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

Flavonols: Quercetin, Rutin and Troxerutin

Quercetin is a dietary flavonol mainly occurring as glycosides and abundant in red onions, apples, berries, citrus fruits and red wine. Quercetin has been characterized for its potent antioxidant activity both in hepatocytes[11,12] and in experimental liver injury.[13] In recent years, the metabolic effects of rutin have been evaluated in several animal models of diet-induced obesity. Kobori et al. first showed that treatment with quercetin improves insulin sensitivity, increases plasma adiponectin and reduces liver steatosis in mice fed a western diet.[14] Successively, Panchal et al. elegantly demonstrated that in a model of rats fed high-fat and high carbohydrate diet, administration of quercetin prevents liver damage and cardiac remodelling by inhibiting NFkB activation and inducing Nrf-2 and its downstream targets.[15] Marcolin et al. explored the effects of quercetin in the more fibrogenic methionine-choline deficient diet model of NASH revealing that quercetin decreases the number of α-SMA positive cells and reduces TLR-4 expression, NFkB p65 activity and phosphorylation of JNK.[16]

Interestingly, quercetin intake reduces liver fat accumulation by stimulating omega-oxidation of fatty acids.[17] Quercetin was also shown to inhibit activation of rat hepatic stellate cell in vitro[18] and in vivo.[19] However, although all these preclinical results provide a significant molecular rationale for the use of quercetin in patients with NAFLD, no clinical study has been conducted so far.

Rutin, a glycoside of quercetin, is contained in several foods including onions, apples and red wine. Panchal et al. first demonstrated that rats fed high fat and high carbohydrate diet and treated with rutin display decreased adiposity, improved insulin sensitivity and reduced liver damage and cardiac remodeling.[20] Consistently, in a successive study rutin was effective in inhibiting palmitate-induced macrophage activation and reducing liver fat by suppressing transcription of SREBP-1c and Cd36 in the liver.[21] Recently, troxerutin, a trihydroxyethylated derivative of rutin, was also shown to reduce liver steatosis and improve metabolic phenotype of mice fed a high fat diet by suppressing oxidative stress-mediated NAD depletion and stimulating fat oxidation.[22] Nonetheless, neither experimental nor clinical studies assessed the effects of rutin on NASH-induced fibrosis.