Nicotinamide protects hepatocytes against palmitate-induced lipotoxicity via SIRT1-dependent autophagy induction

Abstract Lipotoxicity induced by saturated fatty acids (SFAs) plays a pathological role in the development of non-alcoholic fatty liver disease (NAFLD); however, the exact mechanism remains to be clearly elucidated. Palmitate is the most abundant SFA in the circulation and major lipotoxic inducer. Accumulating evidence supports that autophagy induction is protective against palmitate-induced cell death in a variety of cell types, including hepatocytes. Nicotinamide is the amide form of nicotinic acid (vitamin B3, Niacin) and a dietary supplementation as a source of vitamin B3. We previously reported that nicotinamide endowed hepatocytes resistance to palmitate-induced ER stress via upregulating SIRT1, with cAMP/PKA/CREB pathway activation being a fundamental mechanism. This study was undertaken to investigate the potential anti-lipotoxic effect of nicotinamide and to elucidate underlying mechanism(s). Our data demonstrated that nicotinamide supplementation protected hepatocytes against palmitate-induced cell death. Mechanistic investigations revealed that nicotinamide supplementation activated autophagy in hepatocytes. Importantly, we showed that the anti-lipotoxic property of nicotinamide was abolished by autophagy inhibitors, suggesting that autophagy induction plays a mechanistic role in nicotinamide's anti-lipotoxic effect. Furthermore, we showed that SIRT1 inhibition blunted autophagy induction in response to nicotinamide supplementation and similarly abrogated the anti-lipotoxic effect conferred by nicotinamide supplementation. In conclusion, our data suggest that nicotinamide protects against palmitate-induced hepatotoxicity via SIRT1-dependent autophagy induction and that nicotinamide supplementation may represent a therapeutic choice for NAFLD.