Hepatocyte nuclear factor 4alpha attenuates hepatic fibrosis in rats.
OBJECTIVE
Hepatocyte nuclear factor 4alpha (HNF4alpha) is a central transcriptional regulator of hepatocyte differentiation and function. The aim of this study was to evaluate the effect of HNF4alpha on attenuation of hepatic fibrosis.


METHODS
The adenoviruses carrying HNF4alpha gene or containing siRNA targeting HNF4alpha were injected through tail vein on two distinct hepatic fibrosis models either induced by dimethylnitrosamine or by bile duct ligation in rats. Moreover, HNF4alpha, 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 HNF4alpha and epithelial markers accompanied by enhanced expression of mesenchymal markers occurred in fibrotic liver. More importantly, forced expression of HNF4alpha remarkably alleviated hepatic fibrosis and improved liver function with suppression of EMT in both fibrosis models. In contrast, downregulation of HNF4alpha 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 HNF4alpha could suppress the EMT process of hepatocytes induced by transforming growth factor-beta1 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 HNF4alpha. Additionally, HNF4alpha deactivated the myofibroblasts through inducing the mesenchymal-to-epithelial transition and inhibited their proliferation.


CONCLUSIONS
Our study suggests that HNF4alpha is critical for hepatic fibrogenesis and upregulation of HNF4alpha might present as an ideal option for the treatment of hepatic fibrosis.
Yue
H-Y
HY
Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
Yin
C
C
Hou
J-L
JL
Zeng
X
X
Chen
Y-X
YX
Zhong
W
W
Hu
P-F
PF
Deng
X
X
Tan
Y-X
YX
Zhang
J-P
JP
Ning
B-F
BF
Shi
J
J
Zhang
X
X
Wang
H-Y
HY
Lin
Y
Y
Xie
W-F
WF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1