Hepatic SATB1 induces paracrine activation of hepatic stellate cells and is upregulated by HBx.

Jin Gong,Jingmei Liu,Jian Han,Jiayi He,Ping Han,Dean Tian,Yunwu Wang,Jiazhi Liao,Wei Tu,Mei Liu,Mengke Li

doi:10.1038/srep37717

Abstract

Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver diseases, but its involvement in hepatic fibrogenesis remains unclear. Special AT-rich binding protein 1 (SATB1) has been implicated in reprogramming chromatin organization and transcription profiles in many cancers and non-cancer-related conditions. We found that hepatic SATB1 expression was significantly up-regulated in fibrotic tissues from chronic hepatitis B virus (HBV)-infected patients and HBV transgenic (HBV-Tg) mouse model. Knockdown of SATB1 in the liver significantly alleviated CCl4-induced fibrosis in HBV-Tg mouse model. Moreover, we suggested HBV encoded x protein (HBx) induced SATB1 expression through activation of JNK and ERK pathways. Enforced expression of SATB1 in hepatocytes promoted the activation and proliferation of hepatic stellate cells (HSCs) by secretion of connective tissue growth factor (CTGF), Interleukin-6 (IL-6) and platelet derived growth factor-A (PDGF-AA). Our findings demonstrated that HBx upregulated hepatic SATB1 which exerted pro-fibrotic effects by paracrine activation of stellate cells in HBV-related fibrosis.

Highlights

Special AT-rich binding protein 1 (SATB1), a nuclear matrix attachment regions (MARs)-binding protein, is found predominantly in thymocytes
Our results showed that endogenous SATB1 was rarely detected in normal liver tissues, while positive staining of SATB1 was mainly observed in the nucleus of hepatocytes from HBV-infected samples (Fig. 1a)
Further analysis of 68 cases of patients IHC staining for SATB1 expression showed that SATB1 was significantly upregulated in chronic hepatitis B (CHB) and liver cirrhosis (LC) patients (Table 1)

Summary

Introduction

Special AT-rich binding protein 1 (SATB1), a nuclear matrix attachment regions (MARs)-binding protein, is found predominantly in thymocytes. SATB1 regulates gene expression by recruiting chromatin remodeling complexes and tethering specialized DNA sequences[19,20]. Previous studies revealed SATB1 was critical for the development and maturation of thymocytes and T cells[21]. Consistent with other reports, our former study revealed that SATB1 promoted development and progression of liver cancer by regulation of genes related to cell www.nature.com/scientificreports/. (b) IHC was used to determine the expression of α-SMA in CCl4-induced fibrosis in HBV-Tg mouse model. (c) Real-time PCR showed the expression of SATB1 in HBV-Tg mouse model induced by CCl4 for 4 and 8 weeks (n = 6 in each group). (d) Western blot analyses of SATB1 and α-SMA in the fibrotic livers from HBV-Tg mouse model (n = 3 in each group).

Methods

Results

Conclusion