Hepatocyte nuclear factor 4α attenuates hepatic fibrosis in rats
- H-Y Yue1,
- C Yin1,
- J-L Hou1,
- X Zeng1,
- Y-X Chen1,
- W Zhong1,
- P-F Hu1,
- X Deng1,
- Y-X Tan2,
- J-P Zhang3,
- B-F Ning1,
- J Shi1,
- X Zhang4,
- H-Y Wang2,
- Y Lin1,
- W-F Xie1
- 1Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
- 2International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
- 3Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China
- 4Chinese National Human Genome Center at Shanghai, Shanghai, China
- Correspondence to Dr W-F Xie, Department of Gastroenterology, Shanghai Changzheng Hospital, 415 Fengyang Road, Shanghai 200003, China;
- Revised 25 June 2009
- Accepted 21 July 2009
- Published Online First 10 August 2009
Background and aims Hepatocyte nuclear factor 4α (HNF4α) is a central transcriptional regulator of hepatocyte differentiation and function. The aim of this study was to evaluate the effect of HNF4α on attenuation of hepatic fibrosis.
Methods The adenoviruses carrying HNF4α gene or containing siRNA targeting HNF4α were injected through tail vein on two distinct hepatic fibrosis models either induced by dimethylnitrosamine or by bile duct ligation in rats. Moreover, HNF4α, 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 HNF4α and epithelial markers accompanied by enhanced expression of mesenchymal markers occurred in fibrotic liver. More importantly, forced expression of HNF4α remarkably alleviated hepatic fibrosis and improved liver function with suppression of EMT in both fibrosis models. In contrast, downregulation of HNF4α by siRNA aggravated hepatic fibrosis and decreased the expression of E-cadherin in association with the enhanced expression of vimentin and fibroblast-specific protein-1. In vitro study revealed that HNF4α could suppress the EMT process of hepatocytes induced by transforming growth factor-β1 and increase the expression of liver-specific genes. A similar phenomenon of the EMT process was observed during the activation of HSCs, which was abrogated by HNF4α. Additionally, HNF4α deactivated the myofibroblasts through inducing the mesenchymal-to-epithelial transition and inhibited their proliferation.
Conclusions Our study suggests that HNF4α is critical for hepatic fibrogenesis and upregulation of HNF4α might present as an ideal option for the treatment of hepatic fibrosis.
Supplementary material (four figures, and one file with materials, methods and seven tables) is published online only at http://gut.bmj.com/content/vol59/issue2
H-YY, CY and J-LH contributed equally to this work.
Funding This work was supported by grants from the National Science Fund for Distinguished Young Scholars (No. 30825020), the National Natural Science Foundation of China (No. 30570838), the Natural Science Foundation of Shanghai (No. 08ZR1404800) and Chenguang Project Foundation of Shanghai (No. 2007CG50).
Competing interests None.
Ethics approval This study was approved by the local ethics committee of the Second Military Medical University, Shanghai.
Provenance and peer review Not commissioned; externally peer reviewed.