Succinate causes α-SMA production through GPR91 activation in hepatic stellate cells

Li, Y.H.; Woo, Sung Hoon; Choi, Dong‐Young; Cho, Eunhee

doi:10.1016/j.bbrc.2015.06.023

Cited by 83 publications

(80 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In a previous study, we demonstrated that the succinate receptor GPR91 is overexpressed in HSC activation, and GPR91 siRNA treatment of LX2 cells showed decreased ␣-SMA protein expression (32). In this study, we demonstrated that GPR91 knockdown by GPR91 shRNA tail vein injection decreased ␣-SMA expression in the liver, isolated HSCs, and ameliorated the NASH phenotype in MCD diet-fed mice, suggesting that GPR91 could be a therapeutic target for the treatment of NAFLD.…”

Section: Discussionmentioning

confidence: 57%

“…In a previous study, 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-SDH-GPR91 signaling in NASH.…”

Section: Nonalcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 95%

“…In a previous study, we demonstrated overexpression of GPR91 protein, decreased SDH activity, and increased succinate concentrations in isolated HSCs of MCD diet-fed mice as a model of NAFLD (32). In this study, we applied a novel gene therapeutic approach using recombinant adeno-associated virus (AAV)-mediated RNA knockdown of GPR91 gene expression in a mouse model of NAFLD.…”

Section: Aav-gpr91 Shrna Knockdown and Sirt3 Gpr91 And ␣-Sma Expresmentioning

confidence: 99%

“…Vitro-We previously demonstrated that palmitate or MCD medium directly activated HSCs via decreased SDH activity, thus increasing succinate levels and inducing GPR91 activation (32). To establish whether the activation of HSCs was induced indirectly through the paracrine action of hepatocytes, we treated mouse hepatocytes (AML12 cells) with palmitate (300 M) for 20 h. The conditioned medium (CM) from palmitate-treated hepatocytes was transferred to LX2 cells (Fig.…”

Section: Conditioned Medium Treatment From Hepatocytes Exposed To Palmentioning

confidence: 99%

See 3 more Smart Citations

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

Choi

Lee

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 57%

Section: Nonalcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 95%

Section: Aav-gpr91 Shrna Knockdown and Sirt3 Gpr91 And ␣-Sma Expresmentioning

confidence: 99%

Section: Conditioned Medium Treatment From Hepatocytes Exposed To Palmentioning

confidence: 99%

See 2 more Smart Citations

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

Choi

Lee

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Succinate, which was increased in faecal, serum and liver samples from patients with NAFLD, is an extracellular signalling molecule as well as an intermediate in the citric acid cycle. It might promote progression of NAFLD by causing production of α-smooth muscle actin, a biomarker of fibrogenic response, by activating GPR91 in hepatic stellate cells 125. Succinate is an important metabolite that is produced by mammalian cells and by intestinal microbes such as Bacteroidaceae and Prevotella 126 127—these microbes are increased in faecal samples of patients with NASH 45 111…”

Section: Changes Of Other Metabolites In Nafldmentioning

confidence: 99%

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

Chu

Duan

Yang

et al. 2018

Gut

271

209

View full text Add to dashboard Cite

The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis, commonly associated with obesity, to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD pathophysiology involves environmental, genetic and metabolic factors, as well as changes in the intestinal microbiota and their products. Dysfunction of the intestinal barrier can contribute to NAFLD development and progression. Although there are technical limitations in assessing intestinal permeability in humans and the number of patients in these studies is rather small, fewer than half of the patients have increased intestinal permeability and translocation of bacterial products. Microbe-derived metabolites and the signalling pathways they affect might play more important roles in development of NAFLD. We review the microbial metabolites that contribute to the development of NAFLD, such as trimethylamine, bile acids, short-chain fatty acids and ethanol. We discuss the mechanisms by which metabolites produced by microbes might affect disease progression and/or serve as therapeutic targets or biomarkers for NAFLD.

show abstract

Nutritional and metabolic signalling through GPCRs

et al. 2022

View full text Add to dashboard Cite

Deregulated metabolism is a well-known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone-like molecules by activating cell surface G-protein-coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis-derived and b-oxidation-derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite-sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.

show abstract

Succinate causes α-SMA production through GPR91 activation in hepatic stellate cells

Cited by 83 publications

References 28 publications

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

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

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

Nutritional and metabolic signalling through GPCRs

Contact Info

Product

Resources

About