Regression effect of hepatocyte nuclear factor 4α on liver cirrhosis in rats.

Abstract

OBJECTIVE:

The aim of this study was to determine whether cirrhosis could be reversed after treated with hepatocyte nuclear factor 4α (HNF4α), a key transcriptional regulator of hepatocyte differentiation and function.

METHODS:

Early and advanced stages of liver cirrhosis were induced by thioacetamide (TAA) administration. The adenovirus carrying HNF4α gene was injected into cirrhotic rats via the tail vein. The effect of HNF4α on cirrhosis was evaluated by histological and immunohistochemical examination.

RESULTS:

Early stage of cirrhosis was remarkably resolved by HNF4α to a nearly-normal extent and advanced cirrhosis was partially ameliorated in vivo. The enforced expression of HNF4α downregulated profibrogenic factors remarkably including α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, fibroblast-specific protein (FSP)-1, collagen I and III. In vivo and in vitro studies revealed that HNF4α administration inhibited extracellular signal-regulated kinase (ERK) signaling pathway through the downregulation of phosphorated ERK and phosphorated JunD. In addition, HNF4α readjusted the balance between extracellular matrix deposition and degradation through the upregulation of matrix metalloproteinase and downregulation of its inhibitors. Moreover, HNF4α treatment inhibited angiogenesis as determined by CD31 and CD34 immunostaining.

CONCLUSIONS:

Our findings broaden the knowledge on the reversibility of different stages of cirrhosis as HNF4α could present a promising alternative for the treatment of liver cirrhosis.

• Authors: Ting Ting Fan, Ping Fang Hu, Jian Wang, Ji Wei, Qing Zhang, Bei Fang Ning, Chuan Yin, Xin Zhang, Wei Fen Xie, Yue Xiang Chen, Bin Shi
• Journal: Journal of digestive diseases (J Dig Dis) Vol. 14 Issue 6 Pg. 318-27 (Jun 2013) ISSN: 1751-2980 [Electronic] Australia
• PMID: 23374293 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The Authors. Journal of Digestive Diseases © 2013 Wiley Publishing Asia Pty Ltd and Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine.

Chemical References

• Hepatocyte Nuclear Factor 4
• Thioacetamide

Topics

• Animals
• Cells, Cultured
• Extracellular Matrix (metabolism)
• Hepatocyte Nuclear Factor 4 (therapeutic use)
• Liver Cirrhosis, Experimental (chemically induced, drug therapy)
• MAP Kinase Signaling System (drug effects)
• Male
• Neovascularization, Pathologic (prevention & control)
• Rats
• Rats, Sprague-Dawley
• Thioacetamide