title: Upregulation of hepatoma-derived growth factor is involved in murine hepatic fibrogenesis.
abstract: 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.
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
authors.forename: Chao-Long
authors.initials: CL
authors.lastname: Chen
authors.forename: Bruno
authors.initials: B
authors.lastname: Jawan
authors.forename: Yueh-Hua
authors.initials: YH
authors.lastname: Chung
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Shiao-Mei
authors.initials: SM
authors.lastname: Kuo
authors.forename: Tsung-Hui
authors.initials: TH
authors.lastname: Hu
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Hoi-Hung
authors.initials: HH
authors.lastname: Chan
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Cheng
authors.forename: Den-Chyang
authors.initials: DC
authors.lastname: Wu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Goto
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Cheng
authors.forename: David
authors.initials: D
authors.lastname: Chao
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Tai
mesh_terms: 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*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; C051610:hepatoma-derived growth factor; D002251:Carbon Tetrachloride