Upregulation of hepatoma-derived growth factor is involved in murine hepatic fibrogenesis.
OBJECTIVE
Hepatoma-derived growth factor (HDGF) expression is correlated with progression of hepatocellular carcinoma. Since liver fibrosis frequently occurs before hepatoma development, this study investigated the expression profile of HDGF and its relationship with transforming growth factor-beta (TGF-beta) signaling in experimental models of hepatofibrogenesis.


METHODS
Liver fibrosis was induced in mice receiving bile duct ligation (BDL) or carbon tetrachloride (CCl(4)) administration. The expression levels of HDGF and other fibrosis-related markers were measured using quantitative RT-PCR, Western blotting, and enzyme-linked immunosorbent assays. Hepatic HDGF overexpression was achieved by adenovirus gene delivery. Rat hepatocytes were used to study the interplay between HDGF and TGF-beta1.


RESULTS
In both liver fibrosis models, HDGF de novo synthesis significantly increased during the progression of fibrosis. The HDGF upregulation was observed mainly in hepatocytes and correlated with the expression of TGF-beta1 and collagen COL1A1 and COL1A2 proteins. Hepatic HDGF overexpression itself deteriorated hepatocellular structure and integrity, and aggravated the extents of BDL- and CCl(4)-induced liver fibrosis with concomitant upregulation of TGF-beta1 and COL1A1. Exogenous TGF-beta1 stimulated HDGF expression only in cultured primary hepatocytes grown on collagen matrix, whereas exogenous HDGF also increased TGF-beta1 production in hepatocytes in a collagen-dependent manner. Moreover, HDGF enhanced Smad2 phosphorylation dose-dependently and the TGF-beta1-driven luciferase activities.


CONCLUSIONS
HDGF plays a pro-fibrogenic role during liver fibrosis in mice through activation of TGF-beta pathway. The mutual regulation between TGF-beta1 and HDGF may facilitate a vicious cycle to promote the progression of hepatic fibrogenesis.
Kao
Ying-Hsien
YH
Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Chen
Chao-Long
CL
Jawan
Bruno
B
Chung
Yueh-Hua
YH
Sun
Cheuk-Kwan
CK
Kuo
Shiao-Mei
SM
Hu
Tsung-Hui
TH
Lin
Yu-Chun
YC
Chan
Hoi-Hung
HH
Cheng
Kuang-Hung
KH
Wu
Den-Chyang
DC
Goto
Shigeru
S
Cheng
Yu-Fan
YF
Chao
David
D
Tai
Ming-Hong
MH
D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008026:Ligation / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; C051610:hepatoma-derived growth factor; D002251:Carbon Tetrachloride