title: Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion.
abstract: SIRT1 (silent information regulator 1), a conserved NAD+-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-β1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-β1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up-regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis.
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China. Electronic address: wuyuting1302@sina.com.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Meng
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
authors.forename: Fengyun
authors.initials: F
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China. Electronic address: lj@ahmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002251:Carbon Tetrachloride; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D007328:Insulin; C557040:Malat1 long non-coding RNA, mouse; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014970:Xanthines; D003907:Dexamethasone; D002251:Carbon Tetrachloride; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Apoptosis; Liver fibrosis; MALAT1; Reversion; SIRT1