title: Protein inhibitor of activated STAT 4 (PIAS4) regulates liver fibrosis through modulating SMAD3 activity.
abstract: Excessive fibrogenesis disrupts normal liver structure, impairs liver function, and precipitates the development of cirrhosis, an irreversible end-stage liver disease. A host of factors including nutrition surplus contribute to liver fibrosis but the underlying mechanism is not fully understood. In the present study, we investigated the involvement of protein inhibitor for activated stat 4 (PIAS4) in liver fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH). We report thatPIAS4silencing using short hairpin RNA (shRNA) attenuated high-fat high-carbohydrate (HFHC) diet induced liver fibrosis in mice. Quantitative PCR and Western blotting analyses confirmed thatPIAS4knockdown downregulated a panel of pro-fibrogenic genes including type I and type III collagens, smooth muscle actin, and tissue inhibitors of metalloproteinase. Mechanistically,PIAS4silencing blocked the recruitment of SMAD3, a potent pro-fibrogenic transcription factor, to the promoter regions of pro-fibrogenic genes and dampened SMAD3 acetylation likely by upregulating SIRT1 expression. In conclusion, PIAS4 may contribute to liver fibrosis by modulating SIRT1-dependent SMAD3 acetylation.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Tian
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China; yjxu@njmu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
keywords: PIAS4; SMAD3; acetylation; liver fibrosis; transcriptional regulation