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 that PIAS4 silencing using short hairpin RNA (shRNA) attenuated high-fat high-carbohydrate (HFHC) diet induced liver fibrosis in mice. Quantitative PCR and Western blotting analyses confirmed that PIAS4 knockdown downregulated a panel of pro-fibrogenic genes including type I and type III collagens, smooth muscle actin, and tissue inhibitors of metalloproteinase. Mechanistically, PIAS4 silencing 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.
Highlights
Non-alcoholic steatohepatitis or non-alcoholic steatohepatitis (NASH) has become a significant health threat in a growing number of nations accompanying the global pandemic of obesity and type 2 diabetes[1]
Histological measurements showed that protein inhibitor for activated stat 4 (PIAS4) silencing largely abrogated high-fat high-carbohydrate (HFHC) diet induced liver fibrosis (Fig. 1A and Fig. 1B)
We report here that PIAS4 may play a critical role in liver fibrosis by modulating SMAD3 activity, likely through SIRT1dependent deacetylation
Summary
Non-alcoholic steatohepatitis or NASH has become a significant health threat in a growing number of nations accompanying the global pandemic of obesity and type 2 diabetes[1]. Liver fibrosis is one of the many complications associated with NASH[2]. The mechanism accounting for liver fibrosis during NASH pathogenesis is not fully appreciated. Inside the ECM-producing cells, fibrogenesis is dictated by a network of growth factors, cytokines, and transcription factors[6]. Transforming growth factor (TGF-β) is by far the most extensively studied profibrogenic factor in the liver, signaling primarily through the SMAD family of transcription factors[7]. Upon binding to its receptor, TGF-β triggers the Received 9 April 2016, Revised 29 June 2016, Accepted 11 July 2016, Epub 1 August 2016 CLC number: R657.31, Document code: A The authors reported no conflict of interests
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