期刊
GUT
卷 59, 期 2, 页码 236-246出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gut.2008.174904
关键词
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资金
- National Science Fund [30825020]
- National Natural Science Foundation of China [30570838]
- Natural Science Foundation of Shanghai [08ZR1404800]
- Chenguang Project Foundation of Shanghai [2007CG50]
Background and aims Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a central transcriptional regulator of hepatocyte differentiation and function. The aim of this study was to evaluate the effect of HNF4 alpha on attenuation of hepatic fibrosis. Methods The adenoviruses carrying HNF4 alpha gene or containing siRNA targeting HNF4 alpha were injected through tail vein on two distinct hepatic fibrosis models either induced by dimethylnitrosamine or by bile duct ligation in rats. Moreover, HNF4 alpha, 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 alpha and epithelial markers accompanied by enhanced expression of mesenchymal markers occurred in fibrotic liver. More importantly, forced expression of HNF4 alpha remarkably alleviated hepatic fibrosis and improved liver function with suppression of EMT in both fibrosis models. In contrast, downregulation of HNF4 alpha 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 HNF4 alpha could suppress the EMT process of hepatocytes induced by transforming growth factor-beta 1 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 HNF4 alpha. Additionally, HNF4 alpha deactivated the myofibroblasts through inducing the mesenchymal-to-epithelial transition and inhibited their proliferation. Conclusions Our study suggests that HNF4 alpha is critical for hepatic fibrogenesis and upregulation of HNF4 alpha might present as an ideal option for the treatment of hepatic fibrosis.
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