Effect of resveratrol on experimental non‐alcoholic fatty liver disease depends on severity of pathology and timing of treatment

Heebøll, Sara; El-Houri, Rime Bahij; Hellberg, Ylva; Haldrup, David; Pedersen, Steen B.; Jessen, Niels; Christensen, Lars Porskjær; Grønbæk, Henning

doi:10.1111/jgh.13151

Cited by 20 publications

(13 citation statements)

References 41 publications

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“…Therefore, our observations support the work of Bhardwaj et al . RSV concentrations used in our in vitro study were much higher than those of clinical studies 20 21 22 . However, the suppressive effect of 5 μM RSV on STAT3 activation and CD14 expression appeared very weak (even though significant suppression by 5 μM RSV was observed).…”

Section: Discussionmentioning

confidence: 67%

“…RSV inhibited protein levels of p-STAT3 and CD14 mRNA in a dose-dependent manner. Significant inhibition of the p-STAT3:STAT ratio (a marker of STAT3 activation) and expression of CD14 mRNA was observed at RSV concentrations >5 μM, which is a very high concentration compared with systemic RSV concentrations documented in clinical studies (C max < 4 μM, C mean ≪ 1 μM) 20 21 22 .…”

Section: Resultsmentioning

confidence: 85%

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Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis

Kessoku

Imajo

Honda

et al. 2016

Sci Rep

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The natural polyphenol compound resveratrol (RSV) is considered to have a broad spectrum of beneficial biological activities upon human health. However, the exact effect of RSV on steatosis (a phenotype of non-alcoholic fatty liver [NAFL]) or fibrosis and inflammation (major phenotypes of non-alcoholic steatohepatitis [NASH]) is not known. Our data showed that administration of RSV (2 or 20 mg/kg/day) did not suppress steatosis in a high-fat diet-induced model of NAFL in mice. In contrast, identical concentrations of RSV dramatically inhibited inflammation and fibrosis in a low-dose lipopolysaccharide-induced model of NASH. These data suggested that RSV administration-mediated improvement of inflammation and fibrosis was due to the inhibition of LPS reactivity controlled by CD14 expression in Kupffer cells. These findings suggest that RSV could be a candidate agent for the treatment of NASH.

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Section: Discussionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 85%

Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis

Kessoku

Imajo

Honda

et al. 2016

Sci Rep

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“…For example, high dietary resveratrol intake (400 mg/kg bw) for 15 weeks significantly suppressed the body weight gain and fat accumulation in HFD-fed mice [ 19 ]. However, treated with resveratrol (400 mg/kg bw) for 8-week was observed to have a weak protective effect on the hepatic steatosis in HFD-fed Wistar rats [ 38 ]. Moreover, resveratrol (100 mg/rat/day) treatment for 8 weeks had no consistent therapeutic effect in alleviating manifest experimental steatohepatitis in HFD-fed rats [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats

Ding¹,

Jiang²,

Zhang³

et al. 2017

PLoS ONE

149

109

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BackgroundStudies have demonstrated that resveratrol (a natural polyphenol) and caloric restriction activate Sirtuin-1 (SIRT1) and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD) development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy.Methods and resultsEight-week-old male Wistar rats (40) were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw); and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER) stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw) and caloric restriction (30%) partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD-induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight.ConclusionWe conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30%) and resveratrol (a pharmacological SIRT1 activator) supplementation against HFD-induced hepatic steatosis.

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“…Indeed, this contradicts what have been published using rodent models of obesity/diabetes/fat feeding [107]; however, our mice are essentially “normal” and not subject to high-risk features for metabolic syndrome or diabetes. Furthermore, some rodent and clinical studies have provided contradictory findings with respect to SIRT1 activation (resveratrol) in humans [108–111]. Thus, it is potentially possible that the presence of PXR could attenuate the inhibitory properties of resveratrol on hepatic steatosis.…”

Section: Discussionmentioning

confidence: 99%

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

Pasquel¹,

Doricakova²,

Li³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Pregnane X receptor (PXR) is a major transcriptional regulator of xenobiotic metabolism and transport pathways in the liver and intestines, which are critical for protecting organisms against potentially harmful xenobiotic and endobiotic compounds. Inadvertent activation of drug metabolism pathways through PXR is known to contribute to drug resistance, adverse drug–drug interactions, and drug toxicity in humans. In both humans and rodents, PXR has been implicated in non-alcoholic fatty liver disease, diabetes, obesity, inflammatory bowel disease, and cancer. Because of PXR's important functions, it has been a therapeutic target of interest for a long time. More recent mechanistic studies have shown that PXR is modulated by multiple PTMs. Herein we provide the first investigation of the role of acetylation in modulating PXR activity. Through LC–MS/MS analysis, we identified lysine 109 (K109) in the hinge as PXR's major acetylation site. Using various biochemical and cell-based assays, we show that PXR's acetylation status and transcriptional activity are modulated by E1A binding protein (p300) and sirtuin 1 (SIRT1). Based on analysis of acetylation site mutants, we found that acetylation at K109 represses PXR transcriptional activity. The mechanism involves loss of RXRα dimerization and reduced binding to cognate DNA response elements. This mechanism may represent a promising therapeutic target using modulators of PXR acetylation levels.

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Effect of resveratrol on experimental non‐alcoholic fatty liver disease depends on severity of pathology and timing of treatment

Abstract: These experimental findings suggest that a weak hepatic benefit of RSV treatment is seen in prevention of steatosis only.

Cited by 20 publications

References 41 publications

Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis

Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis

Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

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