Resveratrol inhibits hepatic stellate cell activation by regulating autophagy and apoptosis through the SIRT1 and JNK signaling pathways.

Abstract

Resveratrol, which is a natural polyphenol found in grapes, berries, peanuts, and medicinal plants, has previously been reported to perform several biological functions, including inhibition of hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the major cellular source of matrix protein-secreting myofibroblasts, which are the major drivers of liver fibrogenesis. Numerous studies on the protective effects of resveratrol against liver fibrosis have focused on the inhibition of HSC activation. Although the underlying mechanisms remain to be fully elucidated, the regulation of autophagy and apoptosis might be intimately related. The mouse HSC line JS1 was stimulated with resveratrol to assess the mechanism and relationship between autophagy and apoptosis. Resveratrol modulated JS1 cell viability in a dose-dependent manner. Moreover, resveratrol inhibited JS1 cell activation and induced autophagy and apoptosis. This antifibrotic effect was attenuated when autophagy was inhibited using chloroquine (CQ) or 3-methyladenine (3-MA) or when apoptosis was inhibited using Z-VAD-FMK. Furthermore, whether the Sirtuin1 (SIRT1) and c-Jun N-terminal kinase (JNK) signaling pathways were associated with the resveratrol-mediated induction of autophagy and apoptosis in JS1 cells was examined. The SIRT1 inhibitor EX527 reversed autophagy, and the JNK inhibitor SP600125 reversed both autophagy and apoptosis induced by resveratrol. These findings suggest that the SIRT1 and JNK signaling pathways may be involved in the resveratrol-mediated inhibition of HSC activation by regulating autophagy and apoptosis. SIRT1 may be responsible for inducing autophagy, while JNK affects both autophagy and apoptosis. This study highlighted autophagy and apoptosis as therapeutic targets by which resveratrol can attenuate fibrosis. PRACTICAL APPLICATIONS: Resveratrol, which is a natural polyphenol found in grapes, berries, peanuts, and medicinal plants, has previously been reported to inhibit hepatic fibrosis. Since activated HSCs are the major drivers of liver fibrogenesis, many studies on the anti-hepatic fibrosis effects of resveratrol have focused on inhibiting HSC activation. The objective of this study was to evaluate the inhibitory effect of resveratrol on HSC activation and focused on the mechanism by which resveratrol modulated autophagy and apoptosis in JS1 cells, a mouse immortalized HSC line. It was shown that resveratrol inhibited HSC activation by inducing autophagy and apoptosis in a dose-dependent manner, and the mechanism may be associated with the SIRT1 and JNK signaling pathways. This study highlighted autophagy and apoptosis as therapeutic targets by which resveratrol can attenuate fibrosis. These findings may provide a new framework for understanding the mechanism by which resveratrol inhibits HSC activation.