Protein inhibitor of activated STAT 4 (PIAS4) regulates pro-inflammatory transcription in hepatocytes by repressing SIRT1

Lina Sun,Yong Xu,Huihui Xu,Min Li,Wenfang Tian,Zhiwen Fan,Xiaoyan Wu,Jun Xia,Mingming Fang,Junliang Chen

doi:10.18632/oncotarget.9864

Abstract

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.

Highlights

Nutrient surplus induces a pro-inflammatory niche and inflicts insults in different types of cells and organs
A hallmark event in the pathogenesis of non-alcoholic steatohepatitis (NASH) is augmented hepatic inflammation leading to irreversible end-stage liver disease
We demonstrate for the first time that protein inhibitor of activated STAT 4 (PIAS4) expression and activity alter in response to energy input in mouse livers and in cultured hepatocytes

Summary

Introduction

Nutrient surplus induces a pro-inflammatory niche and inflicts insults in different types of cells and organs. This scenario constitutes the major mechanism underlying the pathogenesis of non-alcoholic steatohepatitis (NASH) characterized by numerous inflammatory infiltrates in the liver eventually transitioning into cirrhosis and hepatocellular carcinoma [1]. Expression of pro-inflammatory is programmed by a handful of evolutionarily conserved transcription factors such as NF-κB [4]. The activity of these factors and the intensity of proinflammatory transcription are regulated at multiple levels. SIRT1 stands at a critical juncture of cellular inflammatory responses by modifying and fine-tuning the activities of key transcription factors

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Results

Conclusion