Resveratrol attenuates HFD-induced hepatic lipotoxicity by up-regulating Bmi-1 expression

BACKGROUND AND PURPOSE Resveratrol (RES), a natural polyphenol phytoalexin, has been reported to attenuate nonalcoholic fatty liver disease (NAFLD). However, its roles on protection of liver from lipotoxicity and underlying mechanism are not fully understood. In this study, we investigated the impacts of RES on alleviating hepatic lipotoxicity and corresponding molecular mechanism. EXPERIMENTAL APPROACH Impacts of RES on oleic acid (OA)-induced lipotoxicity were assessed in L02 cells and C57BL/6J mice, respectively. In L02 cells, lipotoxicity was assessed by detection of apoptosis, mitochondrial function, oxidative stress and ROS-related signaling. In mice, lipotoxicity was evaluated by detecting hepatic function, serum enzyme activity, and reactive oxygen species (ROS) levels. KEY RESULTS In L02 cells, RES reduced OA-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA damage. RES also decreased expression of cleaved caspase-3 and p53, and increased expression of Bcl-2. Importantly, RES protected mice from HFD-induced hepatic lipotoxicity, demonstrated by reduced ROS levels and lipid peroxidation. Mechanically, Bmi-1 expression and anti-oxidative superoxide dismutase was increased after RES treatment. Further mechanistic analysis indicated that protection effects of RES against OA-induced lipotoxicity were abrogated by Bmi-1 siRNA in L02 cells. Significance Statement Results from clinical studies about the effect of RES on NAFLD are inconsistent and inconclusive. Our study confirms the protective role of RES as an anti-ROS agent and its ability to alleviate DNA damage through a pathway involving p53/p21 signaling. Further mechanistic analysis indicated that protection effects of RES was relative with Bmi-1. This is the first study on the role of Bmi-1 in the pathogenesis of NAFLD and the target of resveratrol against NAFLD.