Expert Review of Gastroenterology & Hepatology

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Olive oil and non-alcoholic fatty liver disease

Ludovico Abenavoli, Maja Milanović, Nataša Milić, Francesco Luzza & Angelo Maria Giuffrè

To cite this article: Ludovico Abenavoli, Maja Milanović, Nataša Milić, Francesco Luzza & Angelo Maria Giuffrè (2019) antioxidants and non-alcoholic fatty liver disease, Expert Review of Gastroenterology & Hepatology, 13:8, 739-749, DOI: 10.1080/17474124.2019.1634544 To link to this article: https://doi.org/10.1080/17474124.2019.1634544

Accepted author version posted online: 19 Jun 2019. Published online: 25 Jun 2019.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ierh20 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 2019, VOL. 13, NO. 8, 739–749 https://doi.org/10.1080/17474124.2019.1634544

REVIEW Olive oil antioxidants and non-alcoholic fatty liver disease

Ludovico Abenavolia, Maja Milanovićb, Nataša Milićb, Francesco Luzzaa and Angelo Maria Giuffrèc aDepartment of Health Sciences, University “Magna Græcia”, Catanzaro, Italy; bFaculty of Medicine, Department of Pharmacy, University of Novi Sad, Novi Sad, Serbia; cDepartment of Agricultural, University “Mediterranea”, Reggio, Calabria, Italy

ABSTRACT ARTICLE HISTORY Introduction: Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 25% of adult people Received 25 March 2019 worldwide. Nowadays, there is no definite treatment for NAFLD. International guidelines define an Accepted 10 June 2019 approach based on lifestyle changes, included a health alimentary regimen. The KEYWORDS (MD) represents the gold standard in preventive medicine, probably due to the harmonic combination Food; Mediterranean diet; of many elements with and anti-inflammatory properties. Its prescription is also recom- metabolism; inflammation; mended in patients with NAFLD. Olive oil, as part of MD, is associated with benefits on human health treatment; prevention especially regarding the cardiovascular system, obesity, diabetes and related metabolic disorders. Areas covered: An overview of the beneficial effects of olive oil in the prevention and treatment of NAFLD is given. Expert opinion: A large body of evidence emphasizes that olive oil, used as primary source of fat in MD, may play a crucial role in the health benefits of NAFLD patients. However, there are still scarce clinical data that evaluate the direct effect of olive oil in human with NAFLD.

1. Introduction NAFLD will probably become the leading indication for liver transplantation worldwide [8]. Olive oil, as part of the Mediterranean diet (MD), is associated Nowadays, there is no definite treatment for NAFLD. with benefits on human health especially regarding the cardi- International guidelines define an approach based on lifestyle ovascular system, obesity, diabetes, and related metabolic changes, to achieve weight loss as the main target in the man- disorders [1]. U.S. Food and Drug Administration recommend agement of NAFLD [9]. The Mediterranean alimentary regimen is daily consumption of 20 g of olive oil as a preventive treat- the well accepted, highly palatable, and favorable diet and is ment for [2]. There is also assumptions linked to a higher adherence rate. In the era of evidence-based that the low rate of prostate, rectal, and colon cancer in medicine, the MD represents the gold standard in preventive animals and humans is related to olive oil consumption medicine, probably due to the harmonic combination of many through the diet. Besides the fact that olive oil presents the elements with antioxidant and anti-inflammatory properties. Its major source of fat in MD, it also contains significant amount prescription is also recommended in patients with NAFLD and of different phenols, more than 30 [3]. It is believed that the NASH [5,10]. Following the Mediterranean pattern of using food combination of phenols and squalenes are responsible for the rich in antioxidants and fibers, it is possible to act on the patho- oil beneficial health effects [4]. However, the content of anti- genic mechanisms of oxidative damage. The extra virgin olive oil, oxidant compounds is related to the climatological conditions, organic and subjected to a controlled supply chain, must be tree variety, production, and storage properties [3,4]. a major component of the diet-therapy [5]. This is an important Non-alcoholic fatty liver disease (NAFLD) is an emerging source of energy mainly to the presence of monounsaturated public health issue, being not only a major cause of liver- triglycerides. related morbidity and mortality worldwide, but also an inde- The aim of this review is to describe the major role of olive pendent risk factor for the development of noncommunicable oil and its antioxidant components in the improvement of diseases. NAFLD refers to a wide spectrum of liver disease, fatty liver. ranging from simple fat accumulation, to nonalcoholic steato- hepatitis (NASH) that can evolve in 5–7% of the cases, to advanced fibrosis, cirrhosis, and its related complications [5]. 2. Composition of olive oil The worldwide prevalence of NAFLD in general population, is Olive oil is mainly composed by glycerides (98–99%) and the estimated to be 20–30% in Europe and is as high as 46% in the remaining part are the minor components (Table 1)[11–13]. United States [6]. It is directly related to metabolic changes, in , phenols, and carotenes have antioxidant properties fact is currently reported that 80% of NASH patients are obese, useful to preserve oil and have positive implications on the 44% have diabetes mellitus type 2, and 72% are at risk of human health [13]. It is important to note that the chemical dyslipidemia [7]. It is estimated that in the next few years

CONTACT :Ludovico Abenavoli [email protected] Department of Health Sciences, University ‘Magna Græcia’, Viale Europa - Germaneto, Catanzaro 88100, Italy © 2019 Informa UK Limited, trading as Taylor & Francis Group 740 L. ABENAVOLI ET AL.

Table 1. Main components of olive oil and their potential beneficial effects in Article highlights NAFLD animal studies. Group Classes Potential beneficial effects ● Non-alcoholic fatty liver disease (NAFLD) is the most common liver Glycerides (98–99%) Monounsaturated – Anti-inflammatory and disease worldwide. triglycerides fatty acids (mainly immunomodulatory ● Mediterranean diet (MD) represents the gold standard in preventive oleic acid, 55–83%) effects medicine. monoglycerides – decrease in DNA damage ● With its high intake of antioxidants, MD contributes to the reduction of the onset of many chronic diseases as a NAFLD. – decrease in CACT ● Considering the high presence of , the olive oil a basic expression component of MD, may be helpful in reducing the progression of – prevention of insulin NAFLD. resistance – regulation of hepatic This box summarizes key points contained in the article. enzymes – decrease in hepatic para- oxonase activity – decrease in hydrogen per- oxide production composition and quality of virgin olive oil, are influenced by – change in membrane fluid- many factors, as geographical production area, climatic condi- ity and membrane peroxi- tions prevalent in the year of production, the type of cultivation, dation and the extraction process [14,15]. Polyunsaturated – Suppress oxidative stress 4–20% Saturated fatty acids (9–14%) 2.1. Tocopherols Minor components Sterols (1–2%) Waxes Tocopherols are lipophilic phenols with a high molecular weight. Policosanol α β γ Tocopherols Four tocopherols are commonly found in virgin olive oil: -, -, -, Phenols – Inhibition of NF-κB and and δ-tocopherols [16,17]. α- represents at least the arachidonic lipoxygenase 90% of total tocopherols in an olive oil. The heteroacid structural – decrease in AST, ALT, tri- formulas of tocopherols are described in Figure 1. Tocopherols glycerides, and exert their antioxidant activity by two different mechanisms: (1) cholesterol the tocopherol gives to lipid radicals its phenolic H atom (chain- – improved insulin sensitivity breaking donor mechanism); (2) involving an O2 scavenging and – activation of AMPK quenching and an inhibition of oxidation caused by excited sing- phosphorylation let oxygen (chain-breaking acceptor mechanism).Tocopherol con- – decrease in TNFα,IL-1,IL-10, adipokines, arachidonic tent in extra virgin and virgin olive oil was found to be influenced acid, oxidized DNA, and by many factors such as: olive cultivar, olive tree irrigation, oil ROS species centrifugation, removal of oxygen by nitrogen stripping method – decrease in lipid after oil extraction, storage, and heating [17]. peroxidation Many Authors studied and verified the dependency of – normalize hepatic fatty acid oxidation and desatur- tocopherol content by olive cultivar and the high variability ase activity in liver was found in many geographical areas. In North-East Italy – restoration of PPAR-α, (Veneto Region) and in Central Italy (Abruzzo Region) were FGF21 mRNA levels, and studied the extra virgin olive oils of one and six cultivars, ACC phosphorylation respectively, and the different α-tocopherol content was Squalenes – Inhibition of HMG-CoA found: Grignano cv (300 mg/kg), Carpinetana cv (428 mg/kg), reductase Dritta cv (450 mg/kg), Gentile di Chieti cv (289 mg/kg), Intosso Triterpenes cv (393 mg/kg), Leccino cv (246 mg/kg), and Rustica cv Chlorophylls (213 mg/kg) [18]. The findings on total tocopherol content in Carotenes extra virgin olive oil were: 326.7 mg/kg in Saurani cv from Turkey; 222 and 255 mg/kg, respectively in Spanish Arbequina cv and Italian Coratina cv grown in Argentina; 577 mg/kg in oil exposure caused a more consistent depletion, with of nonirrigated trees from Chemlali cv grown in Tunisia a − 69.6% total tocopherol content after 120 min heating at [18,19]. The total tocopherol content was found to be influ- 180°C and a fast dramatic fall (−53.5%) after 30 min at 220° enced by cultivar and ripening index in seven cultivars grown C[21]. in South West Spain and a depletion of this class of com- pounds was recorded with fruit ripening. However, a loss in 2.2. Phenols total tocopherol content can be related to centrifugation and storage with depletion of antioxidants [20]. In addition, the Phenols detectable in a virgin olive oil can be grouped as: depletion in total tocopherol content was also studied in extra simple phenols (i.e. and ), secoiridoids virgin olive oil heated at 180 and 220°C for 30, 60, and (i.e. , oleacein, and oleocanthal), and lignans [22]. 120 min. Both temperature and heating duration significantly A more detailed classification of hydrophilic phenols include: influenced these molecules even if the time of heating phenolic alcohols, phenolic acids, , lignans, and EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 741

Hydroxytyrosol and secoiridoids were found to have the most effective antioxidant activity between the natural com- pounds [22,24]. Unfortunately, qualitative and quantitative changes happen in virgin olive oil during storage, with decrease of secoiridoids for oxidation [25].

2.3. Carotenes

The human body cannot synthesize , which have to be assumed by the diet. The most important carotenoids in virgin olive oil are lutein and β-carotene, and in lower quan- tity, there are β-criptoxanthin and epoxidizedxanthophylls such as neoxanthin, violaxanthin, antheraxanthin, and their furanoid isomers [26]. The influence of cultivar on content was evidenced in seven Italian cultivars whose lutein Figure 1. Structural formulas of α-, β-, γ-, and δ-tocopherols. and β-carotene content expressed as mg/kg was respectively: 4.3 and 3.0 in Carpinetana cv; 3.3 and 2.3 in Dritta cv, 3.3 and secoiridoids (Table 2). Hydrophilic phenols can be found exclu- 4.3 in Gentile di Chieti cv, 3.9 and 2.0 in Grignano cv, 3.5 and 3.1 sively in virgin olive oil whereas tocopherols and carotenes in Intosso cv, 4.1 and 3.2 in Leccino cv, 3.5 and 2.9 in Rustica cv can be found also in fats of animal origin and in other vege- [18]. A variability in carotenoid content was also found in four table oils. Phenols influence oil stability and flavor. Mediterranean Countries, and in particular Italy, Greece, Oleuropein derivatives, that is, the dialdehydic form of dec- Tunisia, Spain, in which β-carotene, lutein, and β- arboxymethyl elenolic acid linked to hydroxytyrosol (3,4-DHPEA- criptoxanthin of extra virgin olive oils varied both in function EDA) and the isomer of oleuropein aglycone (3,4-DHPEA-EA) are of cultivar and geographical production area [14]. the main responsible of the resistance to oxidation of a virgin The quality of irrigation water was found to affect the lutein olive oil [23]. These two compounds are secoiridoids linked to and β-carotene contents in oil of Chemlali cv. In detail, in two elenoic acid or its derivatives. 3,4-DHPEA-EDA in addition to harvest years lutein was always higher in oil obtained from 4-DHPEA-EA and to p-HPEA-EDA the dialdehydic form of decar- trees irrigated with purified waste water from Sfax city (1.51 boxymethyl linked to tyrosol, and to p-HPEA-EA the ligstroside and 1.62 mg/kg) with respect to the oil obtained from trees aglycone, are the secoiridoids in highest quantity in virgin oil irrigated with good quality water (1.20 and 1.40 mg/kg) and [13,23]. with respect to the lutein content in oil from fruits of trees used as control and before irrigation (1.27 mg/kg). In the same work, an inverse trend was verified for β-carotene whose Table 2. Hydrophilic phenols in virgin olive oil. content was lower in oil obtained from trees irrigated with Classes of purified waste water (4.65 and 16.67 mg/kg) with respect to compounds Name of compounds the oil obtained from trees irrigated with good quality water Phenolic alcohols Tyrosol (4-hydroxyphenethyl alcohol) (p-HPEA) (5.72 and 19.97 mg/kg) [27]. Hydroxytyrosol (3,4-dihydroxyphenethyl alcohol) It is well known that the pigments content in oil decrease (3,4-DHPEA) Phenolic acids Benzoic acid constantly with olive fruit ripening and it is inversely related Caffeic acid with the ripening index. Many scientific works have been Chlorogenic acid conducted on the effect of the extraction system on oil com- o-Coumaric m-Coumaric position. In a study carried out in Portugal on Cobrançosa cv, p-Coumaric the authors mixed olives (6–7 ripening index) with a 1%, 2.5%, Ferulic acid 5%, and 10% in weight of leaves and milled together fruits Gallic acid Protocatechuic acid and leaves. After milling and malaxation, the mixture was Salicilic acid centrifuged to obtain the oil, which was found to contain an Sinapic acid increasing lutein and β-carotene content with the leaves Syringic acid Vanillic acid increasing percentage. In detail, the increase of lutein was 2,4-Dihydroxybenzoic acid from 6.5 mg/kg (control without added leaves) to 8.3 mg/kg 4-Hydroxybenzoic acid in olives and 10% leaves. At the same time, β-carotene Flavonoids Apigenin Luteolin increased from 1.6 to 4.4 mg/kg under the same conditions. Lignans Pinoresinol This could be a simple, natural and not expensive method to 1-Acetoxypinoresinol improve the antioxidant properties of oil from overmatures hydroxypinoresinol Secoiridoids Oleuropein fruits [28]. The effect of malaxation temperature on carotenoid Oleocanthal content was observed in oil of Caroleo and Leccino cvs Oleacein obtained by malaxing at 20, 25, 30, and 35°C. In both cultivars, 3,4-DHPEA-EDA p-HPEA-EDA, was evidenced a carotenoids increased in oils malaxed at 20 3,4- DHPEA-EA and 30°C and a little decrease was found in oils obtained from p-HPEA-EA olive paste [29]. 742 L. ABENAVOLI ET AL.

Carotenoids are thermo-sensible molecules and their cell function and express protective effect on low-density diminution is related to the loss in color of oil. The most stable lipoprotein (LDL) oxidation [33]. Based on the study in intact is lutein followed by β-carotene and β-cryptoxanthin. β- rat peritoneal leukocytes, de la Puerta and coauthors hypothe- carotene depletion during oil heating is not only determined sized that hydroxytyrosol also inhibits lipox- by the reaction against free radicals but also by the interaction ygenase, platelet aggregation and the production of with other antioxidants such as phenols and tocopherols and leukotriene B4 and therefore reduce the risk of atherosclerosis by the oxygen partial pressure which may contribute to the and coronary heart disease [38]. These results are important lower antioxidant action of carotenoids [30]. The negative due to the fact that NAFLD is related to the higher risks of effect of storage duration in carotenoids depletion was cardiovascular adverse events [39]. observed in extra virgin olive oil from Bosana cv obtained by Considering the oxidative stress, it is known that the a two-phases centrifugation system and stored for 16 months damaged fatty acids by the reactive oxygen species (ROS) trigger in which the carotenoid content showed a tendency to the lipid peroxidation chain reaction. As a consequence of the decrease. More in detail, the highest depletion was observed destroyed cell membrane, and necrosis processes in the first 8 months of storage from an initial 4.72 mg/kg to occur. When the food supply of mitochondria is increased, the 3.44 mg/kg. At the same time a significant negative effect was mitochondrial membrane fluidity is reduced, the intake of free noticed in oil exposed to the light as well as in oil stored in the fatty acids is elevated and that all lead to the increase in ROS dark [31]. The same cultivar was processed in the same generation. Consequently, mitochondria become the significant harvest year by a tree-phases centrifugation system and an source of ROS [40]. The accumulation of fatty acids is involved in initial carotenoid content was observed (9.31 mg/kg). The development of liver disease. NAFLD is therefore related to same decreasing trend in carotenoids during oil storage was mitochondrial disorders such as increase in mitochondrial mem- found and 6.32 mg/kg were observed after 18 months sto- brane and the intermembrane space, as well as the mitochon- rage [32]. drial respiratory chain and oxidative phosphorylation impairment [41]. Inflammatory cytokines (tumor necrosis factor α (TNF-α), transforming growth factor-β (TGF-β), interleukin 6 (IL- 3. Pre-clinical evidences 6)) as well as adipokines (leptin and adiponectin) are involved in The fact that oleuropein and hydroxytyrosol have antioxidant mechanism of NAFLD development [42]. properties similar to and It was reported that the saturated fatty acids are responsi- A, supports the concept that phenols are mainly responsible ble for the hepatic steatosis development by promoting the for the positive health effects of olive oil (Table 1)[24,33]. endoplasmic reticulum stress and apoptosis. In MD, the pri- Analyzing the scavenging capacity of hydroxytyrosol and mary source of fatty acids is oleic acid from olive oil. Oleic acid oleuropein, it was assumed that hydroxytyrosol may be is n-9 monounsaturated fatty acid (MUFA). Based on the inves- a scavenger of aqueous peroxyl radicals nearby the membrane tigational studies Assy et al. proposed the possible mechanism surface. To the contrary, oleuropein can scavenge chain- of oleic acid in NAFLD through the decrease in NF-κB activa- propagating lipid peroxyl radicals within membranes. Also it tion, LDL oxidation and insulin resistance (IR) that are related was obtained that the antioxidant properties of oleuropein to the TNF-α, IL-6, C-reactive protein, and JNK-mediated phos- aglycone and hydroxytyrosol are related to the fatty acid phorylation of IRS-1 decrement [33]. Additionally, the effect of unsaturation degree. According to the available data oleuro- MUFA (olive oil) on the activity and expression of tricarboxy- pein, hydroxytyrosol and caffeic acid could act as promising late carrier (TCC) and the /acylcarnitine translocase scavenger against nitric oxide and peroxynitrite. In vitro anti- (CACT) was evaluated in rat liver model. By consuming extra oxidant potential of phenolic compounds from olive oil was virgin olive oil the decrease in CACT expression and activity investigated and the beneficial effects of hydroxytyrosol was noticed. This enzyme catalyzes the transport reaction of against human erythrocytes that were damaged by hydrogen fatty acids into the mitochondrial matrix. However, olive oil peroxide were found. In addition, it was observed that oleur- had no influence on TCC activity or gene expression, that is opein and hydroxytyrosol act as scavenger for superoxide involved in transport of mitochondrial acetyl-CoA into the anions, generated by the xanthine/xanthine oxidase system cytosol, where the process of lipogenesis happens [43–45]. as well as in human polymorphonuclear cells, and against the Therefore, olive oil rich in phenols might influence the mito- inflammation product of hypochlorous acid [34,35]. Also the chondrial pathways related to the fat accumulation in liver ingestion of olive oil could interfere with the iron absorption (Figure 2), but there is still no data about the positive effect of that is important in oxidative stress pathway. Therefore, it is olive oil diet on the mitochondrial citrate carrier, which is believed that, besides the increase stability of olive oil, the involved in the lipogenesis regulation in liver. phenols in oil are important for the antioxidant, anti- Some animal studies on Wistar and Sprague-Dawley rats fed inflammatory and antitumor properties [36,37]. with diet that contains 7.5–10% of olive oil (4–12 weeks) demon- Polyphenols, in particular hydroxytyrosol and oleuropein, strated the increase in hepatic lipids [46,47]. Additionally, de novo are related to the reduction of oxidative damage of cellular lipogenesis occurred in rats after high fat enrich diet that con- DNA, positive epigenetic changes and RNA microexpression tains 20 or 40% of olive oil [48,49]. Rats used as the control group pattern, and for the inhibition of NF-κB that suppresses the in these studies were fed with polyunsaturated fatty acid (PUFA) tumor growth. Therefore, olive oil expresses the anti- enriched diet and that may be a reason for the observed increase inflammatory properties and reduces the risk for cancer devel- in hepatic lipogenesis in the olive oil group of animals. opment. Besides that hydroxytyrosol improves the endothelial Additionally, in the study on C57Bl/6J male mice on high fat EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 743

Figure 2. Mechanisms of action of olive oil components on NAFLD.

diet (41% fat) the consumption of olive oil (14.3 g/100 g) stimu- effect of extra virgin olive oil in high fat diet in NAFLD mouse lated the lower liver fat accumulation and the fat amount in mice model was related to the anti-inflammatory effects in adipose was comparable to the control group (chow diet). Apart the tissue and modifications of signaling pathways and liver lipid positive effect, olive oil in this study triggered the lobular inflam- composition. Particularly, high fat diet with extra virgin olive oil mation that was related to transcriptomic alteration of amino (41.7% of energy was derived from olive oil) reduced body acid and fatty acid metabolism [50]. On the contrary, in the same weight, regulated levels of plasma lipids, interferon gamma animal model (C57BL/6J male mice) extra virgin olive oil (INF-γ), IL-6 and leptin. Additionally, it was obtained that olive (100 mg/kg/day) together with long chain PUFA (n-3) (100 mg/ oil reduced NAFLD activity score, infiltration and kg/day) inhibited high fat induced liver steatosis, improved insu- modified lipid composition in liver through the increase in oleic lin sensitivity, suppressed oxidative stress and proinflammatory acid and decrease in saturated fatty acids [55]. responses, regulated dyslipidemia as well as lipogenic and lipo- Having in mind that both NAFLD and NASH are described lytic hepatic enzymes altered by high fed induced diet (60% fat) by hepatosteatosis the effects of olive oil was evaluated also in [51]. In another study, the methionine choline deficient diet rich NASH rodent model. Surprisingly, it was obtained that fat in olive oil decreased the fat acid accumulation in liver of induced changes in liver were independent of IR. Although Sprague-Dawley rats with NAFLD, mostly decreased hepatic atherogenic diet with olive oil as well as without cholate paraoxonase activity, increased the serum triglycerides (TG) and improve hepatic inflammation in cholesterol induced NASH, decreased the release of free fatty acids from peripheral adipose the parameters of metabolic syndrome and fat deposition tissue. However, the greatest antioxidant activity was not were promoted [56]. observed after olive oil administration using the rats on chow The role of olive oil rich in polyphenols as well as olive oil diet as control [52]. The study performed on Wistar rats after the without polyphenols in high-fat diet fed male Sprague-Dawley induced steatoses with high fat diet demonstrated that normal rats were studied. Both polyphenols rich virgin olive oil and lipid diet (5% of olive oil or sunflower oil diet) decreased the olive oil without polyphenols significantly improved glucose collagen deposition, serum aminotransferase level and signifi- homeostasis and inflammatory status through regulation of cantly increased the glial fibrillary acidic protein (GFAP) expres- TNF-α IL-1, IL-10, and adipokines as well as attenuated the sion that is related to the functional status of hepatocytes. The high fat diet induced oxidative and nitrosative stress in liver recovery from hepatic steatosis were more pronounced in group and elevated hepatic fatty acid oxidation. Diet with olive oil on diet rich in olive oil [53]. Rincón-Cervera and coauthors eval- rich in polyphenols reduced release and uated the effects of extra virgin olive oil in mice after the high fat aconitase activity that are of most importance for the emission diet. It was recorded that the supplementation with extra virgin of mitochondrial ROS [42]. Protective effects of hydroxytyrosol, olive oil (100 mg/day) with the highest antioxidant content and oleic acid, tocopherols and PUFAs were analyzed in rats with capacity significantly reduced fat accumulation in liver, normal- iron-induced NAFLD. Iron diet (200 mg iron/kg diet) induced ized desaturase activities, prevent the oxidative stress, decrease liver steatoses, oxidative stress, lipid peroxidation and protein the long-chain PUFA content in liver and normalized metabolic oxidation, and was related to the mitochondrial dysfunction, disturbances caused by high fat diet [54]. Also, the protective decrease of PUFA, and significant increase in SREBP-1c/PPAR-α 744 L. ABENAVOLI ET AL. ratio as well as upregulation of nuclear factor erythroid caused by high fat diet. The mechanism of hydroxytirosol 2-related factor 2 (Nrf2) compared to the control (20 mg amelioration of the WAT dysfunction in mice is explained iron/kg diet). Supplementation with extra virgin olive oil rich through the regulation of NF-κB, Nrf2, SREBP-1c, and PPAR-γ in antioxidants (100 mg/day) in combination with iron admin- [63]. Lim et al. clarified the new biochemical route responsible istration (200 mg iron/kg diet) prevent the progression of the for oleic acid activity and contribution to lipid homeostasis liver disease and the obtained results corresponding to the [64]. The mechanism of oleic acid action includes the stimula- control [57]. Pirozzia et al. demonstrated the antioxidant, anti- tion of the cAMP/protein kinase A pathway, and the sirtuin inflammatory and protective effect of hydroxytyrosol in high 1-mediated deacetylation of peroxisome proliferator-activated fat induced NAFLD male rats. The rats fed with hydroxytyrosol receptor γ coactivator 1α (SIRT1-PGC1α) transcriptional com- (10 mg/kg/day) had lower aspartate transaminase (AST), ala- plex in skeletal muscle cells. Also oleic acid triggers the expres- nine transaminase (ALT) and cholesterol serum levels, better sion of genes related to fatty acid oxidation pathway in the glucose tolerance and insulin sensitivity. Supplementation SIRT1-PGC1α. The promote effects of oleic acid on the fatty with hydroxytyrosol reduced liver inflammation, lipid peroxi- acid oxidation are related to the anti-inflammatory, dyslipi- dation, oxidative and nitrosative stress, production of ROS, and demic, and IR properties of oleic acid present in olive oil. significantly increased peroxisome proliferator-activated Concerning the presented animal data the mechanisms of receptor alpha (PPAR-α) and its downstream-regulated gene action of olive oil components on NAFLD is given in Figure 2. fibroblast growth factor 21 (FGF21), the acetyl-CoA carboxy- lase (AAC) phosphorylation and the mRNA carnitine palmitoyl- 4. Clinical evidences transferase 1a [58]. Also, oleuropein-related positive effects on liver steatosis were analyzed in C57BL/6J mice of both gender Based on the experimental data, after ingestion more than on normal and high fat diet. It was suggested that oleuropein 50% of phenols from olive oil are absorbed in humans while in correct the diet-related liver steatosis by targeting the AMPK- rats the bioavailability of phenols is between 70 and 99% [65– dependent phosphorylation of ULK1 at Ser-555 in NAFLD 67]. It is suggested that incomplete gut absorption of phenols female and male mice. Oleuropein activation in autophagy is responsible for their antioxidative activity in the gastroin- was observed in normal and high-fat-fed mice but the testinal tract [68]. The absorption of hydroxytyrosol and tyr- mechanism of protein kinase B/mammalian target of rapamy- osol is dose dependent in animals and humans and the cin (Akt/mTOR) pathway regulation were gender-specific [59]. maximum level in plasma is reached until 1 h of ingestion It is known that the increase in TNF-α and the white adi- [69,70]. The dose-dependent relationship was also observed in pose tissue (WAT) mass promotes lipolysis and the release of urine and therefore concentration of tyrosol and hydroxytyr- free fatty acids into the plasma, that triggers lipotoxicity in osol in urine might be used as biomarkers of the consumption nonadipose tissues and lead to the NAFLD [60]. Ebaid et al. of olive oil phenols [71]. When considering the levels of hydro- [37] reports that olive oil and its phenolic compounds oleur- xytyrosol in urine, the fact that hydroxytyrosol is important opein and caffeic-acid, induced the fat oxidation in adipose metabolite of the dopaminergic pathway should be taken into and cardiac tissue in obese rats. The optimized cardiac energy account [72]. metabolism and improved myocardial oxidative stress were Due to the extensive first pass metabolism, it is suspected also observed under the standard caloric diet while in hyper- that the metabolites of phenols are responsible for the posi- caloric fed rats antioxidant properties of olive oil were not tive effects of olive oil and they express higher antioxidative noticed [37]. The lipid hydroperoxide was decreased and effect compared to the parent compound [3]. This assumption total antioxidant substances were elevated in rats under the is supported by the experimental data that glucuronide con- standard caloric diet rich in olive oil and oleuropein. jugate of hydroxytyrosol is more potent than the parent com- Hypercaloric diet intake is related to the permanent oxidative pound [73]. stress and this may be a reason why antioxidant activity of A dose-dependent relationship was noticed between intake olive oil and its phenolic compounds in cardiac tissue under and binding of olive oil phenols to LDL [74]. The olive oil hypercaloric diet was not observed. Based on the available improved resistance to LDL oxidation in peripheral vascular data hydroxytirosol promote biogenesis of mitochondria in disease, in hyperlipidemic and mildly hyperlipidemic humans cultured adipocytes. Moreover, hydroxytirosol increases the [75]. Also the protective effect of phenols on DNA oxidation in mitochondrial complexes I, II, III, and V expression and activity, perimenopausal women was recorded [76]. The increased total enhances oxygen consumption, and finally decreases the fatty antioxidant capacity and protective effects on lipid peroxide in acid amount in cultured adipocytes [61,62]. The novel study group of patients that consumed olive oil were additionally performed on male C57BL/6 J mice evaluated the anti- observed. Although in vivo studies have demonstrated posi- inflammatory, antioxidant and antilipogenic properties of tive effects of olive oil phenols on oxidation of LDL and DNA, hydroxytirosol supplementation and their impact on dysfunc- the impact on plasma F2-isoprostanes were not observed tional WAT in mice on high fat diet (60%). It was obtained that [71,77]. hydroxytirosol improved the WAT dysfunction related altera- Based on the analysis of Vissers et al. [66] and the calcu- tions in moderately obese mice on high fat diet: ameliorated lated differences in lag time of LDL oxidisability between the lipid oxidation and adipose hypertrophy, regulated long chain high and low phenol oil administered groups (3.7 ± 2.2 min), polyunsaturated fatty acids levels and adipokines and conse- the protective effect on LDL oxidisability in humans is not quently decreased promotion of lipogenesis and inflammation confirmed. In the studies performed in humans there are lot EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 745

of inconsistency. Although in some studies the increase in hypocaloric diet. The low caloric olive oil rich diet improve- total phenol concentration after the consumption of olive oil ment of the liver status in NAFLD patients was not associated was noticed, the variability between results usually interfere with oxidative stress parameters, reduction of liver enzymes, with the obtained conclusions [78,79]. The group of authors correction of cardiometabolic risk factors, and anti- obtained the lower oxidation of arachidonic acid and LDL, the inflammatory parameters. It was measured the decrement in reduced in vitro uptake of oxidized LDL by as serum AST, TG and fat mass in NAFLD patients on olive oil rich well as an increase of antioxidant capacity of plasma samples diet but with no significant differences between groups. after the consumption of olive oil rich in phenols [69,75,79]. Therefore, apart the lower fat accumulation in the liver, the However, for various oxidation markers human studies are still intake of 20 g of olive oil per day for 12 weeks did not correct limited. metabolic disorders related to NAFLD. The results of multicenter clinical study performed on 200 However, the one-year consumption of olive oil enriched volunteers supported the assumption that the protective with n-3 PUFA (6.5 ml of olive oil) cased significant decrease of effects of olive oil phenols on lipid oxidation are mostly pro- liver enzymes and TG with a significant increase of adiponec- nounced under the oxidative stress conditions [80,81]. It was tin levels. Also, a significant improvement of liver echo-texture observed that consumption of olive oil increased high-density and the Doppler Perfusion Index were observed after long lipoprotein (HDL), reduced versus oxidized ratio as consumption of olive oil enriched with n-3 PUFA in NAFLD well as decreased DNA oxidation, total cholesterol versus HDL patients [83]. ratio and serum TG. The olive oil with high content of phenols Additionally, in another randomized clinical trial performed showed positive effects on oxidized LDL, conjugated dienes, on 50 humans with mean body mass index of 29.7 kg/m2 the hydroxy fatty acids as well as decreased LDL versus HDL ratio. significant decrease in the liver enzymes (ALT and AST) were Apart from the positive effect of olive oil on oxidized LDL, the observed in NAFLD patients on hypocaloric olive oil diet com- beneficial effects on serum malondialdehyde, interleukine 6, pared to NAFLD patients on hypocaloric normal fat diet and total antioxidant capacity were not observed in (p < 0.01). In both groups significant weight loss is recorded humans [82]. but none of the patients in both groups had lost more than In Table 3, currently available clinical results about the 7% of weight. No differences in steatosis were noticed association of olive oil with NAFLD are summarized. In the between these two groups although the improvement was double-blind clinical trial performed on 66 NAFLD patients the more expressed in NAFLD patients on hypocaloric olive oil diet significant differences between NAFLD patients fed with olive [84]. On contrary, Nigam et al. reported that the consumption oil and sunflower oil were only noticed in fatty liver grade, of 20 g of olive oil or canola oil during 6 months improved the skeletal muscle mass and body fat percentage [1]. In both fatty liver grade in male Asian Indians with NAFLD compared groups decrement in weight, waist circumference, blood pres- to the control (soybean/safflower oil). The fatty liver improve- sure and serum ALT were noticed probably due to the ment was probably related to the obtained reduction of

Table 3. Summary of the effects of olive oil and MD on NAFLD in adults. Experimental design Effects of olive oil References – Randomized, double-blind, 66 patients – Significant differences in fatty liver grade, skeletal muscle mass Rezaei et al. [1] – Olive or sunflower oil and body fat % – 20 g per day for 12 weeks – Hypocaloric diet (500 kcal/day) – 11 patients – Significant decrease in liver enzymes and TG Sofi et al. [83] – 6.5 ml olive oil with n-3 PUFA per day for 12 months – A significant improvement of adiponectin levels – Randomized, 50 patients – Significant differences in the ALT and AST between groups Shidfar et al. [84] – 20% of energy requirement from olive oil for 12 weeks vs. normal oil intake – Hypocaloric diet – 93 males – Significant decrease in weight and BMI, fasting insulin level, Nigam et al. [85] – Olive oil, canola oil and soyabean/safflower oil (control) HOMA-IR – Cooking medium (not exceeding 20 g/day) for 6 months – Improvements in fatty liver grade and span – 276 participants, 57% NAFLD – Waist circumference reduction Cueto-Galán – MD with extra virgin olive oil (1 l/week), MD with nuts (30 g/day) and – Lower change in the fatty liver index over time et al. [90] control (low fat diet) – 6-year follow-up – 73 patients – Negatively correlated to ALT, insulin, IR index and severity of Kontogianni et al. – adherence to MD via MedDietScore steatosis [92] – Positively correlated to adiponectin level – Randomized, crossover, 12 patients – MD significantly decreased steatosis Ryan et al. [93] – MD and control diet (low fat-high carbohydrate diet) – Improved insulin sensitivity – 6-week wash-out period in between – 90 patients, BMI 31.01 ± 5.18 – A significant decrease of Bright Liver Score after 6 months Trovato et al. [94] – MD diet intervention 746 L. ABENAVOLI ET AL. weight and IR. However, the significant decrease in steatosis in Concerning the fact that NAFLD is recognized as hepatic patients that daily consumed 20 g of olive oil was not enough form of metabolic syndrome and that there is a close relation- to persuade the significant decrease in AST [85]. This is in ship between NAFLD and obesity, dyslipidemia, IR, type 2 dia- agreement with Bes-Rastrollo et al. [86] cross-sectional study, betes and hypertension promising results such as an increase in as well as the 6 year prospective cohort [87] that the intake of lipid oxidation and a decrease in IR that were obtained in few olive oil is not related to the higher incidence of obese. To the human studies, may imply the olive oil rich diet in patient with contrary, Benítez-Arciniega [88] reported a positive correlation NAFLD. Fraser et al. [96]reportedthatmodifiedMDwiththe between olive oil intake and body mass index. high content of MUFAs was associated with lower ALT levels in MD characterizes the intake of extra virgin olive oil rich in obese patients with type 2 diabetes in comparing to patients MUFA as the main source of fat. Based on Zelber-Sagi et al. that were on American Diabetes Association diet and low gly- MD contains a daily intake of 15–80 g of olive oil [89]. The role cemic index diet. In another study performed on 30 men and 8 of MD in the management of NAFLD was evaluated in several women, the diet rich in MUFAs (28% of total intake) reduced the clinical trials. Total of 276 participants were enrolled in the liver fat content for 30% through increased postprandial hepatic 6 year follow-up clinical trial, conducted in Spain, in order to fatty acid β oxidation [97]. The impact of MUFA intake (28% of investigate the effect of MD enriched with extra virgin olive oil total energy administrated as olive oil that contains 50% MUFA) or dried fruit and nuts on NAFLD using fat liver score. In on hepatic insulin sensitivity and liver fat fraction was evaluated control group volunteers were on low-fat diet and the pre- in 55 prediabetes volunteers. In the control group, patients were valence of NAFLD was 57%. In contrast to the control, waist on control-habitual diet. After 12 weeks, liver fat fraction was circumference reduction was observed in MD extra virgin olive significantly decreased in MUFA group and both hepatic and oil group. Although the fatty liver index trend over time was total insulin sensitivity were improved [98]. similar to the control group, the increased change was slower (−3.90 ± 1.9) in MD extra virgin oil group compare to the control. The finding that MD could delay the progression of 5. Conclusion NAFLD could not be supported without liver fat quantification, Based on the epidemiological studies it is very difficult to deter- because fatty liver index is an indirect measure of NAFLD [90]. mine the positive effects of olive oil in vivo. Some of the possible The beneficial effects of MD diet were investigated in a Greek explanation for the inconstancy between in vitro and in vivo case control study on 351 volunteers. The association of diet- studies, is that the main focus in past was on the antioxidative ary habits with common NAFLD biomarkers was investigated. effects of phenols present in the olive oil. Also, it is very hard to It was obtained that the diet with unsaturated fatty acid analyze the influence of olive oil, as a single item in MD apart reduced odds of developing NAFLD for 55.7% and was related from other normal constituents of diet such as wine and coffee, to lower triacylglycerol and levels [91]. In the cross- in the improvement of LDL protection against oxidation. sectional study that measured the impact of adherence to MD Therefore, more studies should be focus on the antioxidative on the presence and severity of NAFLD 73 patients take part. effects of the olive oil metabolites present in plasma. Before Although the higher adherence to MD was not associated with decisive conclusion, future clinical studies should be focused lower possibility for NAFLD, the less liver steatosis was on the examination of olive oil role in prevention of liver stea- obtained by liver biopsy. Also, the lower rate of IR was mea- tosis in healthy volunteers as well as in those under high-risk. sured in NAFLD with higher adherence to MD. Patients with NASH showed the lower adherence to MD versus patients with simple fatty liver [92]. Similar results were obtained in the 6. Expert opinion study performed on 12 adults that were both on the MD Currently, NAFLD has become an emerging healthy problem and a control diet (low fat-high carbohydrate diet) in random worldwide due to the high prevalence. Efforts to diagnosis, order. Weight loss did not differ between these two diets. prevention, and treatment are important and must be so in After 6 weeks, MD significantly decreased hepatic steatosis the future, since the NALFD can progress in cirrhosis and is based on the magnetic resonance (1)H spectroscopy and related to cardiovascular and metabolic diseases. Based on the improved the insulin sensitivity (glucose, insulin and GGT risk factors underlying the development of NALFD, the treat- test were used) [93]. In another clinical trial performed on 90 ment that showed the best result was the multidisciplinary one. nondiabetic volunteers with body mass index (BMI) In this way, the nutritional intervention that drives the adhesion 31.01 ± 5.18 and diagnosed fatty liver adherence to MD to a Mediterranean dietary pattern and physical activity is more induced a significant decrease in liver fat [94]. Moreover, the effective than any single pharmacological option. The use of MD relationship between adherence to the MD and NAFLD were in patients with NAFLD resulted in the improvement of clinical investigated in 240 obese children and adolescents, with and biochemical data, with a reduction of liver fat accumulation laboratory and liver biopsy evaluation. Level of adherence to and improvement of metabolic and anthropometric parameters. MD was measured according to the clinical index based on A large body of evidence emphasizes that olive oil, used as a nutritional score (Mediterranean Diet Quality Index for chil- primary source of fat in MD, may play a crucial role in the health dren and adolescents, KIDMED). The low KIDMED score was benefits of NAFLD patients. Many of these positive effects are significantly prevalent in NASH patients and poor MD adher- attributed to olive oil, which is one of the essential components ence was associated with liver damage, increase of C-reactive of this regimen. Olive oil is able to reduce hepatic fat accumula- β protein, fasting insulin, IR, and cell function [95]. tion independently from metabolic pathways, probably through EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 747 increased fatty acid oxidation. Apart from the lower LDL oxida- for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice tion, it is suspected that the main mechanism of olive oil ben- guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1338–1340. eficial effects in NAFLD includes also the decrease in NF-κB 10. Abenavoli L, Milic N, Peta V, et al. Alimentary regimen in activation and the improvement of IR. non-alcoholic fatty liver disease: mediterranean diet. World Further studies, especially in human are required to confirm J Gastroenterol. 2014;20(45):16831–16840. the metabolic protective effects of olive oil and its compo- 11. Giuffrè AM. Variation in triacylglycerols of olive oils produced in nents, in patients with NAFLD and also to elucidate the under- Calabria (Southern Italy) during olive ripening. Riv Ital Sostanze Grasse. 2014;91(4):221–240. lying mechanisms involved. In particular, it would be 12. Giuffrè AM, Louadj L, Poiana M, et al. Sterol composition of oils necessary to better define the synergic effects of different extracted from olives cultivars of the province of Reggio Calabria olive oil compounds in the context of a healthy alimentary (South of Italy). Riv Ital Sostanze Grasse. 2012;89(3):177–183. regimen, as a Mediterranean diet. 13. Bendini A, Cerretani L, Carrasco-Pancorbo A, et al. Phenolic mole- cules in virgin olive oils: a survey of their sensory properties, health effects, antioxidant activity and analytical methods. An overview of Funding the last decade. Molecules. 2007;12(8):1679–1719. 14. Lazzerini C, Cifelli M, Domenici V. Pigments in extra virgin olive oils This research was supported by Distretto ad alta tecnologia agroindus- produced in different mediterranean countries in 2014: near UV-vis triale della Calabria AGRIFOODTECH – PROGETTO PON03PE_00090_2, spectroscopy versus HPLC-DAD. LWT - Food Sci Technol. Sustainable models and new technologies for olives and olive oil. 2017;84:586–594. 15. Abenavoli LM, Proto AR. Effects of the divers olive harvesting systems on oil quality. Agron Res. 2015;13(1):7–16. Declaration of interest 16. Tarchoune I, Sgherri C, Eddouzi J, et al. addition increases olive oil nutraceutical properties. Molecules. 2019 Feb 2;24(3):545. The authors have no relevant affiliations or financial involvement with any 17. Kamal-Eldin A, Appelquist LA. The chemistry and antioxidant prop- organization or entity with a financial interest in or financial conflict with erties of tocopherols and . Lipids. 1996;31(79):671–701. the subject matter or materials discussed in the manuscript. This includes 18. Ambra R, Patella F, Lucchetti S, et al. α-Tocopherol, β-carotene, employment, consultancies, honoraria, stock ownership or options, expert lutein, squalene and secoiridoids in seven monocultivar Italian testimony, grants or patents received or pending, or royalties. extra-virgin olive oils. Int J Food Sci Nutr. 2017;68(5):538–545. 19. Ghanbari Shendi E, SivriOzay D, Ozkaya MT, et al. Changes occur- ring in chemical composition and oxidative stability of virgin olive Reviewer disclosures oil during storage. OCL. 2018;25(6):A602. Peer reviewers on this manuscript have no relevant financial or other 20. Franco MN, Galeano-Díaz T, Sánchez J, et al. The phenolic com- relationships to disclose. pounds and tocopherols profiles of seven olive oil varieties grown in the South-West Spain. J Oleo Sci. 2014;63(2):115–125. 21. Giuffrè AM, Caracciolo M, Zappia C, et al. Effect of heating on References chemical parameters of extra virgin olive oil, pomace olive oil, soybean oil and palm oil. Ital J Food Sci. 2018;30(4):715–739. Papers of special note have been highlighted as either of interest (•)orof 22. Serreli G, Deiana M. Biological relevance of extra virgin olive oil considerable interest (••) to readers. polyphenols metabolites. Antioxidants (Basel). 2018;7(12):pii:E17. 1. Rezaei S, Akhlaghi M, Sasani MR, et al. Olive oil lessened fatty liver 23. Carrasco-Pancorbo A, Cerretani L, Bendini A, et al. Evaluation of the severity independent of cardiometabolic correction in patients antioxidant capacity of individual phenolic compounds in virgin with non-alcoholic fatty liver disease: A randomized clinical trial. olive oil. J Agric Food Chem. 2005;3(23):8918–8925. Nutrition. 2019;57:154–161. 24. Faine LA, Diniz YS, Galhardi CM, et al. Synergistic action of olive oil • Randomized, double-blind clinical study conducted on supplementation and dietary restriction on serum lipids and car- patients with NAFLD. diac antioxidant defences. Can J Physiol Pharmacol. 2004;82 2. U.S. food & drug administration [Internet]. Washington (DC): FDA. (11):969–975. [cited 2019 May 10]. Available from: https://www.fda.gov/food/ 25. Brenes M, García A, García P, et al. Acid hydrolysis of secoiridoida- cfsan-constituent-updates/fda-completes-review-qualified-health- glycons during storage of virgin olive oil. J Agric Food Chem. claim-petition-oleic-acid-and-risk-coronary-heart-disease 2001;49(11):5609–5614. 3. Tuck KL, Hayball PJ. Major phenolic compounds in olive oil: meta- 26. Gandul-Rojas B, Mínguez-Mosquera MI. Chlorophyll and carotenoid bolism and health effects. J Nutr Biochem. 2002;13(11):636–644. composition in virgin olive oils from various Spanish olive varieties. 4. Gorini I, Iorio S, Ciliberti R, et al. Olive oil in pharmacological and J Sci Food Agric. 1996;72:31–39. cosmetic traditions. J Cosmet Dermatol. 2019. in press. 27. Bedbabis S, Ben Rouina B, Boukhris M, et al. Effects of irrigation 5. Abenavoli L, Di Renzo L, Boccuto L, et al. Health benefits of with treated wastewater on root and fruit mineral elements of Mediterranean diet in nonalcoholic fatty liver disease. Expert Rev Chemlali olive cultivar. ScientificWorldJournal. 2014;2014:973638. Gastroenterol Hepatol. 2018;12(9):873–881. 28. Malheiro R, Casal C, Teixeira H, et al. Effect of olive leaves addition •• Review on health effects of Mediterranean diet in preventing during the extraction process of overmature fruits on olive oil major chronic diseases including NAFLD quality. Food Bioprocess Technol. 2013;6:509–521. 6. Younossi ZM. Non-alcoholic fatty liver disease - A global public 29. Ranalli A, Malfatti A, Lucera L, et al. Effects of processing techniques health perspective. J Hepatol. 2019;70(3):531–544. on the natural colourings and the other functional constituents in 7. Abenavoli L, Milic N, Di Renzo L, et al. Metabolic aspects of adult virgin olive oil. Food Res Int. 2005;38:873–878. patients with nonalcoholic fatty liver disease. World 30. Aparicio-Ruiz R, Mínguez-Mosquera MI, Gandul-Rojas B. Thermal J Gastroenterol. 2016;22(31):7006–70016. degradation kinetics of lutein, β-carotene and β-cryptoxanthin in 8. Iqbal U, Perumpail BJ, Akhtar D, et al. The epidemiology, risk virgin olive oils. J Food Compos Anal. 2011;24:811–820. profiling and diagnostic challenges of nonalcoholic fatty liver 31. Del Caro A, Vacca V, Poiana M, et al. Influence of technology, disease. Medicines (Basel). 2019; 6(1): pii E41. storage and exposure on components of extra virgin olive oil 9. European Association for the Study of the Liver (EASL); European (Bosana cv) from whole and de-stoned fruits. Food Chem. Association for the Study of Diabetes (EASD); European Association 2006;98:311–316. 748 L. ABENAVOLI ET AL.

32. Vacca V, Del Caro A, Poiana M, et al. Effect of storage period and 52. Hussein O, Grosovski M, Lasri E, et al. Monounsaturated fat exposure conditions on the quality of Bosana extra virgin olive oil. decreases hepatic lipid content in non-alcoholic fatty liver disease J Food Qual. 2006;29:139–150. in rats. World J Gastroenterol. 2007;13(3):361–368. 33. Assy N, Nassar F, Nasser G, et al. Olive oil consumption and 53. Hernández R, Martínez-Lara E, Cañuelo A, et al. Steatosis recovery non-alcoholic fatty liver disease. World J Gastroenterol. 2009;15 after treatment with a balanced sunflower or olive oil-based diet: (15):1809–1815. involvement of perisinusoidal stellate cells. World J Gastroenterol. •• Review paper about effects of olive oil on NAFLD. 2005;11(47):7480–7485. 34. De la Puerta R, Dominguez MEM, Ruiz-Gutierrez V, et al. Effects of 54. Rincón-Cervera MA, Valenzuela R, Hernandez-Rodas MC, et al. virgin olive oil phenolics on scavenging of reactive nitrogen spe- Supplementation with antioxidant-rich extra virgin olive oil pre- cies and upon nitrergic neurotransmission. Life Sci. vents hepatic oxidative stress and reduction of desaturation capa- 2001;69:1213–1222. city in mice fed a high-fat diet: effects on fatty acid composition in 35. Visioli F, Bellomo G, Galli C. Free radical-scavenging properties of liver and extrahepatic tissues. Nutrition. 2016;32(11–12):1254–1267. olive oil polyphenols. Biochem Biophys Res Commun. 55. Jurado-Ruiz E, Varela LM, Luque A. An extra virgin olive oil rich diet 1998;247:60–64. intervention ameliorates the nonalcoholic steatohepatitis induced 36. Visioli F, Poli A, Galli C. Antioxidant and other biological activities of by a high-fat “Western-type” diet in mice. Mol Nutr Food Res. phenols from olives and olive oil. Med Res Rev. 2002;22:65–75. 2017;61(3):1600549. 37. Ebaid GM, Seiva FR, Rocha KK, et al. Effects of olive oil and its minor 56. Buettner R, Ascher M, Gäbele E, et al. Olive oil attenuates the phenolic constituents on obesity-induced cardiac metabolic cholesterol-induced development of nonalcoholic steatohepatitis changes. Nutr J. 2010;9:46. despite increased insulin resistance in a rodent model. Horm Metab 38. De la Puerta R, RuizGutierrez V, Hoult JR. Inhibition of leukocyte Res. 2013;45(11):795–801. 5-lipoxygenase by phenolics from virgin olive oil. Biochem 57. Barrera C, Valenzuela R, Rincón MÁ. Molecular mechanisms related Pharmacol. 1999;57:445–449. to the hepatoprotective effects of antioxidant-rich extra virgin olive 39. Patil R, Sood GK. Non-alcoholic fatty liver disease and cardiovascu- oil supplementation in rats subjected to short-term iron lar risk. World J Gastrointest Pathophysiol. 2017;8(2):51–58. administration. Free Radic Biol Med. 2018;126:313–321. 40. Novelli ELB, Santos P, Assalin H, et al. N- in high 58. Pirozzi C, Lama A, Simeoli R, et al. Hydroxytyrosol prevents meta- sucrose induced obesity: energy expenditure metabolic shifting bolic impairment reducing hepatic inflammation and restoring for cardiac health. Pharmacol Res. 2009;59:74–79. duodenal integrity in a rat model of NAFLD. J Nutr Biochem. 41. Priore P, Cavallo A, Gnoni A, et al. Modulation of hepatic lipid 2016;30:108–115. metabolism by olive oil and its phenols in nonalcoholic fatty liver • The study evaluated the beneficial therapeutic effects of disease. IUBMB Life. 2015;67(1):9–17. hydroxytyrosol in rat NAFLD model. •• Critical review about the knowledge on the protective role of 59. Porcu C, Sideri S, Martini M, et al. Oleuropein induces olive oil in NAFLD. ampk-dependent autophagy in nafld mice, regardless of the 42. Lama A, Pirozzi C, Mollica MP, et al. -rich virgin olive oil gender. Int J Mol Sci. 2018;19(12). reduces insulin resistance and liver inflammation and improves 60. Valenzuela R, Videla LA. Crosstalk mechanisms in hepatoprotection: mitochondrial dysfunction in high-fat diet fed rats. Mol Nutr Food thyroid hormone-docosahexaenoic acid (DHA) and DHA-extravirgin Res. 2017;61(3):1600418. olive oil combined protocols. Pharmacol Res. 2018;132:168–175. • This study evaluated the beneficial effects of olive oil in rats 61. Hao J, Shen W, Yu G, et al. Hydroxytyrosol promotes mitochondrial fed high-fat diet. biogenesis and mitochondrial function in 3T3-L1 adipocytes. J Nutr 43. Siculella L, Sabetta S, Damiano F, et al. Different dietary fatty acids Biochem. 2010;21:634–644. have dissimilar effects on activity and gene expression of mito- 62. Bullon P, Battino M, Varela-Lopez A, et al. Diets based on virgin chondrial tricarboxylate carrier in rat liver. FEBS Lett. olive oil or fish oil but not on sunfloweroil prevent age-related 2004;17:280–284. alveolar bone resorption by mitochondrial related mechanisms. 44. Ferramosca A, Savy V, Zara V. Olive oil increases the hepatic tria- PLoS One. 2013;8:e74234. cylglycerol content in mice by a distinct influence on the synthesis 63. Illesca P, Valenzuela R, Espinosa A, et al. Hydroxytyrosol supple- and oxidation of fatty acids. Biosci Biotechnol Biochem. mentation ameliorates the metabolic disturbances in white adi- 2008;72:62–69. pose tissue from mice fed a high-fat diet through recovery of 45. Priore P, Stanca E, Gnoni GV, et al. Dietary fat types differently transcription factors Nrf2, SREBP-1c, PPAR-γ and NF-κB. Biomed modulate the activity and expression of mitochondrial carnitine/ Pharmacother. 2019;109:2472–2481. acylcarnitine translocase in rat liver. BiochimBiophysActa. 64. Lim JH, Gerhart-Hines Z, Dominy JE, et al. Oleic acid stimulates 2012;1821:1341–1349. complete oxidation of fatty acids through protein kinase 46. Ferramosca A, Zara V. Modulation of hepatic steatosis by dietary A-dependent activation of SIRT1-PGC1α complex. J Biol Chem. fatty acids. World J Gastroenterol. 2014;20(7):1746–1755. 2013;288(10):7117–7126. 47. Ruiz-Gutiérrez V, Pérez-Espinosa A, Vázquez CM, et al. Effects of 65. Tuck KL, Freeman MP, Hayball PJ, et al. in vivo fate of hydroxytyr- dietary fats (fish, olive and high- oleicacid sunflower oils) on lipid osol and tyrosol, antioxidant phenolic constituents of olive oil, after composition and antioxidant enzymes in rat liver. Br J Nutr. intravenous and oral dosing of labeled compounds to rats. J Nutr. 1999;82:233–241. 2001;131:1993–1996. 48. Portillo MP, Chávarri M, Durán D, et al. Differential effects of diets 66. Vissers MN, Zock PL, Katan MB. Bioavailability and antioxidant that provide different lipid sources on hepatic lipogenic activities in effects of olive oil phenols in humans: a review. Eur J Clin Nutr. rats under ad libitum or restricted feeding. Nutrition. 2004;58(6):955–965. 2001;17:467–473. 67. Vissers MN, Zock PL, Roodenburg AJ, et al. Apparent absorption of 49. Takeuchi H, Nakamoto T, Mori Y, et al. Comparative effects of olive oil phenols in humans. J Nutr. 2002;132:409–417. dietary fat types on hepatic enzyme activities related to the synth- 68. Ursini F, Zamburlini A, Cazzolato G, et al. Postprandial plasma lipid esis and oxidation of fatty acid and to lipogenesis in rats. Biosci hydroperoxides: a possible link between diet and atherosclerosis. Biotechnol Biochem. 2001;65:1748–1754. Free Radical Biol Med. 1998;25:250–252. 50. Sales RC, Medeiros PC, Spreafico F, et al. Olive oil, palm oil, and 69. Visioli F, Galli C, Bornet F, et al. Olive oil phenolics are hybrid palm oil distinctly modulate liver transcriptome and induce dose-dependently absorbed in humans. FEBS Lett. NAFLD in mice fed a high-fat diet. Int J Mol Sci. 2018;20:1. 2000;468:159–160. 51. Valenzuela R, Espinosa A, Llanos P, et al. Anti-steatotic effects of an 70. Miró-Casas E, Covas MI, Fitó M, et al. Tyrosol and hydroxytyrosol are n-3 LCPUFA and extra virgin olive oil mixture in the liver of mice absorbed from moderate and sustained doses of virgin olive oil in subjected to high-fat diet. Food Funct. 2016;7(1):140–150. humans. Eur J Clin Nutr. 2003;57:186–190. EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 749

71. Fitó M, de la Torre R, Covas MI. Olive oil and oxidative stress. Mol fatty acids (olive and canola oils) compared with control oil in male Nutr Food Res. 2007;51:1215–1224. Asian Indians with nonalcoholic fatty liver disease. Diabetes Technol 72. Caruso D, Visioli F, Patelli R, et al. Urinary excretion of olive oil Ther. 2014;16(4):255– 261. phenols and their metabolites in humans. Metabolism. 86. Bes-Rastrollo M, Sánchez-Villegas A, de la Fuente C, et al. Olive oil 2001;50:1426–1428. consumption and weight change: the SUN prospective cohort 73. Tuck KL, Hayball PJ, Stupans I. Structural characterization of the study. Lipids. 2006;41(3):249–256. metabolites of hydroxytyrosol, the principal phenolic component 87. Soriguer F, Almaraz MC, Ruiz-de-Adana MS, et al. Incidence of in olive oil in rats. J Agric Food Chem. 2002;50:2404–2409. obesity is lower in persons who consume olive oil. Eur J Clin 74. Covas MI, de la Torre K, Farré-Albaladejo M, et al. Postprandial LDL Nutr. 2009;63(11):1371–1374. phenolic content and LDL oxidation are modulated by olive oil phe- 88. Benítez-Arciniega AD, Gómez-Ulloa D, Vila A, et al. Olive oil con- nolic compounds in humans. Free Radical Biol Med. 2006;40:608–616. sumption, BMI, and risk of obesity in Spanish adults. Obes Facts. 75. Masella R, Di Benedetto R, Coni E, et al. Effects of dietary virgin 2012;5(1):52–59. olive oil phenols on low density lipoprotein oxidation in hyperlipi- 89. Zelber-Sagi S, Salomone F, Mlynarsky L. The Mediterranean dietary demic patients. Lipids. 2001;36:1195–1202. pattern as the diet of choice for non-alcoholic fatty liver disease: 76. Salvini S, Sera F, Caruso D, et al. Daily consumption of a evidence and plausible mechanisms. Liver Int. 2017;37(7):936–949. high-phenol extra-virgin olive oil reduces oxidative DNA damage 90. Cueto-Galán R, Barón FJ, Valdivielso P. Changes in fatty liver index in postmenopausal women. Br J Nutr. 2006;95:742–751. after consuming a Mediterranean diet:6-Year follow-up of the 77. Marrugat J, Covas MI, Fitó M, et al. Effects of differing phenolic PREDIMED-Malaga trial. Med Clin (Barc). 2017;148(10):435–443. content in dietary olive oils on lipids and LDL oxidation.A rando- 91. Kalafati IP, Borsa D, Dimitriou M, et al. Dietary patterns and mized controlled trial. Eur J Nutr. 2004;43:140–147. non-alcoholic fatty liver disease in a Greek case-control study. 78. Gimeno E, Fito M, Lamuela-Raventos RM, et al. Effect of ingestion of Nutrition. 2019;61:105–110. virgin olive oil on human low-density lipoprotein composition. Eur 92. Kontogianni MD, Tileli N, Margariti A, et al. Adherence to the J Clin Nutr. 2002;56:114–120. Mediterranean diet is associated with the severity of 79. Bonanome A, Pagnan A, Caruso D, et al. Evidence of postprandial non-alcoholic fatty liver disease. Clin Nutr. 2014 Aug;33(4):678–683. absorption of olive oil phenols in humans. Nutr Metab Cardiovasc • Cross-sectional study that measured adherence to MD on the Dis. 2000;10:111–120. presence and severity of NAFLD. 80. Covas MI, Nyyssönen K, Poulsen HE, et al. The effect of polyphenols 93. Ryan MC, Itsiopoulos C, Thodis T, et al. The Mediterranean diet in olive oil on heart disease risk factors. Ann Int Med. improves hepatic steatosis and insulin sensitivity in individuals with 2006;145:333–341. non-alcoholic fatty liver disease. J Hepatol. 2013;59(1):138–143. 81. Machowetz A, Poulsen HE, Gruendel S, et al. Effect of olive oils on 94. Trovato FM, Catalano D, Martines GF, et al. Trovato GM2. biomarkers of oxidative DNA stress in North and South Europeans. Mediterranean diet and non-alcoholic fatty liver disease: the need Faseb J. 2007;21:45–52. of extended and comprehensive interventions. Clin Nutr. 2015;34 82. Hohmann CD, Cramer H, Michalsen A, et al. Effects of high phenolic (1):86–88. olive oil on cardiovascular risk factors: a systematic review and 95. Della Corte C, Mosca A, Vania A, et al. Good adherence to the meta-analysis. Phytomedicine. 2015;22:631–640. Mediterranean diet reduces the risk for NASH and diabetes in 83. Sofi F, Giangrandi I, Cesari F, et al. Effects of a 1-year dietary pediatric patients with obesity: the results of an Italian Study. intervention with n-3 polyunsaturated fatty acid-enriched olive oil Nutrition. 2017;39–40:8–14. on non-alcoholic fatty liver disease patients: a preliminary study. 96. Fraser A, Abel R, Lawlor DA, et al. A modified Mediterranean diet is Int J Food Sci Nutr. 2010;61(8):792–802. associated with the greatest reduction in alanine aminotransferase 84. Shidfar F, Bahrololumi SS, Doaei S, et al. The effects of extra virgin levels in obese type 2 diabetes patients: results of a olive oil on alanine aminotransferase, aspartate aminotransferase, quasi-randomised controlled trial. Diabetologia. 2008;51 and ultrasonographic indices of hepatic steatosis in nonalcoholic (9):1616–1622. fatty liver disease patients undergoing low calorie diet. Can 97. Bozzetto L, Costabile G, Luongo D, et al. Reduction in liver fat by J Gastroenterol Hepatol. 2018;2018:1053710. dietary MUFA in type 2 diabetes is helped by enhanced hepatic fat • The study examined the effect of virgin olive oil on transami- oxidation. Diabetologia. 2016;59(12):2697–2701. nase levels and status of steatosis in the NAFLD patients. 98. Errazuriz I, Dube S, Slama M, et al. Randomized controlled trial of 85. Nigam P, Bhatt S, Misra A, et al. Effect of a 6-month intervention with a MUFA or fiber-rich diet on hepatic fat in prediabetes. J Clin cooking oils containing a high concentration of monounsaturated Endocrinol Metab. 2017;102(5):1765–1774. 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

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