Nobiletin alleviates high-fat diet-induced nonalcoholic fatty liver disease by modulating AdipoR1 and gp91phox expression in rats.

Nobiletin, one of the polymethoxylated flavonoids isolated from citrus peels, is reported to possess various biological activities. The current study investigates the effect and possible mechanisms of nobiletin on nonalcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-fed rats. Male Sprague-Dawley rats were administrated with HFD and fructose (15%) in drinking water for 16 weeks to induce NAFLD. HFD-fed rats were treated with nobiletin (20 or 40 mg/kg/day) or vehicle for the last 4 weeks. Treatment of HFD-fed rats with nobiletin significantly reduced systolic blood pressure, adiposity, hyperlipidemia, insulin resistance, hepatic lipids content, NAFLD activity score and liver fibrosis. Nobiletin significantly increased plasma adiponectin levels, together with up-regulation of liver adiponectin receptor 1 (AdipoR1) expression. Additionally, decreased malondialdehyde levels and increased superoxide dismutase activity in plasma and hepatic tissue, consistent with down-regulation of liver NADPH oxidase subunit gp91phox expression, were also observed after nobiletin treatment. Furthermore, high dose of nobiletin exhibited higher therapeutic effect as a compared to low dose. These findings suggest that nobiletin alleviates HFD-induced NAFLD and metabolic dysfunction in rats. There might be an association between the observed inhibitory effect of nobiletin on NAFLD and modulation of AdipoR1 and gp91phox.