Sirtuin 3 (SIRT3) is an NAD+ -dependent protein deacetylase. Recent studies have shown
that SIRT3 expression is decreased in nonalcoholic fatty liver disease (NAFLD). Moreover, SIRT3 is a key regulator of succinate dehydrogenase (SDH), which catalyzes the oxidation of succinate to fumarate. Increased succinate concentrations and the specific G
protein-coupled receptor 91 (GPR91) are involved in the activation of hepatic stellate
cells (HSCs). In this study, we aimed to establish whether SIRT3 regulated the SDH
activity, succinate, and GPR91 expression in HSCs and an animal model of NAFLD. Our
goal was also to determine whether succinate released from hepatocytes regulated HSC
activation. Inhibiting SIRT3 using SIRT3 siRNA exacerbated HSC activation via the SDHsuccinate-GPR91 pathway and SIRT3 overexpression or honokiol treatment attenuated
HSC activation in vitro. In isolated liver and HSCs from methionine- and choline-deficient (MCD) diet-induced NAFLD, the expression of SIRT3 and SDH activity was decreased and the succinate concentrations and GPR91 expression
were increased. Moreover, we found that GPR91 knockdown or resveratrol treatment
improved the steatosis in MCD diet-fed mice. The present investigation revealed a novel mechanism of SIRT3-SDH-GPR91 cascade in MCD diet induced HSC activation in NAFLD.These findings highlight the biological significance of novel strategies aimed at targeting SIRT3 and GPR91 in HSCs with the goal of improving NAFLD treatment.

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