Research Papers: Pathology:
Protein inhibitor of activated STAT 4 (PIAS4) regulates pro-inflammatory transcription in hepatocytes by repressing SIRT1
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Lina Sun1,2,*, Zhiwen Fan1,3,*, Junliang Chen1,4,*, Wenfang Tian1, Min Li1, Huihui Xu1, Xiaoyan Wu1, Mingming Fang1,5, Jun Xia6 and Yong Xu1
1 State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China
2 Department of Pathology and Pathophysiology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China
3 Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
4 Department of Pathophysiology, School of Basic Medical Sciences, Jiangnan University, Wuxi, China
5 Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China
6 Department of Respiratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China
* These authors contributed equally to this work
Yong Xu, email:
Jun Xia, email:
Keywords: transcriptional regulation; inflammation; PIAS4; SIRT1; NF-κB; Pathology Section
Received: January 05, 2016 Accepted: May 06, 2016 Published: June 06, 2016
Excessive nutrition promotes the pathogenesis of non-alcoholic steatohepatitis (NASH), characterized by the accumulation of pro-inflammation mediators in the liver. In the present study we investigated the regulation of pro-inflammatory transcription in hepatocytes by protein inhibitor of activated STAT 4 (PIAS4) in this process and the underlying mechanisms. We report that expression of the class III deacetylase SIRT1 was down-regulated in the livers of NASH mice accompanied by a simultaneous increase in the expression and binding activity of PIAS4. Exposure to high glucose stimulated the expression PIAS4 in cultured hepatocytes paralleling SIRT1 repression. Estrogen, a known NASH-protective hormone, ameliorated SIRT1 trans-repression by targeting PIAS4. Over-expression of PIAS4 enhanced, while PIAS4 knockdown alleviated, repression of SIRT1 transcription by high glucose. Lentiviral delivery of short hairpin RNA (shRNA) targeting PIAS4 attenuated hepatic inflammation in NASH mice by restoring SIRT1 expression. Mechanistically, PIAS4 promoted NF-κB-mediated pro-inflammatory transcription in a SIRT1 dependent manner. In conclusion, our study indicates that PIAS4 mediated SIRT1 repression in response to nutrient surplus contributes to the pathogenesis of NASH. Therefore, targeting PIAS4 might provide novel therapeutic strategies in the intervention of NASH.
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