title: Succinate causes α-SMA production through GPR91 activation in hepatic stellate cells.
abstract: Succinate acts as an extracellular signaling molecule as well as an intermediate in the citric acid cycle. It binds to and activates its specific G protein-coupled receptor 91 (GPR91). GPR91 is present in hepatic stellate cells (HSCs), but its role in hepatic fibrogenesis remains unclear. Cultured HSCs treated with succinate showed increased protein expression of GPR91 and α-smooth muscle actin (α-SMA), markers of fibrogenic response. Succinate also increased mRNA expression of α-SMA, transforming growth factor β (TGF-β), and collagen type I. Transfection of siRNA against GPR91 abrogated succinate-induced increases in α-SMA expression. Malonate, an inhibitor of succinate dehydrogenase (SDH), increased succinate levels in cultured HSCs and increased GPR91 and α-SMA expression. Feeding mice a methionine- and choline-deficient (MCD) diet is a widely used technique to create an animal model of nonalcoholic steatohepatitis (NASH). HSCs cultured in MCD media showed significantly decreased SDH activity and increased succinate concentration and GPR91 and α-SMA expression. Similarly, palmitate treatment significantly decreased SDH activity and increased GPR91 and α-SMA expression. Finally, C57BL6/J mice fed the MCD diet had elevated succinate levels in their plasma. The MCD diet also decreased SDH activity, increased succinate concentration, and increased GPR91 and α-SMA expression in isolated HSCs. Collectively, our results show that succinate plays an important role in HSC activation through GPR91 induction, and suggest that succinate and GPR91 may represent new therapeutic targets for modulating hepatic fibrosis.
authors.affiliation: Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.
authors.forename: Ying Hui
authors.initials: YH
authors.lastname: Li
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.
authors.forename: Dae Hee
authors.initials: DH
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea. Electronic address: ehcho@kangwon.ac.kr.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Cho
mesh_terms: D000199:Actins / Q000096:biosynthesis*; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019802:Succinic Acid / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D017931:DNA Primers; D043562:Receptors, G-Protein-Coupled; C557078:SUCNR1 protein, human; D019802:Succinic Acid
keywords: GPR91; Hepatic stellate cell; Nonalcoholic fatty liver disease; Succinate