Resveratrol protects against nonalcoholic fatty liver disease by improving lipid metabolism and redox homeostasis via the PPARα pathway

Resveratrol (RSV), a well-known bioactive compound, has been reported to exert a broad range of health benefits. Accumulating evidence suggests that RSV is beneficial for many metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). This study investigated the preventive and therapeutic effects of RSV on high-fat diet (HFD)-induced NAFLD in rats and pahnitate acid (PA)-induced hepatocyte steatosis in HepG2 cells. Hepatocytes were incubated with inhibitors of peroxisome proliferator-activated receptor alpha (PPAR alpha) or short interfering RNAs (siRNAs) targeting PPAR alpha, AMP-activated protein kinase (AMPK), and protein kinase A (PKA) to determine the underlying mechanisms. We found that RSV noticeably ameliorated HFD-induced hepatic steatosis in rats and inhibited PA-induced lipid accumulation in HepG2 cells. Moreover, RSV improved lipid metabolism, enhanced antioxidant capacity, and restored mitochondrial respiratory chain activities. Incubation with inhibitors of PPAR alpha or PPAR alpha siRNA abolished the protective effects of RSV on lipid metabolism and redox homeostasis. Furthermore, RSV activated the PKA/AMPK/PPAR alpha signaling pathway. Our results provided direct evidence for a novel, PPAR alpha-mediated mechanism responsible for the beneficial effects of RSV on hepatic steatosis. These findings may have important theoretical and application prospects for the prevention and treatment of NAFLD. Novelty RSV improved lipid metabolism and redox homeostasis and oxidative stress in NAFLD via the PKA/AMPK/PPAR alpha signaling pathway. RSV may have a greater beneficial effect in the early prevention of hepatic steatosis.