Overexpression of Heparin-binding Epidermal Growth Factor-like Growth Factor Mediates Liver Fibrosis in Transgenic Mice

Abstract Background The role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver fibrosis is not clear and is sometimes even contradictory. To clarify this role, a HB-EGF transgenic (Tg) mouse model was, for the first time, used to evaluate the functions of HB-EGF in liver fibrosis. Methods For the in vivo study, carbon tetrachloride (CCl4 ) injection and bile duct ligation (BDL) treatment were used to induce liver fibrosis in HB-EGF Tg mice and wild-type (WT) mice, respectively. Primary hepatic satellite cells (HSCs) were isolated from HB-EGF Tg and WT mice for the in vitro study. Results Compared with the WT mice, HB-EGF Tg mice were shown to develop more severe liver fibrosis when treated with CCl4 or bile duct ligation (BDL), with increased MMP-13 activity and enhanced expression of fibrogenic genes including α-smooth muscle actin (α-SMA) and collagen I. HB-EGF gene transfer led to an increase in proliferation and a decrease in apoptosis in primary HSCs. The ERK signaling pathway was more highly activated in primary HSCs from HB-EGF Tg mice than in those from WT mice. Conclusion Our investigation confirmed the profibrotic effect of HB-EGF on the liver using a transgenic mouse model. This result may contribute to the elucidation of HB-EGF as a therapeutic target in liver fibrosis.