Hepatocyte nuclear factor 4 attenuates hepatic fibrosis in rats

Hai-Yan Yue ¹, Chuan Yin ¹, Jun-Liang Hou ¹, Xin Zeng ¹, Yue-Xiang Chen ¹, Wei Zhong ¹, Ping-Fang Hu ¹, Xing Deng ¹, Jun-Ping Zhang ², Bei-Fang Ning ¹, Jian Shi ¹, Xin Zhang ³, Yong Lin ¹ and Wei-Fen Xie ^1*

¹ Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, China
² Department of Pharmacology, School of Pharmacy, Second Military Medical University, China
³ Chinese National Human Genome Center at Shanghai, China

^* To whom correspondence should be addressed. E-mail: weifenxie{at}medmail.com.cn.

Accepted 21 July 2009

Abstract

Background & Aims: Hepatocyte nuclear factor 4 (HNF4) is a central transcriptional regulator of hepatocyte differentiation and function. The aim of this study is to evaluate the effect of HNF4 on attenuation of hepatic fibrosis.

Methods: The adenoviruses carrying HNF4 gene or containing siRNA targeting HNF4 were injected through tail vein on two distinct hepatic fibrosis models either induced by dimethylnitrosamine or by bile duct ligation in rats. Moreover, HNF4, epithelial-mesenchymal transition (EMT)-related and fibrotic markers in hepatocytes, hepatic stellate cells (HSCs) and liver tissues were detected by real time PCR, immunofluorescence or immunohistochemistry.

Results: We demonstrated that decreased expression of HNF4 and epithelial markers accompanied by enhanced expression of mesenchymal markers occurred in fibrotic liver. More importantly, forced expression of HNF4 remarkably alleviated hepatic fibrosis and improved liver function with suppression of EMT in both fibrosis models. In contrast, down-regulation of HNF4 by siRNA aggravated hepatic fibrosis and decreased the expression of E-cadherin in company with the enhanced expression of vimentin and fibroblast-specific protein-1. In vitro study revealed that HNF4 could suppress the EMT process of hepatocytes induced by transforming growth factor-1 and increase the expression of liver-specific genes. Similar phenomenon of EMT process was observed during the activation of HSCs, which was abrogated by HNF4. Additionally, HNF4 deactivated the myofibroblasts through inducing the mesenchymal to epithelial transition and inhibited their proliferation.

Conclusions: Our study suggests that HNF4 is critical for hepatic fibrogenesis and up-regulation of HNF4 might present as an ideal option for the treatment of hepatic fibrosis.