Natural Antioxidants for Non-alcoholic Fatty Liver Disease

Molecular Targets and Clinical Perspectives

Federico Salomone; Justyna Godos; Shira Zelber-Sagi


Liver International. 2016;36(1):5-20. 

In This Article


Resveratrol is a polyphenolic compound mainly contained in red grapes, mulberries, peanuts and cocoa.[80] Resveratrol exists in two isomeric forms: trans-resveratrol is naturally found in the skin of grape and is found in red grape juice at a concentration of 3.4 mg/L;[81] cis-resveratrol is present in red wine but not grape and can be derived from the exposure of trans-resveratrol to UV irradiation. Most of the experimental and clinical studies conducted so far have examined the effects of trans-resveratrol in the metabolic area. Two seminal studies in 2006 showed that resveratrol favourably impacts on metabolic health and ageing by activating AMPK and SIRT-1.[82,83] Further studies in animal models of genetic and diet-induced obesity have revealed that resveratrol is able to reduce liver fat accumulation although not reducing body weight by different mechanisms, including decreased lipogenesis (down-regulation of SREBP-1, FAS, ACC and HMG-CoA reductase) and increased fatty acid oxidation (up-regulation of CPT-1 and ACO).[84–88] Moreover, resveratrol has been demonstrated to reduce lipid peroxidation in rats fed high-fructose diet by promoting Nrf2-depending antioxidant response[89] and improving gut dysbiosis induced by HFD, increasing the Bacteroidetes-to-Firmicutes ratio, inhibiting the growth of Enterococcus faecalis, and increasing the growth of Lactobacillus and Bifidobacterium.[90] However, results of two clinical trials showed contradictory results. In an 8-week randomized trial of 3000 mg daily supplementation with resveratrol, no improvement in insulin sensitivity and liver fat accumulation was demonstrated in men with NAFLD as compared to baseline; similarly no change in plasma antioxidant activity was observed. Noteworthy, supplementation with resveratrol increased plasma levels of liver enzymes (ALT and AST), indicating hepatic stress.[91] On the other hand, in a randomized, double-blinded, controlled trial, 50 NAFLD patients supplemented with 500-mg resveratrol for 12 weeks displayed improvement of liver enzymes and inflammatory cytokines, although antioxidant effects were not reported.[92] The conflicting results may stem from, the differences in dosages, subjects' baseline health status, and investigation protocols. Further studies are needed in order to establish whether resveratrol, apart from its metabolic effects, may exert antifibrogenic activity.