title: 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.
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Ying Hui
authors.initials: YH
authors.lastname: Li
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Dae Hee
authors.initials: DH
authors.lastname: Choi
authors.affiliation: Department of Molecular Bioscience, College of Biomedical Science, and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Lee
authors.affiliation: Department of Molecular Bioscience, College of Biomedical Science, and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Su Ryeon
authors.initials: SR
authors.lastname: Seo
authors.affiliation: Anatomic Pathology, School of Medicine, and.
authors.forename: Seungkoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: From the Departments of Internal Medicine and ehcho@kangwon.ac.kr.
authors.forename: Eun-Hee
authors.identifier: http://orcid.org/0000-0002-1349-8894
authors.initials: EH
authors.lastname: Cho
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D002796:Choline Deficiency; D004032:Diet; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056566:Sirtuin 3 / Q000502:physiology*; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C491545:SDHD protein, human; C557078:SUCNR1 protein, human; D008715:Methionine; D013385:Succinate Dehydrogenase; D056566:Sirtuin 3; D002794:Choline
keywords: G protein-coupled receptor (GPCR); hepatic stellate cell (HSC); hepatocyte; liver injury; sirtuin