Upregulation of hepatoma-derived growth factor is involved in murine hepatic fibrogenesis

Background & Aims: 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 (CCl4) 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-beta 1. 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-beta 1 and Collagen COL1A1 and COL1A2 proteins. Hepatic HDGF overexpression itself deteriorated hepatocellular structure and integrity, and aggravated the extents of BDL- and CCl4-induced liver fibrosis with concomitant upregulation of TGF-beta 1 and COL1A1. Exogenous TGF-beta 1 stimulated HDGF expression only in cultured primary hepatocytes grown on Collagen matrix, whereas exogenous HDGF also increased TGF-TGF-beta 1 production in hepatocytes in a Collagen-dependent manner. Moreover, HDGF enhanced Smad2 phosphorylation dose-dependently and the TGF-beta 1-driven luciferase activities. Conclusion: HDGF plays a pro-fibrogenic role during liver fibrosis in mice through activation of TGF-beta pathway. The mutual regulation between TGF-beta 1 and HDGF may facilitate a vicious cycle to promote the progression of hepatic fibrogenesis. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.