is accompanied by an increase in the expression of genes involved genes of expression the in increase an by accompanied is [174] rate of of rate -
CoA dehydrogenase. PPARβ/δ activation also upregulates the the upregulates also activation PPARβ/δ dehydrogenase. CoA skeletal muscle myocytes exhibit a shift in skeletal muscle skeletal in shift a exhibit myocytes muscle skeletal lower oxidative capacity, leading to obesity and T2DM and obesity to leading capacity, oxidative lower nig bst ad nui resistance insulin and obesity enting
. ggest PPAR that
glucose clearance glucose s
that are that o e cuuae i seea msl ad te tissues other and muscle skeletal in accumulated be to - specific PPAR specific s -
1α in
[172] skeletal muscle FA uptake uptake FA muscle skeletal upregulated by PPARβ/δ PPARβ/δ by upregulated in as [136,
body fat mass fat body , which itself is a PPARβ/δ target genetarget PPARβ/δ a is itself which , estrogen β/δ FA 169,
β/δ activation ofFAs, increases theoxidation [168] derivatives such as diacylglycerol or or diacylglycerol as such derivatives
172] overexpression results in a switch to switch a in results overexpression - eae rcpo γ (ERRγ)/miRNA γ receptor related . In addition, s addition, In . The increase in FAO caused FAO in increase The .
[169] . Conversely, mice with mice Conversely, .
[173] in vivo in are keletal muscle is an an is muscle keletal .
lo ope to coupled also eet findings Recent -
CoA synthase synthase CoA include genes include β/δ - mediated favoring
[171] [171] fiber , an ,
35 by - . .
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by with Consistent quadriceps, in expressed highly levels lipid intramyocellular high by paralleled rats, control normoglycemic lean in than diabetes 2 was content containing fibers in content protein human in specific type fiber muscle is expression protein ADRP intracellular adipophilin target PPARβ/δ activity lipase lipoprotein reducing byoverload lipid against heart the protecting at aimed mechanism feedback stimulation β FA increased of states during lipolysis tissue adipose enhance to proposed secr ANGPTL4 muscle skeletal in increase lipo inhibiting genes several of expression the knockout the resistance insulin and inflammation induces that process a stress, ER induced in elevation the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : observed
mice
of cardiac of oxidative oxidative F or of increase in increase
As. ADRP is ADRP As. - protein lipase protein [177]
[
o 3 to
perilipin bs non obese 175] the ee s a is gene
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Moreover, PPARβ/δ acts as a FA sensor in skeletal muscle by regulating regulating by muscle skeletal in sensor FA a as acts PPARβ/δ Moreover, FA 10.1016/j.plipres.2016.09.001 Angptl4 Comment citer cedocument: ACCEPTED MANUSCRIPT vastus lateralis muscle, the largest and most powerful most and largest the muscle, lateralis vastus
2 osed role osed the levels of levels the , lpd droplet lipid a ), metabolism might explain explain might metabolism ioye differentiation dipocyte -
ibtc n oee ibtc ains n h fsig state fasting the in patients diabetic obese and diabetic involved in intram in involved [178]
,
xrsinb FA by expression including -
xdto, uh s atn ad exercise and fasting as such oxidation, and activ and of ADRP of
the
ER stress markers in the skeletal muscle skeletal the in markers stress ER most intramyocellular lipids. lipids. intramyocellular most Angptl4 ating lipolysis in adipose tissue tissue adipose in lipolysis ating -
to cue b FA by caused etion associated protein that binds to and sequesters sequesters and to binds that protein associated in , hydrolyzing
uscular lipid accumulation and T2DM and accumulation lipid uscular
ensur the in s and this elevation in ADRP protein levels protein ADRP in elevation this and
-
diabetic animals diabetic [176 eae poen (ADRP protein related via PPARβ/δ has been considered part of a of part considered been has PPARβ/δ via progression of progression ing why ,177]
the
ligands of this receptor prevent lipid prevent receptor this of ligands plasma plasma
, which affects lipid metabolism by metabolism lipid affects which , supply s - activated TGs
T2DM ad as with rats, and s
[182] f FAs of The m The
to release FA release to . In hu In . , also , ADRP expression ADRP
uscle
PR/ hs been has PPARβ/δ [112, [176] o kltl muscle skeletal to , component
and s man
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s the
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Another Another
highest
[183] of the the of β/δ . The . 181]
was
36 ex4 as as is - . .
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by of transition the understood, may which benign be can NAFLD ac lipid neutral excessive and persistent is NAFLD of hallmark considered is and disease 7. activation of PPAR hypothesis autocrine and endocrine ( 21 factor growth fibroblast of expression PPAR of effects o pattern muscle glucose T metabolism, FA muscle controlling of effects detrimental sequester to act upregulated the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : ransgenic 3
NASH Liver - Non enriched transcription factor myocyte enhancer factor 2 (MEF2) 2 factor enhancer myocyte factor transcription enriched oxid f changes induced by PPAR by induced changes f
cruaig G2 lvl ae nrae i hmn i rsos t pharmacological to response in humans in increased are levels FGF21 circulating , pathology. m - under alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver liver chronic of form common most the is (NAFLD) disease liver fatty alcoholic result ation ice ice β/δ over FA
by skeletal muscles skeletal by circumstances of improved glucosetolerance. improved of circumstances β/δ n irss n/r cancer and/or fibrosis in on fructose on s
ACCEPTED MANUSCRIPTexpressingPPAR
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ACCEPTED MANUSCRIPT but it predisposes it but from effects TGs s o be to
. on insulin insulin on
- NAFLD induced insulin resistance may involve increased involve may resistance insulin induced in discrete lipid droplets that could protect muscle from the the from muscle protect could that droplets lipid discrete in h hptc aietto o mtblc syndrome metabolic of manifestation hepatic the n abhdae n lpd eaoim Cnitn wt this with Consistent metabolism. lipid and carbohydrate on
,
β/δ h da PPAR dual the PPARβ/δ through β/δ
to activity resembles that following exercise. following that resembles
specifically in muscle specificallyin NASH is considered a criticalconsidereda is NASH individuals
Fgf21 [188] the
is n guoe tolerance. glucose and
novd n lcs mtbls i muscles. in metabolism glucose in involved cooperation Wie the While . )
α/ [185]
to non to
gns Srgiaa (Lipaglyn) Saroglitazar agonist a omn wt a ie ag of range wide a with hormone a , - alcoholic steatohepatitis (NASH) steatohepatitis alcoholic of
The u The etiolog exhibited increased capacityincreased exhibited cumulation within hepatocytes. within cumulation AMP kinase (AMPK) and the the and (AMPK) kinase AMP pregulation of ADRP may may ADRP of pregulation of y
[184] point point lal, i Clearly,
Additional protective Additional NASH . Interestingly, this . in the progressionin the skeletal muscle muscle skeletal adto to addition n
is not well well not is [187]
[189] The . for for 37 , ,
Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by reported article exogenous to response in regulation gene coordinating in involved Interestingly,SREBP LXRare regulated byand ChREBP signal ge of transcription (glucose)the coordinate nutritional and (insulin) hormonal integrate to appear in transcriptional feeding which by mechanism in active membranes unsaturated NASH effect beneficial the for responsible be may acti the modulate to PPARβ/δ of ability chylomicrons, in accumulate that (Elafibranor) GFT505 pre trials clinical T with patients in which the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : hs rcs. mn the Among process. this - clinical clinical
. for India in launched was
Lipogenesis is an enzymatic pathway that allows the cell to cell the allows that pathway enzymatic an is Lipogenesis
murine [190] or FA evaluating
de novo de [195] to s
,
ht PR/ sprse lpgnss y euig SREBP reducing by lipogenesis suppresses PPARβ/δ that liver 2DM n clinical and w rdc lipid produce . Numerous transcription factors have been shown to shown been have factors transcription Numerous . ih a b ue to used be can hich
- ACCEPTED MANUSCRIPT soito with association
1c targeting of both PPARα and PPARβ/δ in the treatment of NASH. of treatment the in PPARβ/δ and PPARα both of targeting
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lipogenesis and/or lipogenesis tissue tissue ACCEPTED MANUSCRIPT not controll not
[198] t efc i aut AH patients. NASH adult in effect its e rncito factors transcription se fe feeding after , ChREBP , [191] - the treatment of treatment the dependent nes encoding lipogenic enzymes. Importantly, both SREBP both Importantly, enzymes. lipogenic encoding nes euae te ciiy f ioei ezms s largely is enzymes lipogenic of activity the regulates
[193] able
tde ha studies
AL my orig may NAFLD
vity of vity by statins by , [199]
a nuclear receptor that is activated by oxysterols thatis receptor a nuclear decreased
replace s but signaling
of PPARβ/δ activation in activation PPARβ/δ of , LXR ,
s components components
s erse i rsos t fasting to response in repressed is hypertriglyceridemia and diabetic dyslipidemia dyslipidemia diabetic and hypertriglyceridemia ihihe te oeta o te dual the of potential the highlighted , is now also now is , bt SREBP both , TG
lipid lipid [200
molecules
nry stores energy ,201] degradation nt fo icesd pae from uptake increased from inate utemr, eet vdne from evidence recent Furthermore, important
and PPARβ/δ and under examination examination under . - 1c e novo De produce FA
[196]
to , [192 s
in lipogenesis and lipogenesis in
relation to relation (Figure 5) (Figure play a significant role role significant a play
,193] , respectively s,
generate saturated and mono and saturated n ChREBP and ioeei i very is lipogenesis
[202] - . Therefore, the the Therefore, . 1c
.
NAFLD
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in Phase III Phase in In fact In lipid levels [194] - agonist -
Lipids
, based based The . [197] [192]
, one one , FA
that that and and and - 38 1c O ic -
. Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by from control lipogenesi of control circadian provide hepatocytes in PPARβ/δ lacking specifically report recent and unique one Finally, lipotoxicity. signaling formation activation hepatic liver mediated enhancing the and glycolysis increasing by production GW501516 [204 tr longer whereas treatment, of PPAR promote sensitivity insulin high a fed mice cleavage SREBP (Insig) gene induced SREBP reduces PPARβ/δ which by ameliorat consequently the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : ,205] hepatocyt β / δ by e novo de Tee idns ugs that suggest findings These .
e novo de .
agonist has been reported to be strictly time strictly be to reported been has agonist
has been shown to shown been has f auae Fs laig to leading FAs, saturated of ioeei i te liver the in lipogenesis - PR/ sgiiaty nlecs whole influences significantly PPARβ/δ C treated omparison - e - etitd PR/ atvto confirmed activation PPARβ/δ restricted fat diet and treated with GW501516 showed reduced lipogenesis and lipogenesis reduced showed GW501516 with treated and diet fat s -
activating protein (SCAP)/SREBP complex complex (SCAP)/SREBP protein activating
lipogenesis euae te rdcin of production the regulates lipogenesis. [204] db/db ACCEPTED MANUSCRIPT - 1 protein, which protein, 1 10.1016/j.plipres.2016.09.001 ing Comment citer cedocument: ACCEPTED MANUSCRIPT s .
oee, several However, f h gn epeso poie o liver of profiles expression gene the of hepatic steatosis in obese diabetic diabetic obese in steatosis hepatic
ie ugs ta PAβδ ciain eue hptc glucose hepatic reduces activation PPARβ/δ that suggest mice
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[174] eatments
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eai lipid hepatic - r pentose phosphate shunt as shunt phosphate pentose gltd ioeei poet against protects lipogenesis egulated that
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ed S [203] between control and and control between pecifically,
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by pancreas mouse the of compartment epithelial the in and sensitivity insulin improved function pancreaticislet with association in levels glucose blood reduces agonist diabetic and obese of treatment prolonged which by mechanism ablat resto lipolytic glucose and function mitochondrial in involved and load glucose oral tolerance glucose an improved after incretin this of levels plasma increased to leading intestine, wild pancreatic of function and morphology the preserve can incretins ho polypeptideinsulinotropic glucagon (GIP)and to due sensitivity insulin in decrease 7 effects clinical contrast have studies shown involve to contributes and cells stellate the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : . 4 rmones that stimulate insulin release from the pancreas in response to nutrients. In addition, In nutrients. to response in pancreas the from release insulin stimulate that rmones
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nitiate tumor 235] s
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by results explain or status inflammatory as such other influence might conditions housing animal discrepan the for adenoma that evidence considerable is in mice impact specific background genetic differences other while background, genetic mixed a development of background have failed cancer development. marker better a be could genes target its of antibodies considered Grimaldi and Neels by extensively the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by and TGFβ1 involving cascade molecular dependent UV in involved be to reported development tumor of component originating pro the increasing mutations genetic with concert in of process the pro cancers and known ovarian relationship PPAR tumors meta a Furthermore, SCC. human in initiation samples PPAR tra mesenchymal progression and keratosis actinic sensitize PPARβ/δ model, EGFR/Erk1/2 the upregulating PPAR and methodologica the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : - carcinogenic role carcinogenic β β , including human SCC, revealed a positive interaction between interaction positive a revealed SCC, human including , / / - δ δ tumorigenic tumorigenic from human skin human from
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by pathway clearly thatis pro TGFβ1 injury skin after clearly have laboratories could which response, of importance the highlights the alter activities the that proposed been pro a Moreover,UVBa modelof in However the model DMBA/TPA in metastasis and conversion malignant a as acts it the on depend as in pro a as PPARβ/δ of function modulate could environment studies between results pathway Src/EGFR of independent Erk1/2 MAPK downstream the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
skin carcinoma, which has been defined as a PPARβ/δ target gene target PPARβ/δ a as defined been has which carcinoma, skin both a a both tumor - tumorigenic tumorigenic [277]
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by low comparatively role a suggest observations in reported been has expression not but neurons and oligodendrocytes in expressed be caudate and callosum corpus the in levels hippocampus and hypothalamus cortex, entorhinal the in levels high particularly with brain mouse of abundantmost the is PPAR cord, spinal rat the In rats. of cortex cerebellar and cortex telencephalic hippocampus, postnatally CNS rat the PPAR and embryogenesis, rat of (CNS) 9. factors that in PPARβ/δ by regulated findings cellular during is function its the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : PPAR tumor Together,
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mice
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by expression, PPAR activated GW0742 amide neuroprotective ligand on dependent GW0 Conversely, functions. of administration that may and (SCI) gene demonstrated of role in responses inflammatory brain the in MCAO as well as injury. hypothalamic wild with and doubled was damage support the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : s 7 , such as 2 n motor on 42 that Apoptosis in neurons and oligodendrocytes and neurons in Apoptosis for a for PPAR
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ACCEPTED MANUSCRIPTIndeed, [287] function
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by IFN blocking by mice C57BL/6 of findings to contrast In conditions. inflammatory chronic and autoimmune other as well as EAE in (IL)interleukin secrete that cells CD4(+)T inflammation thought previously were cells (Th1) self for specific cells T that evidence s numerous because interesting IL and activation GW0742, by affected progression. lesions cortical new of appearance A immunization. symptoms clinical attenuated modestly on MS. encephalitogenic (EAE) encephalomyelitis autoimmune Experimental However damaged. permanently become or deteriorate to themselves deficiencies nerve covers that myelin the attacks system immune the MS, the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
lncl outcome clinical
I nterestingly, treatment with treatment nterestingly, Multiple sclerosis (MS sclerosis Multiple , treatments can help speed recovery from attacks from recovery speed help can treatments ,
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although
brain and the and brain (2005) yln lgdnrct glycoprotein oligodendrocyte myelin euto in reduction . Polak et al et Polak Oral administration of GW07 of administration Oral ) is a potentially disabling disease of the brain and spinal cord. In cord. spinal and brain the of disease disabling potentially a is ) tudies using this animal model animal this using tudies - two , γ and IL and γ
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by [ protein precursor peptide of symptoms subsequent the and brain the in neurons of degradation the to contribute to thought is tangles neurofibrillary multiple cognitive by characterized Alzheimer as such diseases, neurological 9.2 attenuating neuro repair anti and inflammatory by EAE cells during PPARβ/δ damage. axon and myelin [286] and weakness hindlimb PPARβ/δ polarization Th17 and Th1 of inhibition with associated [286, the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : Function
292] [286] . The more severe EAE that developed in PPARβ/δ in developed that EAE severe more The . M
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deterioration in association with association in
have have d
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by cytokines reactive (GFAP) protein Aβ in involved with increased for AD associated their and proteins Aβ of actions the by inhibited is proteasome the by tau hyperphosphorylated twisted insoluble, of accumulation the to leads and transport axonal regulating in function normal its microtubule the of phosphorylation patients within and/or BBB the at activity RAGE regulating Thus, flow. blood cerebral reduced and responses inflammatory stress, oxidative to leads BBB the at peptides a In eliminated. AD in generation rate apparent by initiated type large the of plaque toxic, the of production increasing the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : dvanced PPARβ/δ [295,
fibers across the blood the across [296 astrogliosis g that lycation lycation the the 298] - – limiting
IL ex4 298] AD β termed euae srctc yetoh ad proliferation and hypertrophy astrocytic regulate
peptide were - - .
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by [302 diabetes 1 type both with overlap that features biochemical and molecular evaluating needed studies in differences microglial enhanced Malm contrast, In glia. on effects enzyme of expression increased investigators mechanis peptide the that levels been and burden NF factor transcription PPARβ/δ of RAGE and BACE1 TNFα, including all of hallmark understood poorly but ubiquitous a is astrogliosis, reactive the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : – reported by two independent groups independent two by reported
304] AD in the in
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PPAR . the
were GW0742 The ability The s pcfc o xrclua deposits extracellular to specific - as . The expression of RAGE and BACE1 BACE1 and RAGE of expression The .
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by with in non and death termed nigra substantia The system. motor stress andimprovingoxidative and learning memory. the by acetyltrans choline increased and binding and learning, and hypothalamus the preserving agonist curable and preventable deterioration brain overall impaired size, brain diminished tangles,neurofibrillary deposits, and insulin of brain the depletes whic of of disease the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
dopaminergic neurons dopaminergic insulin
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Parkinson's disease (PD) is a degenerative disorder of the CNS CNS the of disorder degenerative a is (PD) disease Parkinson's PD PD in PD PD in
h lead to lead h Lewy bodies, which are which Lewy bodies, and continue to continue and - of insulin of insulin T3D enzymatic oxidation of oxidation enzymatic
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ACCEPTED MANUSCRIPT be down be [306 using , . Experimental model Experimental .
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by induce to pathway nigrostriatal the of parts different Particularly, in PPAR PPAR increase in decrease of destruction mediated 6 of injection infusion MPTP the reduced GW0742 protected not compared treatment model, that molecules toxic radicals, freeof buildup the causes anddeath cell to leadswhich metabolism, mitochondrial of component dopamine 1 cation toxic a produces neurons B oxidase monoamine by oxidation its but toxic, not is itself primates. features clinical and pathological biochemical, the of most induces narcotic the of analog (MPTP) the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
the involvement of involvement the /δ and /δ the s
[311
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neuronal death, death, neuronal rdcn nuos y nefrn wt cmlx o te elect the of I complex with interfering by neurons producing were increased in the damaged the in increased were PPAR distinct xrsin of expression - ,312] hydroxydopamine (6 hydroxydopamine from I cnrs, rcn suy sn aohr D nml model animal PD another using study recent a contrast, In . the .
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by Economía y Competitividad. the of initiative an is CIBERDEM Bonizzi Clinic EUMORPHIA the Program, Science Frontier Human Medicine received WW Diabète. du Francophone of and R] Competitividad y Economía Health of MinistrySingapore ( Education of 2 Tier Council Research Academic the (SRG/14003), Grant Research organizations the from grants by supported was review this in described laboratories authors’ the in research Acknowledgements the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : AM and HG HG and AM ,
CIBER de Diabetes y Enfermedades Metabólicas Asociadas Metabólicas Enfermedades y Diabetes de CIBER Eeswari thank authors The - OND, h Rgo Midi Région the TORNADO, Theler ,
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by [8] [7] [6] [5] [4] [3] [2 [1] References the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI : ]
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disease through inhibition of inflammation, J. Neuroinflamm.disease ofinflammation, 12(2015) J. through inhibition 7. nucl L. Donovan,Landreth, L.J. T. Malm,G.E. M.Mariani,Activation Neilson, of the Biophys. 1241 (2013) Acta 1832 increasedand ofPPARβ/δ BACE1 RAGElevels thecortex in L.Pallàs, Wahl Michalik, W. Rodríguez,M. Anglada Gutiérrez, P. delE. Barroso,L. Valle, J. D.Porquet,Santos, A.M.Vieira Salvadó, R.Rodríguez Alzheimer Res.431 6(2009) and brain a inflammationin transgenic ofAlz mouse model Kalinin,Richardson,S. J. D. Feinstein, burden agonist reduces APPARdelta amyloid of disease, 36(2016) RAGE Neurobiol. inAlzheimer’s Mol. 483 Cell. Z.B.Zhou,Liu, Qin,Y. Wang, Cai,N. M.Xiao, C. Front. Neurosci. 10(2016) Khan,S.S. G.S.Bloom, Tau: Alzheimer's in disease, the center of nexus a signaling Investig. 672 10 (2009) Drugs RAGE inamyloid Bell, B.A.M. Schmidt, Selmer, J.M. Sahagan,R.B.R.Rothlein, The Nelson,J. role of (2016). frompotential limitations theperspective Brain model ofanimal studies, Bull. Res. M. Ohno,Alzheimer’s therapy theβ targeting ear neuroprotectivereceptor is a PPARδ Alzheimer’s transgenic modelof in mouse ACCEPTED MANUSCRIPT 10.1016/j.plipres.2016.09.001 Comment citer cedocument: ACCEPTED MANUSCRIPT - beta peptide beta
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by [309] [308] [307] [306] [305] [304] [303] [302] the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
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Version postprint Tan, N. S.(Auteurde correspondance), Vázquez-Carrera, M.,Montagner, A.,Sng, M.K.,Guillou, H., Wahli, W.(2016).Transcriptional control ofphysiological andpathological processes by [316] [315] [314] [313] [312] [311] [310] the nuclear receptor PPAR beta/delta. Progress inLipid Research, 64, 98-122. DOI :
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- ACCEPTED MANUSCRIPTLewi - 10.1016/j.plipres.2016.09.001 Comment citer cedocument: OHDA lesions ofthe nigrostriatal lesions (2002) Neurol.OHDA pathway, Exp. 175 ACCEPTED MANUSCRIPT s, S. Przedborski, Protocol for the MPTP mouse Przedborski,model of mouse s, S. Parkinson's MPTP Protocol for the 1998. - methyl
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