Sirtuin 3 (SIRT3) Regulates α-Smooth Muscle Actin (α-SMA) Production through the Succinate Dehydrogenase-G Protein-coupled Receptor 91 (GPR91) Pathway in Hepatic Stellate Cells

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.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). NAFLD also increases the cardiometabolic risk (3-5) and all-cause mortality (6, 7) in humans. It is presently regarded as the main cause of cryptogenic liver cirrhosis in the United States (8). During liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into activated myofibroblasts, which produce ␣-smooth muscle actin (␣-SMA) and become a major cell type in hepatic fibrogenesis (9, 10).Sirtuin 3 (SIRT3) is an NAD ϩ -dependent protein deacetylase predominantly localized in the mitochondrial matrix (11-13). SIRT3 is up-regulated during prolonged fasting or a calorierestricted diet and is thus involved in the metabolic regulation of obesity and diabetes (14 -16). 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).Two studies yielded findings showing that SIRT 3 is a major physiological regulator of succinate dehydrogenase (SDH) activity (23, 24). SDH catalyzes the oxidation of succinate to fumarate, thereby decreasing SDH activity, resulting in increased succinate levels (25,26). The succinate receptor (also known as GPR91) is a G protein-coupled receptor expressed in various tissues, including the retina, live...

Hepatic stellate cells as key target in liver fibrosis

“…Sirtuin 3 (SIRT3), an NAD(+)-dependent protein deacetylase decreased in NAFLD, suppresses αSMA expression via GPR91 on HSCs in methionine- and choline-deficient (MCD) diet-fed NAFLD mice [201]. …”

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

“…Furthermore, the HSC activation marker α-SMA is partially dependent on the G protein-coupled receptor 91 (GPR91), also known as succinate receptor 1, which in turn is induced by succinate, an intermediate metabolite of the Krebs cycle. HSCs express the succinate receptor [113][114][115][116][117].…”

The Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease

“…The 'deorphanisation' of GPR91 and the availability of GPR91 knockout mice led to multiple reports linking succinate and GPR91 with the dendritic cell biology (131), haematopoiesis (42), hepatic stellate cell activation in liver damage (23,84), lipolysis in adipose tissue (130) and retinal angiogenesis (135).…”