Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical
University, Nanjing, Jiangsu 211166, China
2.
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical
University, Nanjing, Jiangsu 211166, China.
Funds:
This work was supported by the Natural Science
Fig. 3 PIAS4 modulates SMAD3 activity by influencing SIRT1-dependent deacetylation. C57/BL6 mice were fed on an HFHC-diet or a
chow diet for 16 weeks. Lentivirus carrying either PIAS4 targeting shRNA or a control shRNA was injected weekly via the tail vein. (A) ChIP
assay was performed using liver homogenates with anti-SMAD3 antibody. Precipitated DNA was amplified using primers surrounding the
indicated gene promoters. (B) Immunoprecipitation was performed with anti-SMAD3 using liver homogenates. Western blotting was performed
with anti-SMAD3 or anti-acetyl lysine. n = 3 mice for each group. Data are presented as mean_x0001_S.D. *P < 0.05.
500 Xu H et al. J Biomed Res, 2016, 30(6)
Foundation of China (No. 81500441). YX is a Fellow at
the Collaborative Innovation Center for Cardiovascular
Disease Translation Research.
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.
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