Abrogation of ALK5 in hepatic stellate cells decreases hepatic fibrosis and ameliorates liver damage in mice following treatment with thioacetamide

Abstract

While transforming growth factor-β (TGF-β) is known to be a key inducer of hepatic stellate cell (HSC) activation during liver fibrosis but it is unclear which TGF-β receptor is required for this HSC-mediated fibrogenesis. Here, we report that abrogation of TGF-β type I receptor ALK5 in HSC activation led to reduced collagen deposition and a decreased number of myofibroblasts in livers of mutant mice lacking ALK5 in HSC (Alk5/GFAP-Cre mice) following thioacetamide (TAA) exposure. The reduced fibrosis was accompanied by decreased expression of HSC activation markers in livers. In addition, Alk5/GFAP-Cre mice exhibited decreased immune cell infiltration and reduced production of inflammatory cytokines. Associated with reduced fibrosis and inflammation, amelioration of liver injury was observed in Alk5/GFAP-Cre mice after TAA treatment. In conclusion, our results indicated that TGF-β signaling via ALK5 in HSC enhanced liver fibrogenesis and inflammation led to amplification of hepatic injury in mice exposed to TAA.

Keywords

• TGF-β
• ALK5
• hepatic stellate cells
• fibrosis
• liver injury