Resveratrol improves high-fat diet induced fatty liver and insulin resistance by concomitantly inhibiting proteolytic cleavage of sterol regulatory element-binding proteins, free fatty acid oxidation, and intestinal triglyceride absorption.

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.