Abstract
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 SDH-succinate-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. This investigation revealed a novel mechanism of the 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.
Highlights
Nonalcoholic fatty liver disease (NAFLD)2 is the most common chronic liver disease in many developed countries [1], and nonalcoholic steatohepatitis (NASH), the more severe histological form of NAFLD, is associated with an increased risk for the progression to cirrhosis in 20% of these patients [2]
We evaluated the effects of Sirtuin 3 (SIRT3) on G protein-coupled receptor 91 (GPR91) regulation through succinate dehydrogenase (SDH) to mitigate the progression of NASH in hepatic stellate cells (HSCs) and an animal model, and we determined whether succinate secreted from hepatocytes regulated HSC activation
We provided several lines of evidence that implicate SIRT3 in SDH activity and GPR91 expression in HSC activation in NAFLD
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in many developed countries [1], and nonalcoholic steatohepatitis (NASH), the more severe histological form of NAFLD, is associated with an increased risk for the progression to cirrhosis in 20% of these patients [2]. Based on several recent studies, SIRT3 is a primary regulator of the acetylation of mitochondrial proteins and their biological activity (16 –19) and is associated with NAFLD (20 –22). We showed that decreased SDH activity led to increased cellular succinate levels and succinate receptor (GPR91) overexpression with increased ␣-SMA production in the isolated HSCs of MCD diet-induced NASH mice [32]. These observations led us to question whether SIRT3 expression could modulate HSC activation through SIRT3-SDHGPR91 signaling in NASH. We evaluated the effects of SIRT3 on GPR91 regulation through SDH to mitigate the progression of NASH in HSCs and an animal model, and we determined whether succinate secreted from hepatocytes regulated HSC activation
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