stilbenes and Fatty-Liver

Pterostilbene, a phenolic compound derived from resveratrol, possesses greater bioavailability than its parent compound due to the presence of two methoxyl groups. In this review, the beneficial effects of pterostilbene on diabetes, liver steatosis and dyslipidemia are summarized. Pterostilbene is a useful bioactive compound in preventing type 1 diabetes, insulin resistance and type 2 diabetes in animal models. Concerning type 1 diabetes, the main mechanisms described to justify the positive effects of this phenolic compound are increased liver glycogen content and hepatic glucokinase and phosphofructokinase activities, the recovery of pancreatic islet architecture, cytoprotection and a decrease in serum and pancreatic pro-inflammatory cytokines. As for type 2 diabetes, increased liver glucokinase and glucose-6-phosphatase and decreased fructose-1,6-biphosphatase activities are reported. When insulin resistance is induced by diets, a greater activation of insulin signaling cascade has been reported, increased cardiotrophin-1 levels and liver glucokinase and glucose- 6-phosphatase activities, and a decreased fructose-1,6-biphosphatase activity. Data concerning pterostilbene and liver steatosis are scarce so far, but the reduction in oxidative stress induced by pterostilbene may be involved since oxidative stress is related to the progression of steatosis to steatohepatitis. Finally, pterostilbene effectively reduces total cholesterol, LDL-cholesterol and serum triglyceride levels, while increases HDL-cholesterol in animal models of dyslipidemia.

Topics: Animals; Diabetes Mellitus, Type 2; Fatty Liver; Humans; Insulin Resistance; Lipids; Liver; Stilbenes

Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (

Topics: Animals; Anthocyanins; Antioxidants; Carotenoids; Catechin; Coumestrol; Curcumin; Energy Metabolism; Fatty Liver; Glucosinolates; Humans; Imidoesters; Isothiocyanates; Lipogenesis; Mitochondria; Non-alcoholic Fatty Liver Disease; Nutritional Sciences; Oxidative Stress; Oximes; Polyphenols; Quercetin; Resveratrol; Stilbenes; Sulfoxides; Xanthophylls

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease that is not from excess alcohol consumption, but is often associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD pathogenesis is complicated and involves oxidative stress, lipotoxicity, mitochondrial damage, insulin resistance, inflammation, and excessive dietary fat intake, which increase hepatic lipid influx and de novo lipogenesis and impair insulin signaling, thus promoting hepatic triglyceride accumulation and ultimately NAFLD. Overproduction of proinflammatory adipokines from adipose tissue also affects hepatic metabolic function. Current NAFLD therapies are limited; thus, much attention has been focused on identification of potential dietary substances from fruits, vegetables, and edible plants to provide a new strategy for NAFLD treatment. Dietary natural compounds, such as carotenoids, omega-3-PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol, act through a variety of mechanisms to prevent and improve NAFLD. Here, we summarize and briefly discuss the currently known targets and signaling pathways as well as the role of dietary natural compounds that interfere with NAFLD pathogenesis.

Topics: Adipokines; Animals; Carotenoids; Curcumin; Fatty Acids, Omega-3; Fatty Liver; Flavonols; Humans; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Polyphenols; Resveratrol; Stilbenes

Non-alcoholic fatty liver disease (NAFLD) is usually associated with insulin resistance, central obesity, reduced glucose tolerance, type 2 diabetes mellitus and hypertriacylglycerolaemia. The beneficial effects of resveratrol on metabolic disorders have been shown previously. The aim of this study was to evaluate the effects of resveratrol supplementation on cardiovascular risk factors in patients with NAFLD. In this randomised double-blinded placebo-controlled clinical trial, fifty NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks. Both groups were advised to follow an energy-balanced diet and physical activity recommendations. resveratrol supplementation reduced alanine aminotransferase (ALT) and hepatic steatosis significantly more than placebo (P0·05). There were no significant changes in blood pressure, insulin resistance markers and TAG in either group (P>0·05). Our data have shown that 12-week supplementation of 500 mg resveratrol does not have any beneficial effect on anthropometric measurements, insulin resistance markers, lipid profile and blood pressure; however, it reduced ALT and hepatic steatosis in patients with NAFLD.

Topics: Adult; Alanine Transaminase; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Blood Pressure; Cardiovascular Diseases; Dietary Supplements; Double-Blind Method; Fatty Liver; Female; Humans; Insulin Resistance; Lipid Metabolism; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Phytotherapy; Plant Extracts; Resveratrol; Risk Factors; Stilbenes; Triglycerides

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Resveratrol is a polyphenolic compound with antioxidant capacity that shows beneficial effects on down-regulation of inflammatory mediators and metabolic disorders. We hypothesized that supplementation with resveratrol can further improve the efficacy of lifestyle modifications in the management of NAFLD. In this randomized, double-blinded, controlled clinical trial, 50 NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks. Both groups were advised to follow an energy-balanced diet and received physical activity recommendations. Serum liver enzymes, inflammatory markers, hepatic steatosis and fibrosis, dietary intake, anthropometric measurements, and physical activity were assessed at both baseline and the end of the study. In both groups, anthropometric measurements (weight, body mass index, waist circumference), liver enzymes, and steatosis grade improved (P < 005). Resveratrol supplementation was associated with a significant reduction in liver enzyme alanine aminotransferase, inflammatory cytokines, nuclear factor κB activity, serum cytokeratin-18, and hepatic steatosis grade, as compared with placebo supplementation (P < .05). For the treatment of NAFLD, our results showed that 12 weeks of supplementation of 500 mg resveratrol, along with lifestyle modification, is superior to lifestyle modification alone. This is at least partially due to the attenuation of inflammatory markers and hepatocellular apoptosis. More studies are needed to confirm and increase the clinical application of the present results.

Topics: Adult; Alanine Transaminase; Anthropometry; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Cytokines; Diet; Dietary Supplements; Double-Blind Method; Exercise; Fatty Liver; Female; Humans; Inflammation Mediators; Keratin-18; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Phytotherapy; Plant Extracts; Polyphenols; Resveratrol; Stilbenes

We had reported that cajanolactone A (CLA) from Cajanus cajan dose-dependently inhibited ovariectomy-induced obesity and liver steatosis in mice, showing potential to prevent postmenopausal obesity and fatty liver. In this study, the role of CLA in the regulation of energy and lipid homeostasis was investigated.. Ovariectomized mice treated with CLA or vehicle for 12 weeks were performed a 48 h monitoring for energy metabolism and food uptake. After that, hypothalami, perigonadal (pWATs), inguinal (iWATs) and brown (BATs) adipose tissues, livers, sera, and fecal and cecal contents were collected and analyzed.. In CLA-treated mice, we observed reduced food uptake; increased energy expenditure; inhibited expression of orexigenic genes (ORX, ORXR2, pMCH and Gal) in the hypothalami, of lipogenic genes (CD36, SREBP-1c, ChREBP, PPARγ) in the livers, and of lipid storage proteins in the WATs (FSP27, MEST and caveolin-1) and livers (FSP27, Plin2 and Plin5); stimulated expression of metabolism-related proteins (pATGL and Echs1) in the adipose tissues and of thermogenic protein (UCP1) in the inguinal WATs; increased BAT content; increased mitochondria in the pWATs and livers; inhibited angiogenesis in the pWATs; and altered gut microbiome diversity with an increased abundance of Bacteroides.. CLA prevents ovariectomy-induced obesity and liver steatosis via regulating energy intake and lipid synthesis/storage, promoting UCP1-dependent heat production, and protecting the mitochondrial function of hepatocytes and adipocytes. The improved gut microecology and inhibited angiogenesis may also contribute to the anti-obese activity of CLA.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Cajanus; Energy Intake; Energy Metabolism; Fatty Liver; Female; Lipogenesis; Mice; Mice, Inbred C57BL; Ovariectomy; Stilbenes

The use of phenolic compounds as a new therapeutic approach against NAFLD has emerged recently. In the present study, we aim to study the effect of pterostilbene in the prevention of liver steatosis developed as a consequence of high-fat (saturated) high-fructose feeding, by analysing the changes induced in metabolic pathways involved in triglyceride accumulation. Interestingly, a comparison with the anti-steatotic effect of its parent compound resveratrol will be made for the first time. Rats were distributed into 5 experimental groups and fed either a standard laboratory diet or a high-fat high-fructose diet supplemented with or without pterostilbene (15 or 30 mg per kg per d) or resveratrol (30 mg per kg per d) for 8 weeks. Serum triglyceride, cholesterol, NEFA and transaminase levels were quantified. Liver histological analysis was carried out by haematoxylin-eosin staining. Different pathways involved in liver triglyceride metabolism, including fatty acid synthesis, uptake and oxidation, triglyceride assembly and triglyceride release, were studied. Pterostilbene was shown to partially prevent high-fat high-fructose feeding induced liver steatosis in rats, demonstrating a dose-response pattern. In this dietary model, it acts mainly by reducing de novo lipogenesis and increasing triglyceride assembly and release. Improvement in mitochondrial functionality was also appreciated. At the same dose, the magnitude of pterostilbene and resveratrol induced effects, as well as the involved mechanisms of action, were similar.

Topics: Adipose Tissue; Animals; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Fructose; Lipids; Lipogenesis; Liver; Male; Rats; Rats, Wistar; Resveratrol; Stilbenes; Triglycerides

Pterostilbene is a dimethyl ether derivative of resveratrol, less metabolized than its analogue, due to the substitution of two hydroxyl groups with methoxyl groups. Nevertheless, the amounts of pterostilbene phase II metabolites found in plasma and tissues are higher than those of the parent compound. The first aim of this study was to assess whether pterostilbene-4'-

Topics: Animals; Biomarkers; Biopsy; Cell Line; Cell Survival; Disease Models, Animal; Fatty Acids; Fatty Liver; Hepatocytes; Immunohistochemistry; Lipid Metabolism; Lipogenesis; Mice; Stilbenes; Triglycerides

Polydatin has been recently shown to possess extensive cardiovascular pharmacological activities. However, its protective effect against atherosclerosis in vivo remains poorly understood. The aim of the present study was to evaluate the potential effects of polydatin on high fat diet (HFD)-induced atherosclerosis using ApoE. after 12 weeks treatment, serum samples, mouse aorta, liver, peritoneal macrophages were collected to determine lipid profiles, atherosclerotic lesions, hepatic steatosis, foam cell formation and expression of related molecules. RAW264.7 macrophages were used to study cholesterol efflux.. Polydatin improved serum lipid profiles, attenuated atherosclerosis and hepatic steatosis. Furthermore, polydatin may facilitate RCT by stimulating cholesterol efflux through ATP-binding cassette transporters (ABC) A1, ABCG1 and scavenger receptor class B type I (SR-BI) in macrophages, increasing serum levels of high density lipoprotein and apolipoprotein A-I, promoting of SR-BI-mediated cholesterol uptake of liver, increasing secretion of cholesterol into bile by ABCG5/ABCG8 and improving cholesterol metabolism by CYP7A1 pathway. Polydatin also regulated the protein expressions of hepatic fatty acid synthase and peroxisome proliferator-activated receptor-α. Additionally, polydatin reduced hepatic and aortic reactive oxygen species generation, normalized activities of antioxidant enzymes and increased protein expressions of NADPH-oxidase (NOX) 2 and NOX4 in liver. Polydatin also prevented hepatic and aortic inflammation as evidenced by the reduced macrophage infiltration and mRNA expressions of tumor necrosis factor-α and interleukin-6 in both aorta and liver.. These findings indicated that polydatin can inhibit atherosclerosis through enhancement of overall RCT. In addition, anti-oxidative and anti-inflammatory effect of polydatin may also contribute to its inhibitory effects on atherosclerosis.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; Biological Transport; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Diet, High-Fat; Fatty Liver; Foam Cells; Glucosides; Lipid Metabolism; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Stilbenes

Resveratrol (RES) has the ability to ameliorate nonalcoholic fatty liver disease (NAFLD) and the mechanism remains unclear. Hence, using high-fat diet (HFD) obese rat model, we investigated the effect of a low dose of RES (20 mg/kg) on the hepatic sterol regulatory element-binding protein (SREBPs) - lipogenesis pathway, enzymes involved in β-oxidation and activity of pancreatic lipase. Four groups of rats (n = 8) of control (12% of calories as fat) and HFD (40% of calories as fat) were administered orally with either normal saline as a vehicle or RES as a concomitant treatment for 8 weeks on a daily basis. Then, various biochemical, histological, and molecular experiments were carried out. RES prevented the development and progression of NAFLD and significantly improved insulin sensitivity through (1) inhibiting the proteolytic cleavage of SREBPs-1 and SREBPs-2 without affecting their precursor mRNA or protein levels, (2) inhibiting free fatty acid β-oxidation and generation of reactive oxygen species through significant inhibition of CPT-1 and UCP-2, and (3) decreasing activity of pancreatic lipase in vivo and in vitro. In conclusion, our findings are the first in the literature to show new mechanisms of the hepatoprotective effect of RES against HFD induced NAFLD in rats.

Topics: Animals; Antioxidants; Area Under Curve; Diet, High-Fat; Fatty Acids, Nonesterified; Fatty Liver; Feces; Gene Expression Regulation; Glucose; Glucose Tolerance Test; Insulin Resistance; Intestinal Absorption; Lipase; Liver; Male; Organ Size; Oxidation-Reduction; Oxidative Stress; Proteolysis; Rats, Wistar; Resveratrol; RNA, Messenger; Sterol Regulatory Element Binding Proteins; Stilbenes; Triglycerides

The aim of this study was to evaluate the potential effects of 2,3,4',5-tetrahydroxystilbene-2-O-β-d-glucoside (TSG) on the development of atherosclerotic plaque in ApoE

Topics: Animals; Apolipoproteins E; Atherosclerosis; Biological Transport; Cholesterol; Fatty Liver; Foam Cells; Glucosides; Hyperlipidemias; Inflammation; Lipid Metabolism; Macrophages; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; RAW 264.7 Cells; Stilbenes

Topics: Acetyl-CoA Carboxylase; Animals; Benzoxazoles; Body Weight; Diabetes Mellitus; Enzyme Activators; Fatty Acid Synthases; Fatty Liver; Gene Expression Regulation; Glucose Intolerance; Heterocyclic Compounds, 4 or More Rings; Hypoglycemic Agents; Male; Metabolic Syndrome; Mice, Inbred C57BL; Molecular Docking Simulation; Resveratrol; Sirtuin 1; Sterol Regulatory Element Binding Proteins; Stilbenes

Oxyresveratrol (OXY) is a naturally occurring polyhydroxylated stilbene that is abundant in mulberry wood (Morus alba L.), which has frequently been supplied as a herbal medicine. It has been shown that OXY has regulatory effects on inflammation and oxidative stress, and may have potential in preventing or curing nonalcoholic fatty liver disease (NAFLD). This study examined the effects of OXY on in vitro model of NAFLD in hepatocyte by the liver X receptor α (LXRα)-mediated induction of lipogenic genes and in vivo model in mice along with its molecular mechanism. OXY inhibited the LXRα agonists-mediated sterol regulatory element binding protein-1c (SREBP-1c) induction and expression of the lipogenic genes and upregulated the mRNA of fatty acid β-oxidation-related genes in hepatocytes, which is more potent than genistein and daidzein. OXY also induced AMP-activated protein kinase (AMPK) activation in a time-dependent manner. Moreover, AMPK activation by the OXY treatment helped inhibit SREBP-1c using compound C as an AMPK antagonist. Oral administration of OXY decreased the Oil Red O stained-positive areas significantly, indicating lipid droplets and hepatic steatosis regions, as well as the serum parameters, such as fasting glucose, total cholesterol, and low density lipoprotein-cholesterol in high fat diet fed-mice, as similar with orally treatment of atorvastatin. Overall, this result suggests that OXY has the potency to inhibit hepatic lipogenesis through the AMPK/SREBP-1c pathway and can be used in the development of pharmaceuticals to prevent a fatty liver.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Cell Line, Tumor; Enzyme Activation; Fatty Acids; Fatty Liver; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Lipogenesis; Liver; Liver X Receptors; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Plant Extracts; Protein Serine-Threonine Kinases; Sterol Regulatory Element Binding Protein 1; Stilbenes; Sulfonamides

The aim of the present study was to determine whether the reduction in liver fat previously observed in our laboratory in a cohort of rats which had been fed an obesogenic diet was mediated by changes in the expression of microRNA (miRNA)-103-3p, miRNA-107-3p and miRNA-122-5p, which represent 70% of total miRNAs in the liver, as well as in their target genes. The expression of the three analysed miRNAs was reduced in rats treated with resveratrol. A reduction in sterol-regulatory element binding protein 1 (SREBP1) and an increase in carnitine palmitoyltransferase 1a (CPT1a) were observed in resveratrol-treated rats. No changes were found in fatty acid synthase (FAS). In cultured hepatocytes, SREBP1 protein was increased after the transfection of each miRNA. FAS protein expression was decreased after the transfection of miRNA-122-5p, and CPT1a protein was down-regulated by the over-expression of miRNA-107-3p. This study provides new evidences which show that srebf1 is a target gene for miRNA-103-3p and miRNA-107-3p, fasn a target gene for miRNA-122-5p and cpt1a a target gene for miRNA-107-3p. Moreover, the reduction in liver steatosis induced by resveratrol in rats fed an obesegenic diet is mediated, at least in part, by the increase in CPT1a protein expression and activity, via a decrease in miRNA-107-3p expression.

Topics: Animals; Carnitine O-Palmitoyltransferase; Cell Line; Diet, High-Fat; Down-Regulation; Fatty Acid Synthases; Fatty Liver; Hepatocytes; Liver; Male; MicroRNAs; Rats; Rats, Sprague-Dawley; Resveratrol; Sterol Regulatory Element Binding Protein 1; Stilbenes

The aims of the present study were to analyze the effect of resveratrol on liver steatosis in obese rats, to compare the effects induced by resveratrol and energy restriction and to research potential additive effects. Rats were initially fed a high-fat high-sucrose diet for six weeks and then allocated in four experimental groups fed a standard diet: a control group, a resveratrol-treated group, an energy restricted group and a group submitted to energy restriction and treated with resveratrol. We measured liver triacylglycerols, transaminases, FAS, MTP, CPT1a, CS, COX, SDH and ATP synthase activities, FATP2/FATP5, DGAT2, PPARα, SIRT1, UCP2 protein expressions, ACC and AMPK phosphorylation and PGC1α deacetylation. Resveratrol reduced triacylglycerols compared with the controls, although this reduction was lower than that induced by energy restriction. The mechanisms of action were different. Both decreased protein expression of fatty acid transporters, thus suggesting reduced fatty acid uptake from blood stream and liver triacylglycerol delivery, but only energy restriction reduced the assembly. These results show that resveratrol is useful for liver steatosis treatment within a balanced diet, although its effectiveness is lower than that of energy restriction. However, resveratrol is unable to increase the reduction in triacylglycerol content induced by energy restriction.

Topics: Acetyl-CoA Carboxylase; Alanine Transaminase; AMP-Activated Protein Kinases; Animals; Aspartate Aminotransferases; Caloric Restriction; Coenzyme A Ligases; Diacylglycerol O-Acyltransferase; Diet, High-Fat; Fatty Acid Transport Proteins; Fatty Acids; Fatty Liver; Liver; Male; Organ Size; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR alpha; Rats; Rats, Wistar; Resveratrol; Sirtuin 1; Stilbenes; Triglycerides; Uncoupling Protein 2

Oxyresveratrol has been proven effective in inhibiting adipogenesis in a 3T3-L1 cell model. We investigated the preventive effect of oxyresveratrol supplementation on obesity development in high-fat diet-fed mice. Male C57bl/6 mice were randomly subjected to control (5% fat by weight, LF), high-fat (30% fat by weight, HF), and high-fat supplemented with 0.25% and 0.5% oxyresveratrol (OXY1 and OXY2, respectively) diet groups for eight weeks. Oxyresveratrol supplementation effectively alleviated obesity-associated symptoms such as insulin resistance, hyperglycemia, and hepatic steatosis in high-fat diet-fed mice. Compared to the high-fat diet group, oxyresveratrol supplementation suppressed expression of glucose-6-phosphatase, sterol regulatory element-binding proteins 1, fatty acid synthase and CCAAT/Enhancer-binding proteins α, and elevated AMP-activated protein kinase (α2-catalytic subunit) level in liver, upregulated insulin-dependent glucose transporter type 4 level in adipose tissue, and increased expression of insulin receptor substrate 1, insulin-dependent glucose transporter type 4, AMP-activated protein kinase α, peroxisome proliferator-activated receptor γ coactivator-1α, and sirtuin 1 in muscle to regulate lipid and glucose homeostasis in these tissues. This study demonstrated that oxyresveratrol supplementation effectively ameliorated obesity-associated symptoms in high-fat diet-fed mice, presumably attributed to mediating critical regulators involved in lipid and glucose homeostasis in liver, visceral fat, and muscle.

Topics: Adipogenesis; Animals; Diet, High-Fat; Dietary Supplements; Fatty Liver; Glucose; Homeostasis; Hyperglycemia; Insulin Resistance; Intra-Abdominal Fat; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Muscles; Obesity; Plant Extracts; Stilbenes

The pathophysiology of non-alcoholic fatty liver disease remains to be elucidated, and the currently available treatments are not entirely effective. Polydatin, a stilbenoid compound derived from the rhizome of Polygonum cuspidatum, has previously been demonstrated to possess hepatoprotective effects. The present study aimed to determine the effects of polydatin supplementation on hepatic fat accumulation and injury in rats fed a high-fat diet. In addition, the mechanisms underlying the protective effects of polydatin were examined. Male Sprague Dawley rats were randomly divided into four groups and received one of four treatment regimes for 12 weeks: Control diet, control diet supplemented with polydatin, high-fat diet, or high-fat diet supplemented with polydatin. Polydatin was supplemented in the drinking water at a concentration of 0.3% (wt/vol). The results of the present study showed that long-term high-fat feeding resulted in fatty liver in rats, which was manifested by excessive hepatic neutral fat accumulation and elevated plasma alanine aminotransferase and aspartate aminotransferase levels. Polydatin supplementation alleviated the hepatic pathological changes, and attenuated the insulin resistance, as shown by an improved homeostasis model assessment of basal insulin resistance values and a glucose tolerance test. Polydatin supplementation also corrected abnormal leptin and adiponectin levels. Specifically, polydatin supplementation enhanced insulin sensitivity in the liver, as shown by improved insulin receptor substrate 2 expression levels and Akt phosphorylation in the rat liver, following high-fat diet feeding. The results of the present study suggest that polydatin protects rats against high-fat feeding-induced insulin resistance and hepatic steatosis. Polydatin may be an effective hepatoprotective agent and a potential candidate for the prevention of fatty liver disease and insulin resistance.

Topics: Adiponectin; Animals; Body Weight; Diet; Dietary Supplements; Disease Models, Animal; Fatty Liver; Gene Expression; Glucose Tolerance Test; Glucosides; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Liver; Male; Rats; Stilbenes

Resveratrol reportedly improves fatty liver. This study purposed to elucidate the effect of resveratrol on fatty liver in mice fed a high-fat (HF) diet, and to investigate the role of liver macrophages (Kupffer cells).. C57BL/6 mice were divided into three groups, receiving either a control diet, HF diet (50% fat), or HF supplemented with 0.2% resveratrol (HF + res) diet, for 8 weeks. Compared with the HF group, the HF + res group exhibited markedly attenuated fatty liver, and reduced lipid droplets (LDs) in hepatocytes. Proteomic analysis demonstrated that the most downregulated protein in the livers of the HF + res group was adipose differentiation-related protein (ADFP), which is a major constituent of LDs and reflects lipid accumulation in cells. The HF + res group exhibited greatly increased numbers of CD68(+) Kupffer cells with phagocytic activity. Immunohistochemistry showed that several CD68(+) Kupffer cells were colocalized with ADFP immunoreaction in the HF + res group. Additionally, the HF + res group demonstrated markedly decreased TNF-alpha production, which confirmed by both liver mononuclear cells stimulated by LPS in vitro and in situ hybridization analysis, compared with the HF group.. Resveratrol ameliorated fatty liver and increased CD68-positive Kupffer cells with downregulating ADFP expression.

Topics: Adipose Tissue; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Diet, High-Fat; Down-Regulation; Fatty Liver; Kupffer Cells; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Organ Size; Perilipin-2; Proteomics; Resveratrol; Stilbenes; Triglycerides; Tumor Necrosis Factor-alpha

Alcoholic and nonalcoholic fatty liver disease (ALD and NAFLD) are the predominant causes of liver-related mortality in Western countries. We have shown that limiting classical (M1) Kupffer cell (KC) polarization reduces alcohol-induced liver injury. Herein, we investigated whether favoring alternatively activated M2 KCs may protect against ALD and NAFLD. Ongoing alcohol drinkers and morbidly obese patients, with minimal hepatic injury and steatosis, displayed higher hepatic expression of M2 genes, as compared to patients with more severe liver lesions; individuals with limited liver lesions showed negligible hepatocyte apoptosis but significant macrophage apoptosis. Experiments in mouse models of ALD or NAFLD further showed that BALB/c or resveratrol-treated mice fed alcohol or a high-fat diet displayed preponderant M2 KC polarization, M1 KC apoptosis, and resistance to hepatocyte steatosis and apoptosis, as compared to control C57BL6/J mice. In vitro experiments in isolated KC, peritoneal, and Raw264.7 macrophages demonstrated that M1 macrophage apoptosis was promoted by conditioned medium from macrophages polarized into an M2 phenotype by either interleukin (IL)4, resveratrol, or adiponectin. Mechanistically, IL10 released from M2 cells promoted M1 death, and anti-IL10 antibodies blunted the proapoptic effects of M2-conditioned media. IL10 secreted by M2 KCs promoted selective M1 death by a mechanism involving activation of arginase in high inducible nitric oxide synthase-expressing M1 KCs. In alcohol-exposed mice, neutralization of IL10 impaired M1 apoptosis.. These data uncover a novel mechanism regulating the M1/M2 balance that relies on apoptotic effects of M2 KCs towards their M1 counterparts. They suggest that promoting M2-induced M1 KC apoptosis might prove a relevant strategy to limit alcohol- and high fat-induced inflammation and hepatocyte injury.

Topics: Adult; Animals; Apoptosis; Arginase; Biomarkers; Diet, High-Fat; Enzyme Activation; Ethanol; Fatty Liver; Female; Humans; Interleukin-10; Kupffer Cells; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Obesity, Morbid; Paracrine Communication; Resveratrol; Stilbenes

In this study, we aimed to investigate the therapeutic effects and involved mechanisms of resveratrol on an established non-alcoholic fatty liver disease (NAFLD) murine model. Wild-type and autophagic mediator ULK1 heterozygous knockout mice were induced to have NAFLD by high-fat diet for 8weeks. After that, resveratrol treatment was applied with the high-fat diet feeding for another 4weeks. Typical features of NAFLD, including histological changes, fibrosis, insulin resistance, oxidative status, and inflammation were characterized. After-treatment with resveratrol showed ameliorative effects on all measured features of NAFLD, from histology, insulin resistance, glucose tolerance to oxidative stress and inflammation. resveratrol treatment also reduced the activity of nuclear factor-κB (NF-κB) through the restoration of its inhibitor IκBα. Partial inhibition of ULK1 expression impaired the ameliorative effects of resveratrol on hepatic histology, fibrosis, oxidative status, inflammation, and NF-κB activity. In conclusion, resveratrol improved NAFLD-caused hepatic injury partially through regulating autophagic and IκBα-NF-κB pathways.

Topics: Animals; Autophagy; Diet, High-Fat; Disease Models, Animal; DNA Primers; Fatty Liver; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Polymerase Chain Reaction; Resveratrol; Stilbenes

Raw and processed Polygoni Multiflori Radix (PMR and PMRP) are used in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD), hyperlipidemia or related diseases. In our previous research, 2, 3, 5, 4'-tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) displayed the most important role in the total cholesterol (TC) lowering effect among all the chemical constituents of Polygonum multiflorum. Emodin and physcion displayed more favorable triglyceride (TG) reducing effects than TSG. However, there are few researches focus on the approach and mechanism of how do Polygonum multiflorum exhibit good lipid regulation activity. The targeted sites of active substances of Polygonum multiflorum are still not clearly elucidated. This research pays close attention to how major chemical components of Polygonum multiflorum affect the TC and TG contents in liver cells.. In this research, a sensitive, accurate and rapid in vitro model, steatosis hepatic L02 cell, was used to explore target sites of active chemical substances of Polygonum multiflorum for 48h. Steatosis hepatic L02 cell was exposed to emodin, physcion and TSG, respectively. The contents of four key enzymes in the pathway of synthesis and decomposition of TC and TG were investigated after exposure. Meanwhile, the contents of lipid transfer protein were also tested. The diacylgycerol acyltransferase 1 (DGAT1) controlled the biosynthesis of TG from free fatty acids while 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) limited the biosynthesis of TC. Hepatic triglyceride lipase (HTGL) and cholesterol 7α-hydroxylase (CYP7A) played the key role in the lipolysis procedure of TG and TC.. The synthesis of TC and TG in steatosis L02 cells were apparently increased in the model group compared to the control group. Intracellular contents of HMG-CoA reductase and DGAT1 increased 32.33% and 56.52%, while contents of CYP7A and HTGL decreased 21.61% and 47.37%. Emodin, physcion and TSG all showed down-regulation effects on HMG-CoA reductase, while up-regulation effects on CYP7A. The most remarkable effect on HMG-CoA reductase was found on emodin. Emodin could reduce the DGAT1 content from 438.44 ± 4.51 pg/mL in model group to 192.55 ± 9.85 pg/mL (100 μm). The content of HTGL in 300 μm physcion group was 3.15 ± 0.15 U/mL, which was more significantly effective than the control, lovastatin and fenofibrate group.. TSG could raise the content of CYP7A and then promote the lipolysis of cholesterol. Moreover, TSG also showed the best LDL-reducing effect. Emodin could inhibit HMG-CoA reductase and DGAT1, which were key enzymes in the synthesis of TC and TG. Physcion increased the content of HTGL, and then could boost the lipolysis of triglyceride. At the same time, physcion showed the best VLDL-reducing effect. In view of the above conclusions, we contributed the lipid regulation activity to an overall synergy of TSG, emodin and physcion.

Topics: Cell Line; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Diacylglycerol O-Acyltransferase; Emodin; Fatty Liver; Glucosides; Humans; Hydroxymethylglutaryl CoA Reductases; Plant Roots; Polygonum; Stilbenes; Triglycerides

Oxaliplatin (OXA) is a platinum compound widely used in the treatment of some solid tumors, especially colorectal cancer. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug, and until now, there is no suitable treatment. Chemotherapy with oxaliplatin also increases the rate of developing hepatic damages with inflammatory activity, termed chemotherapy-associated steatohepatitis (CASH). In the present study, we aimed to compare the effects of a series of antioxidant compounds on simultaneous development of oxaliplatin-induced hepato- and neurotoxicity in mice. Mice BALB/c were treated with oxaliplatin for 6 weeks, 10 mg/kg, intraperitoneally, resulting in mechanical allodynia and hepatic steatosis. We administered the following antioxidant compounds--rutin (RT) (20 mg/kg), resveratrol (RVS) (100 mg/kg), quercetin (QT) (20 mg/kg), and quercetin nanoemulsion (NQT) (20 mg/kg)--daily by gavage to BALB/c, and N-acetylcysteine (NAC) was used as positive control. Treatments with RSV, RUT, or NQT were able to prevent mechanical allodynia when compared to the OXA group, and this effect was associated with decreased c-Fos immunopositivity in the lumbar spinal cord. Regarding the effects on steatohepatitis, RVS, QT, and NQT almost completely reversed the mean liver weight increase induced by OXA. In accordance with these previous data, histological evaluation indicated attenuation of all features of hepatic steatosis evaluated in RSV, RUT, QT, and NQT groups. These compounds were able to reduce the immunopositivity for the apoptosis marker caspase-3. On the other hand, only QT and NQT treatments were able to reduce neutrophil migration measured by myeloperoxidase (MPO) activity. These results suggest that the compounds tested, RSV, RUT, QT, and NQT, would be useful for the clinical treatment of neuro- and hepatoxicity induced by oxaliplatin.

Topics: Alanine Transaminase; Animals; Antineoplastic Agents; Aspartate Aminotransferases; Caspase 3; Emulsions; Fatty Liver; Hyperalgesia; Lumbar Vertebrae; Male; Mice, Inbred BALB C; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Peroxidase; Proto-Oncogene Proteins c-fos; Quercetin; Resveratrol; Rutin; Spinal Cord; Stilbenes

Rhapontin was purified from a methanol extract from the roots of Rheum undulatum, and rhapontigenin was produced by an enzymatic transformation of rhapontin. Rats were fed a high-cholesterol diet to induce hyperlipidemia, followed by oral treatment with rhapontin or rhapontigenin (1-5 mg/kg/day). Rhapontin and rhapontigenin treatment resulted in a significant (p<0.05) dose-dependent decrease in the serum lipid level, while the high-density lipoprotein cholesterol level increased slightly compared with the experimental control. Furthermore, rhapontin and rhapontigenin treatment improved the pathological characteristics of the degenerating fatty liver in high-cholesterol diet-induced hyperlipidemic rats dose-dependently. Aspartate aminotransferase and alanine aminotransferase levels in rhapontin- and rhapontigenin-treated hyperlipidemic rats were not significantly different from those in the control. These results indicate that rhapontin and rhapontigenin can be used as potent antihyperlipidemic agents.

Topics: Animals; Cholesterol; Fatty Liver; Hyperlipidemias; Hypolipidemic Agents; Plant Extracts; Rats; Rats, Sprague-Dawley; Rheum; Stilbenes; Triglycerides

This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is a mixture of major components of GO. Mice were fed a normal diet with RS (0.005% resveratrol and 0.02% schizandrin in diet, w/w) or GO (0.3% grape pomace ethanol extract and 0.05% omija fruit ethanol extract in diet, w/w) for seven weeks. RS and GO not only lowered the levels of blood and plasma glucose, HbA1c, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) with a simultaneous decrease in hepatic gluconeogenic enzymes activities and adiposity, but also improved preservation of the pancreatic β-cells. Plasma leptin and resistin levels were lower while the plasma adiponectin level was higher in the RS and GO groups than in the control group. Especially, GO increased hepatic glucokinase activity and gene expression and improved hepatic steatosis by elevating fatty acid oxidation compared to RS. These findings suggest that GO ameliorates hyperglycemia, adiposity and hepatic steatosis in type 2 diabetic mice.

Topics: Adiponectin; Adiposity; Animals; Biomarkers; Blood Glucose; Cyclooctanes; Diabetes Mellitus, Experimental; Fatty Liver; Fruit; Glycated Hemoglobin; Hyperglycemia; Insulin; Leptin; Lignans; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Plant Extracts; Polycyclic Compounds; Resistin; Resveratrol; Schisandra; Stilbenes; Vitis

Liver X receptor (LXR) has been identified as a potential target for treatment of atherosclerosis and diabetes. Activation of LXR, however, is associated with increased lipogenesis and fat accumulation in the liver. The objective of the current study was to examine the effect of resveratrol on LXR activator-induced fat accumulation in liver using mice as an animal model. Three groups of C57BL/6 mice were studied. Animals in group 1 were treated with T0901317, a potent activator of LXR in mice. Animals in group 2 served as the control and were treated with carrier solution and those in group 3 were treated with T0901317/resveratrol combination. Using histochemical and biochemical methods, we demonstrate that resveratrol treatment significantly suppressed fat accumulation in the liver induced by T0901317. In addition, resveratrol completely blocked elevation of blood levels of triglyceride and cholesterol and reduced blood glucose level. Quantitative PCR analysis revealed that resveratrol treatment did not change the mRNA levels of abca1, abcg1, cyp7a1, srebp-1c, chrebp, and acc genes compared to that of animals treated with T0901317 alone but reduced pepck and g6p gene expressions. Immunohistochemistry and Western blot analyses show resveratrol treatment activated AMP-activated protein kinase (AMPK) and increased phosphorylation of acetyl-CoA carboxylase. Treatment with T0901317 on hepatocytes increased intracellular fat accumulation and this increase was suppressed by resveratrol; the suppressive effect of resveratrol was greatly repressed by Compound C which is an inhibitor of AMPK. Collectively, these data suggest that resveratrol blocks T0901317-induced lipid accumulation in the liver and can be considered for inclusion into the treatment of diseases involving activation of liver X receptor.

Topics: Animals; Cells, Cultured; Fatty Liver; Hepatocytes; Hydrocarbons, Fluorinated; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Resveratrol; Stilbenes; Sulfonamides

In this work, beneficial effects of melatonin and resveratrol drugs on liver damage in rats, induced by application of acute and chronic carbon tetrachloride (CCl4) have been examined. The study consists of three main stages: (1) DATA ACQUISITION: light microscopic images were obtained from 60 rats separated into 10 groups after the preparation of liver tissue samples for histological examination. Rats in first five experimental groups for the four-day and the other five groups for twenty-day were examined. (2) Data processing: by the help of histograms of oriented gradient (HOG) method, obtaining low-dimensional image features (color, shape and texture) and classifying five different group characteristics by using these features with artificial neural networks (ANNs), and support vector machines (SVMs) have been provided. (3) Calculation of drug effectiveness: firstly to determine the differences between group characteristics of rats, a pilot group has been selected (diseased group-CCl4), and the responses of ANN and SVM trained by HOG features have been calculated. As a result of ANN, it has been seen that melatonin and resveratrol drugs have %65.62-%75.12 positive effects at the end of the fourth day, %84.12-%98.89 positive effects on healing steatosis hepatis at the end of the twentieth day respectively and as a result of SVM, it has been seen that melatonin and resveratrol drugs have %62.5-%68.75 positive effects at the end of the fourth day, %45.12-%60.89 positive effects on healing steatosis hepatis at the end of the twentieth day respectively.

Topics: Algorithms; Animals; Computer Systems; Fatty Liver; Humans; Image Processing, Computer-Assisted; Liver; Male; Melatonin; Neural Networks, Computer; Rats; Rats, Sprague-Dawley; Resveratrol; Software; Stilbenes; Support Vector Machine

Autophagy is a lysosomal degradation process that degrades long-lived cellular proteins and damaged organelles as a critical cell survival mechanism in response to stress. We recently reported that acute ethanol induces autophagy, which then reduces ethanol-induced liver injury. However, the mechanisms by which ethanol induces autophagy are not known. In the present study, ethanol treatment significantly increased both mRNA and protein levels of various essential autophagy-related genes in primary cultured mouse hepatocytes and in mouse liver. Both nuclear translocation of FoxO3a and expression of FoxO3a target genes were increased in ethanol-treated primary hepatocytes and mouse liver. Overexpression of a dominant negative form of FoxO3a inhibited ethanol-induced autophagy-related gene expression and enhanced ethanol-induced cell death in primary hepatocytes, which suggests that FoxO3a is a key factor in regulating ethanol-induced autophagy and cell survival. Resveratrol, a well-known SIRT1 agonist, further enhanced ethanol-induced expression of autophagy-related genes, likely via increased deacetylation of FoxO3a. Moreover, acute ethanol-treated Foxo3a(-/-) mice exhibited decreased autophagy-related gene expression, but enhanced steatosis and liver injury, compared with wild-type mice. FoxO3a thus plays a critical role in ethanol-induced autophagy in mouse liver. Modulating the FoxO3a autophagy pathway may offer novel therapeutic approaches for treating alcoholic liver pathogenesis.

Topics: Animals; Autophagy; Central Nervous System Depressants; Enzyme Inhibitors; Ethanol; Fatty Liver; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation; Hepatocytes; Liver; Liver Diseases, Alcoholic; Mice; Mice, Knockout; Resveratrol; Sirtuin 1; Stilbenes

We hypothesized that resveratrol, a natural phytoalexin found in grapes, can prevent oxidative stress, obesity and its related disturbances in obese rats programmed by early weaning. Lactating Wistar rats were separated into two groups: early weaning (EW) - dams who were wrapped with a bandage to interrupt the lactation in the last 3 days of lactation; control - dams whose pups had free access to milk during all lactation. At the 150th day, EW offspring were randomly subdivided into EW+resveratrol (EW+Res) - resveratrol (30 mg/kg/day); EW+vehicle (EW) - rats that received 0.5% (w/v) aqueous methylcellulose. The control group received vehicle. Rats were treated by gavage daily for 30 days. EW offspring developed hyperphagia, higher body weight, visceral obesity, higher systolic (SBP) and diastolic blood pressure (DBP) (+15% and +20%, respectively; P<.05) and higher serum triglycerides (TG) and low-density lipoprotein but lower high-density lipoprotein (+55%, +33% and -13%, respectively; P<.05). Resveratrol normalized food intake, SBP and DBP and prevented obesity and dyslipidemia in EW+Res. EW rats had higher plasma and liver thiobarbituric-acid-reactive substances (TBARS) and lower plasma superoxide dismutase (SOD) and liver glutathione peroxidase activities (+51%, +18%, -58%, -31%, respectively; P<.05), and resveratrol normalized both plasma and liver TBARS and increased the activity of SOD and catalase in plasma. EW rats presented liver steatosis and higher liver TG, and resveratrol prevented these hepatic alterations. In conclusion, this study demonstrated a potential therapeutic use of resveratrol in preventing obesity and oxidative stress and reducing the risk of hypertension, dyslipidemia and steatosis in adult rats programmed by early weaning.

Topics: Animals; Antioxidants; Blood Glucose; Dyslipidemias; Fatty Liver; Female; Glutathione Peroxidase; Hyperphagia; Hypertension; Insulin Resistance; Liver; Obesity; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Weaning

Lipid metabolic disorders are widely considered to be one of the most critical and basic link in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to illustrate the alleviation function of resveratrol (Res) on NAFLD and the roles of hepatic fatty acid synthase (FAS), low density lipoprotein receptor (LDLr), scavenger receptor class B type I (SR-BI), and thyroid hormone receptor β1 (TRβ1), which are the key molecules involved in lipid metabolism. Adult male Wistar rats were fed a normal diet or high fat/sucrose diet (HFS) with or without resveratrol for 13 weeks. HFS induced NAFLD formation and increased the lipids concentrations in serum and livers of rats, while noticeable improvement has been reached by Res intervention. Moreover, Res protected against HFS-induced decrease in hepatic LDLr and SR-BI mRNA and protein expressions, whereas TRβ1 expressions were impervious with/without Res. Unexpectedly, hepatic FAS gene expressions were markedly diminished in NAFLD rats and were gradually increased by treatment with Res. These data indicate that the alleviative effects of Res on NAFLD are associated with up regulation of hepatic LDLr and SR-BI gene expressions, which provide new insights into the pharmacological targets of Res in the prevention of NAFLD.

Topics: Animals; Energy Metabolism; fas Receptor; Fatty Liver; Gene Expression; Lipid Metabolism; Male; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Receptors, LDL; Resveratrol; Scavenger Receptors, Class B; Stilbenes; Thyroid Hormone Receptors beta; Weight Gain

Non-alcoholic fatty liver disease (NAFLD) is one of the most common manifestations of chronic liver disease worldwide. The aim of the present study was to assess the effect of resveratrol on liver fat accumulation, as well as on the activity of those enzymes involved in lipogenesis and fatty acid oxidation in fa/fa Zucker rats. A total of thirty rats were assigned to three experimental groups and orally treated with resveratrol for 6 weeks, or without resveratrol (C: control group; RSV15 group: 15 mg/kg body weight per d; RSV45 group: 45 mg/kg body weight per d). Liver histological analysis was performed by microscopy. Levels of hepatic carnitine palmitoyltransferase-Ia (CPT-Ia), acyl-coenzyme A oxidase (ACO), fatty acid synthase, glucose-6-phosphate dehydrogenase and malic enzyme were assessed by spectrophotometry, and acetyl-CoA carboxylase was assessed by radiometry. Commercial kits were used to determine serum TAG, NEFA, total HDL and non-HDL-cholesterol, glycerol, ketonic bodies, glucose, insulin, adiponectin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), hepatic TAG, thiobarbituric acid reactive substrates, GSH (GSSG) and superoxide dismutase. Resveratrol reduced liver weight and TAG content. It did not modify the activity of lipogenic enzymes but it did increase CPT-Ia and ACO activities. NEFA and ALP were reduced in both resveratrol-treated groups. AST/GOT was reduced only by the lowest dose. ALT/GPT, TAG and adiponectin remained unchanged. Resveratrol reduced liver oxidative stress. This study demonstrates that resveratrol can protect the liver from NAFLD by reducing fatty acid availability. Moreover, resveratrol also protects liver from oxidative stress.

Topics: Acyl-CoA Oxidase; Animals; Antioxidants; Carnitine O-Palmitoyltransferase; Dose-Response Relationship, Drug; Fatty Acids; Fatty Liver; Isoenzymes; Lipid Metabolism; Lipids; Liver; Male; Obesity; Organ Size; Oxidative Stress; Random Allocation; Rats; Rats, Zucker; Resveratrol; Stilbenes; Up-Regulation

Obesity-induced diabetes is associated with chronic inflammation and is considered a risk factor for neurodegeneration. We tested the hypothesis that an AMP-activated protein kinase activator, resveratrol (RES), which is known to exert potent anti-inflammatory effects, would attenuate peripheral and central inflammation and improve memory deficit in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD or an HFD supplemented with RES for 20 weeks. Metabolic parameters in serum were evaluated, and Western blot analysis and immunohistochemistry in peripheral organs and brain were completed. We used the Morris water maze test to study the role of RES on memory function in HFD-treated mice. RES treatment reduced hepatic steatosis, macrophage infiltration, and insulin resistance in HFD-fed mice. In the hippocampus of HFD-fed mice, the protein levels of tumor necrosis factor-α and Iba-1 expression were reduced by RES treatment. Choline acetyltransferase was increased, and the phosphorylation of tau was decreased in the hippocampus of HFD-fed mice upon RES treatment. In particular, we found that RES significantly improved memory deficit in HFD-fed mice. These findings indicate that RES reverses obesity-related peripheral and central inflammation and metabolic derangements and improves memory deficit in HFD-fed diabetic mice.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diet, High-Fat; Fatty Liver; Glucose Tolerance Test; Inflammation; Insulin Resistance; Male; Maze Learning; Memory Disorders; Mice; Obesity; Resveratrol; Stilbenes

Consumption of a high-fat diet (HFD) enriched in saturated fat induces excessive weight gain due to adiposity, which can lead to metabolic complications, as well as increased risk of fatty liver disease and CVD. The present study investigated the underlying mechanism and dose-response effects of resveratrol (RV) on obesity, hepatic steatosis and dyslipidaemia in mice fed a HFD. Male C57BL/6J mice were fed a normal diet or a HFD (20 % fat, w/w) combined with 0·005 or 0·02 % (w/w) RV for 10 weeks. As expected, mice fed a HFD developed obesity, as shown by increased body weight gain, visceral fat, hepatic fat and plasma cholesterol. RV significantly reduced visceral fat and plasma NEFA. In the liver of HFD-fed mice, RV significantly reduced TAG and cholesterol, as well as lipid droplet number and size. A low dose of RV (0·005 %) appeared to be more effective than a higher dose of RV (0·02 %) for suppressing adiposity and hepatic steatosis development with a significant decrease in body weight gain, plasma TAG and total cholesterol levels. These changes were seemingly attributable to a suppression of the fatty acid (FA) synthase, glucose-6-phosphate dehydrogenase, and phosphatidate phosphohydrolase and/or an activation of FA oxidation in the liver and epididymal adipose tissue. In conclusion, daily consumption of a low dose of RV is effective for protecting against diet-induced obesity, hepatic steatosis and dyslipidaemia in HFD-fed mice.

Topics: Adiposity; Animals; Cholesterol; Diet; Diet, High-Fat; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fatty Acid Synthases; Fatty Liver; Glucosephosphate Dehydrogenase; Hyperlipidemias; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Phosphatidate Phosphatase; Resveratrol; Stilbenes; Triglycerides; Weight Gain

Resveratrol is a natural polyphenol that has beneficial effects across species and various disease models. Here, we investigate whether resveratrol is effective against hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) using HBV X protein (HBx) transgenic mice. We found that resveratrol (30 mg/kg/d) has a therapeutic effect on HBx-induced fatty liver and the early stages of liver damage. Resveratrol decreased intracellular reactive oxygen species and transiently stimulated hepatocyte proliferation. Interestingly, resveratrol inhibited LXRα and downregulated the expression of the lipogenic genes, Srebp1-c and PPARγ. The decrease in Srebp1-c seems to further downregulate the expression of its target genes, Acc and Fas. In addition, resveratrol stimulated the activity of Ampk and SirT1. Thus, resveratrol has a pleiotropic effect on HBx transgenic mice in terms of the downregulation of lipogenesis, the promotion of transient liver regeneration, and the stimulation of antioxidant activity. Furthermore, at the later precancerous stages, resveratrol delayed HBx-mediated hepatocarcinogenesis and reduced HCC incidence from 80% to 15%, a 5.3-fold reduction. Resveratrol should be considered as a potential chemopreventive agent for HBV-associated HCC.

Topics: Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; Carcinoma, Hepatocellular; Disease Models, Animal; Fatty Liver; Glutathione; Humans; Immunoenzyme Techniques; Liver Neoplasms, Experimental; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Trans-Activators; Tumor Cells, Cultured; Viral Regulatory and Accessory Proteins

The pathophysiology of non-alcoholic fatty liver disease remains incompletely elucidated, and available treatments are not entirely satisfactory. Polydatin, a stilbenoid compound derived from the rhizome of Polygonum cuspidatum, has been recognised to possess hepatoprotective and anti-inflammatory activities. The purpose of the present study was to determine whether polydatin has a protective effect against hepatic steatosis induced by a high-fat diet (HFD) and to elucidate its underlying molecular mechanisms in rats. Male Sprague-Dawley rats were randomly divided into four groups, including normal control, HFD model and polydatin-treated groups with polydatin levels of 30 and 90 mg/kg. Following the experimental period, plasma total cholesterol (TC), triglyceride (TG) and hepatic lipid concentrations were determined. To identify a possible mechanism, we examined the changes in liver tumor necrosis factor-α (TNF-α), lipid peroxidation levels and sterol-regulatory element binding protein (SREBP-1c) mRNA and its target genes. Both 30 and 90 mg/kg polydatin treatment alleviated hepatic steatosis and reduced plasma and liver TG, TC and free fatty acid (FFA) concentration significantly in HFD rats. In addition, TNF-α, and malondialdehyde and 4-hexanonenal levels were markedly suppressed by polydatin in the liver of HFD-fed rats. Polydatin also decreased the gene expression of SREBP-1c and its target genes involved in lipogenesis, including fatty acid synthase (FAS) and stearoly-CoA desaturase 1 (SCD1) in HFD-fed rats. These results suggest that the protective effects of polydatin against HFD-induced hepatic steatosis may be partly associated with reduced liver TNF-α expression, lipid peroxidation level and SREBP-1c-mediated lipogenesis.

Topics: Animals; Anti-Inflammatory Agents; Cholesterol; Diet, High-Fat; Fallopia japonica; Fatty Acid Synthases; Fatty Acids, Nonesterified; Fatty Liver; Glucosides; Lipid Peroxidation; Lipogenesis; Liver; Male; Non-alcoholic Fatty Liver Disease; Protective Agents; Rats; Rats, Sprague-Dawley; Rhizome; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Stilbenes; Triglycerides; Tumor Necrosis Factor-alpha

Dietary quercetin and resveratrol have been frequently used in treating various diseases, but the underlying mechanisms are not entirely clear. Here, we report combined transcriptomic and metabonomic profiling that showed that the combined supplementation with quercetin and resveratrol produced synergistic effects on a high-fat diet-induced metabolic phenotype in mice. Histological and phenotypic improvements in serum and hepatic total cholesterol, insulin, fasting blood glucose, and HbA1c were also observed in mice receiving combined quercetin and resveratrol supplementation. This combined quercetin and resveratrol supplementation resulted in significant restoration of gene sets in functional pathways of glucose/lipid metabolism, liver function, cardiovascular system, and inflammation/immunity, which were altered by high fat diet feeding. The integration of transcriptomic and metabonomic data indicated quercetin and resveratrol supplementation enhanced processes of glycolysis and fatty acid oxidation, as well as suppressed gluconeogenesis. These alterations discovered at both the transcriptional and metabolic levels highlight the significance of combined "omics" platforms for elucidating mechanistic pathways altered by dietary polyphenols, such as quercetin and resveratrol, in a synergistic manner.

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Cluster Analysis; Diet, High-Fat; Dietary Supplements; Drug Synergism; Drug Therapy, Combination; Fatty Liver; Gene Expression Profiling; Lipid Metabolism; Lipids; Liver; Male; Metabolome; Metabolomics; Mice; Mice, Inbred C57BL; Molecular Sequence Annotation; Oligonucleotide Array Sequence Analysis; Quercetin; Resveratrol; Stilbenes; Transcriptome

Hepatitis C virus (HCV) core protein plays an important role in the development of hepatic steatosis in patients with chronic HCV infection. Treatment of C57BL/6 mice infected with HCV core recombinant adenoviruses with resveratrol significantly decreased hepatic triacylglycerols (TAG) while the serum TAG level was unaffected. RT-PCR and Western blotting showed that HCV core protein attenuated the expression of Sirt1 and PPAR-α, which would be reversed by resveratrol. This was also confirmed in primary mouse hepatic cells infected with HCV core protein expressing adenovirus. Thus, resveratrol may prevent against hepatic steatosis by blocking the inhibited expression of Sirt1 and PPAR-α induced by HCV core protein.

Topics: Adenoviridae; Animals; Blotting, Western; Cells, Cultured; Fatty Liver; Gastrointestinal Agents; Gene Expression Profiling; Genetic Vectors; Hepacivirus; Hepatitis C, Chronic; Hepatocytes; Liver; Mice; Mice, Inbred C57BL; PPAR alpha; Recombinant Proteins; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Sirtuin 1; Stilbenes; Triglycerides; Viral Core Proteins

To investigate the effects of resveratrol on the morphology of lipid droplet (LD) and the expression of lipid droplet-associated proteins in primary hepatocytes of mice.. We isolated and cultured the primary hepatocytes of mice using collagenase perfusion. The primary hepatocytes were stimulated with 200 μmol/L oleic acid (OA) for 12 h, and then added with 0 (control), 20, 50, 100 μmol/L resveratrol, respectively. Another 12 h later, we utilized Bodipy 493/503 staining to observe the morphology and amount of intracellular lipid droplets under fluorescence microscope. The Folch method and triglyceride (TG) quantitative kit were used to extract the total intracellular lipids and determine the TG contents. Western blotting was applied to analyze the expression levels of perilipin, adipophilin and TIP-47.. Compared with the control, the size and amount of lipid droplets in primary hepatocytes were reduced after treated with different concentrations of resveratrol. The quantitative analysis showed that the intracellular TG contents decreased markedly in a dose-dependent manner, but the most significant decrease was in 50 μmol/L resveratrol group. Western blotting showed that resveratrol reduced the expressions of perilipin, adipophilin and TIP-47 in the primary hepatocytes, especially the perilipin.. Resveratrol could inhibit intracellular lipid accumulation, which is most significant in 50 μmol/L concentration. The inhibiting effect of resveratrol may be caused by mediating the expression levels of lipid droplet-associated proteins in primary hepatocytes of mice.

Topics: Animals; Carrier Proteins; Cells, Cultured; Dose-Response Relationship, Drug; Fatty Liver; Hepatocytes; Lipid Metabolism; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Perilipin-1; Perilipin-2; Phosphoproteins; Resveratrol; Stilbenes; Triglycerides

Obesity is associated with a markedly increased risk of nonalcoholic fatty liver disease. The anti-inflammatory polyphenol resveratrol possess promising properties in preventing this metabolic condition by dampening the pathological inflammatory reaction in the hepatic tissue. However, in the current study, we hypothesize that the beneficial effect of resveratrol is not solely attributable to its anti-inflammatory potential. Eight-week-old male Wistar rats were randomly distributed into 3 groups of 12 animals each: control diet (C), high-fat diet (HF), and HF supplemented with 100 mg resveratrol daily (HFR). After 8 weeks of dietary treatment, the rats were euthanized and relevant tissues were prepared for subsequent analysis. Resveratrol prevented the high fat-induced steatosis assessed by semiquantitative grading, which furthermore corresponded with a complete normalization of the hepatic triglyceride content (P < .001), despite no change in total body fat. In HFR, the hepatic uncoupling protein 2 expression was significantly increased by 76% and 298% as compared with HF and C, respectively. Moreover, the hepatic mitochondria content in HFR was significantly higher as compared with both C and HF (P < .001 and P = .004, respectively). We found no signs of hepatic inflammation, hereby demonstrating that resveratrol protects against fatty liver disease independently of its proposed anti-inflammatory potential. Our data might indicate that an increased number of mitochondria and, particularly, an increase in hepatic uncoupling protein 2 expression are involved in normalizing the hepatic fat content due to resveratrol supplementation in rodents fed a high-fat diet.

Topics: Adipose Tissue; Animals; Biomarkers; Blotting, Western; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Fatty Liver; Ion Channels; Liver; Male; Mitochondrial Proteins; Non-alcoholic Fatty Liver Disease; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resveratrol; RNA, Messenger; RNA, Ribosomal, 18S; Stilbenes; Triglycerides; Uncoupling Protein 2; Up-Regulation

Werner syndrome is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many features of Werner syndrome, including a pro-oxidant status and a shorter mean life span. Here, we show that resveratrol supplementation improved the hyperglycemia and the insulin resistance phenotype in these Wrn mutant mice. In addition, resveratrol reversed liver steatosis, lipid peroxidaton, and the defenestration phenotypes observed in such mice. Resveratrol, however, did not improve the hypertriglyceridemia, inflammatory stress, nor extend the mean life span of these mutant mice. Microarray and biologic pathway enrichment analyses on liver tissues revealed that resveratrol mainly decreased lipidogenesis and increased genes involved in the insulin signaling pathway and the glutathione metabolism in Wrn mutant mice. Finally, resveratrol-treated mutant mice exhibited an increase in the frequency of lymphoma and of several solid tumors. These results indicate that resveratrol supplementation might exert at least metabolic benefits for Werner syndrome patients.

Topics: Animals; Anticarcinogenic Agents; Disease Models, Animal; Fatty Liver; Hyperglycemia; Hypertriglyceridemia; Inflammation; Insulin Resistance; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes; Werner Syndrome

We isolated several stilbene compounds including rhaponticin (3',5-dihydroxy-4'-methoxystilbene 3- O-beta- D-glucopyranoside) from extracts of rhubarb rhizomes. These compounds showed significant hypoglycemic effects in streptozotocin (STZ)-induced type 1 diabetic rats and mice. In this study, we investigated the effect of rhaponticin on glucose utilization, lipid metabolism, and liver and heart function in a KK/Ay type 2 diabetic mouse model. The results showed that oral administration of rhaponticin (125 mg/kg) significantly reduced blood glucose levels and improved oral glucose tolerance of KK/Ay diabetic mice. Elevated plasma triglyceride (TG), low density lipoprotein (LDL), cholesterol (CHO), non-esterified free fatty acids (NEFA), and insulin levels were also markedly attenuated. Serum enzymatic activities of lactate dehydrogenase (LDH), creatine kinase (CK), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in the rhaponticin-treated group significantly decreased in comparison to the untreated model group. Livers of rhaponticin-treated mice had relatively normal cellular size and decreased fibrosis and steatosis. In addition, rhaponticin administration caused a remarkable increase in the hepatic glycogen content and a significant reduction in the hepatic triglyceride content. These results indicate that rhaponticin has a noticeable antidiabetic effect and could be potentially used as a new agent to treat type 2 diabetes mellitus and its complications.

Topics: Animals; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Enzymes; Fatty Acids, Nonesterified; Fatty Liver; Glucose Tolerance Test; Glycogen; Hypoglycemic Agents; Insulin; Lipids; Lipoproteins, LDL; Liver; Mice; Rheum; Rhizome; Stilbenes; Triglycerides

Recent studies in mice have shown that resveratrol can protect the liver from fat accumulation induced by high fat diet. However, the exact mechanism is largely unknown. To explore the possible mechanism, we investigated the anti-lipogenic effect of resveratrol in vitro model. Oil Red O staining revealed that resveratrol could significantly ameliorate the excessive triglyceride accumulation in HepG2 cells induced by palmitate. The results of RT-PCR and Western blotting showed that resveratrol upregulated the expression of Sirt1 and forkhead box O1 (FOXO1), whereas downregulated the expression of sterol regulatory element binding protein1 (SREBP1). Moreover, resveratrol was shown to inhibit the activity of SREBP1, as evaluated by immunofluorescence assay. Our results suggest that resveratrol may attenuate fat deposition by inhibiting SREBP1 expression via Sirt1-FOXO1 pathway and thus may have application for the treatment of NAFLD.

Topics: Animals; Caloric Restriction; Cell Line, Tumor; Cell Survival; Fatty Liver; Forkhead Box Protein O1; Forkhead Transcription Factors; Humans; Hypolipidemic Agents; Mice; Models, Biological; Palmitic Acid; Resveratrol; Signal Transduction; Sirtuin 1; Sirtuins; Sterol Regulatory Element Binding Protein 1; Stilbenes; Triglycerides

The activation of aryl hydrocarbon receptor with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to be antagonized by co-treatment with resveratrol. However, such a protective effect has been suggested from studies using subcutaneous injection of this polyphenol. To evaluate the practical usefulness of resveratrol, this study examined the protective effect of oral resveratrol on the sub-acute toxic effects of TCDD in C57BL/6J mice. A TCDD-induced wasting syndrome was not alleviated by treating mice for 28 d with oral resveratrol. However, subcutaneous injection of resveratrol for 5 d significantly improved the symptoms. Neither oral nor subcutaneous administration of resveratrol alleviated TCDD-induced hepatomegaly and thymic atrophy. Steatosis produced by TCDD was markedly counteracted by co-treatment with oral resveratrol, whereas resveratrol injected subcutaneously had no effect. The reason for the lack of protective effect via the latter dosing route was assumed to be due to the minor accumulation of hepatic lipids 5 d after TCDD treatment. To clarify the mechanisms, the activity of ethoxyresorufin O-deethylase and the content of thiobarbituric acid-reactive substances in the liver were measured. Both indices increased by TCDD treatment were significantly suppressed by subcutaneous injection of resveratrol. In contrast, oral resveratrol failed to rescue them. In agreement with the greater protective effects of subcutaneously-injected resveratrol, pharmacokinetic studies indicated that the area under the curve extrapolated to infinity (AUC(infinity)) was 8.2-times greater following subcutaneous injection compared with oral administration. These data suggest that 1) oral resveratrol is attractive candidate as an agent capable of combating dioxin toxicity and 2) increasing the bioavailability of this polyphenol enhances its protective effect.

Topics: Administration, Oral; Animals; Antioxidants; Biological Availability; Fatty Liver; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Resveratrol; Stilbenes; Toxicity Tests; Wasting Syndrome

To study the effect of resveratrol on the nonalcoholic fatty liver (NAFL).. Thirty Wistar rats were allocated into three groups (10 for each): a normal control group (NC, fed with standard chow), a high fat feeding group (HF, fed with a high fat diet) and a resveratrol treated group (RT). The RT rats were fed a high fat diet all the time (as the HF) and received resveratrol administration (100 mg . kg-1. d-1) started on the 6th week of the experiment. The experiment lasted for 16 weeks. Then all the rats were sacrificed and hyperinsulinemic-euglycemic clamp was performed to evaluate insulin sensitivity. Liver histology was studied by HE stained microscopic preparations of the livers. Phosphorylation of AMP-activated protein kinase (AMPK) levels were determined by Western blot.. Compared to the NC, visceral fat index and liver mass index was lower and fasting serum insulin (FINS) was higher and glucose infusion rate (GIR) was lower in the HF (t=10.554, P less than 0.01). Severe liver steatosis was observed microscopically in the HF. In addition, phosphorylation of AMPK levels in the HF was 45.8% lower than that of the NC (t=8.384, P less than 0.01). Compared with the HF, the visceral fat index, liver mass index, FINS and GIR were all much lower, and the liver steatosis was milder than those in the RT. Further phosphorylation of AMPK seen was 70.2% higher in RT compared with that in the NC (t=3.816, P less than 0.01).. Resveratrol administration improved high-fat feeding induced insulin resistance and fatty liver by activating AMPK.

Topics: AMP-Activated Protein Kinases; Animals; Fatty Liver; Insulin Resistance; Male; Phytotherapy; Rats; Rats, Wistar; Resveratrol; Stilbenes

The prevalence of nonalcoholic fatty liver disease (NAFLD) is high. NAFLD is linked to obesity, diabetes mellitus, and hypertriglyceridemia. Approximately 20% of patients with NAFLD will eventually develop cirrhosis. Our purpose was to investigate whether resveratrol decreased hepatic steatosis in an animal model of steatosis, and whether this therapeutic approach resulted in a decrease in tumor necrosis factor alpha (TNF-alpha) production, lipid peroxidation and oxidative stress.. Male Wistar CRL: Wi (Han) (225 g) rats were randomized into three groups. A control group (n = 12) was given free access to regular dry rat chow for 4 weeks. The steatosis (n = 12) and resveratrol (n = 12) groups were given free access to feed (a high carbohydrate-fat free modified diet) and water 4 days per week, and fasted for the remaining 3 days for 4 weeks. Rats in the resveratrol group were given resveratrol 10 mg daily by the oral route. All rats were killed at 4 weeks and assessed for fatty infiltration and bacterial translocation. Levels of TNF-alpha in serum, hepatic malondialdehyde (MDA), oxidative stress (superoxide dismutase, glutathione peroxidase, catalase and nitric oxide synthase) and biochemical parameters were measured.. Fat deposition was decreased in the resveratrol group as compared to the steatosis group (Grade 1 vs Grade 3, P < 0.05). TNF-alpha and MDA levels were significantly increased in the steatosis group (TNF-alpha; 33.4 +/- 5.2 vs 26.24 +/- 3.47 pg/ml and MDA; 9.08 +/- 0.8 vs 3.17 +/- 1.45 muM respectively, P < 0.05). This was accompanied by increased superoxide dismutase, glutathione peroxidase and catalase and decreased nitric oxide synthase in the liver of resveratrol group significantly (P < 0.05 vs steatosis group). Bacterial translocation was not found in any of the groups. Glucose levels were decreased in the group of rats given resveratrol (P < 0.05).. Resveratrol decreased NAFLD severity in rats. This effect was mediated, at least in part, by TNF-alpha inhibition and antioxidant activities.

Topics: Animals; Antioxidants; Catalase; Disease Models, Animal; Fatty Liver; Glucose; Glutathione Peroxidase; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide Synthase; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Resveratrol; Severity of Illness Index; Stilbenes; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Resveratrol, a polyphenolic activator of the silent information regulation 2 homolog 1 (SIRT1), is known to extend lifespan and improve metabolic disease. The aim of the present study is to test whether resveratrol protects against metabolic steatohepatitis through the modulation of lipid metabolism-related genes.. We used a mouse model in which steatohepatitis can be induced by an atherogenic diet (Ath diet) to evaluate the effects of resveratrol on steatotic hepatitis and hepatic gene expression.. The Ath diet induced excessive weight gain, hepatomegaly, dyslipidemia, and steatohepatitis after 8 weeks. The addition of resveratrol protected against Ath diet-induced changes and also alleviated steatohepatitis. Whole-genome expression analysis revealed that an Ath diet altered the hepatic expression of genes involved in lipid metabolism, and the addition of resveratrol to the diet reversed that effect. Real-time PCR and Western blot analysis confirmed the Ath diet up-regulated the levels of genes related to lipogenesis and down-regulated genes involved in lipolysis. Resveratrol clearly suppressed the Ath diet-induced alterations of the expression of genes related to lipid metabolism.. Resveratrol ameliorated dyslipidemia and steatohepatitis induced by the Ath diet, and its beneficial effects were associated with the altered expression of hepatic genes involved in lipid metabolism.

Topics: Animals; Antioxidants; Body Weight; Diet, Atherogenic; Eating; Fatty Liver; Gene Expression; Lipid Metabolism; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Organ Size; Resveratrol; Stilbenes

To investigate whether resveratrol (RSV) can improve non-alcoholic fatty liver disease (NAFLD) and to find the possible mechanism.. Rats fed a high-fat diet were treated with RSV. The liver histology was observed. Hyperinsulinemic euglycemic clamp was performed to assess insulin sensitivity. Fat accumulation was induced in HepG2 cells, and the cells were treated with RSV. AMP-activated protein kinase (AMPK) phosphorylation levels were determined both in the animal study and cell study.. Rats fed a high-fat diet developed abdominal obesity, NAFLD, and insulin resistance (IR), which were markedly improved by 10 weeks of RSV administration. RSV treatment prevented triacylglycerol (TG) accumulation in HepG2 cells that were incubated with high concentration of glucose and insulin. Both in vivo and in vitro studies showed that RSV treatment could promote the phosphorylation of AMPK, which in this study, suppressed 2 lipogenesis gene expressions, contributing to the improvement of NAFLD and IR.. The results indicated that by reducing TG accumulation and improving IR, RSV could protect the liver from NAFLD. The activation of AMPK was involved in the mechanism. RSV has the therapeutic potential for preventing or treating NAFLD and IR-related metabolic disorders.

Topics: Animals; Antioxidants; Cyclic AMP-Dependent Protein Kinases; Diet; Enzyme Activation; Fatty Liver; Glucose Clamp Technique; Humans; Hyperinsulinism; Liver; Male; Rats; Resveratrol; Stilbenes; Triglycerides