Huang Qi Decoction inhibits differentiation of hepatic oval cells to cholangiocytes via the β-catenin pathway to ameliorate hepatic fibrosis.

Excessive cholangiocyte expansion promotes liver diseases progression. Wnt/β-catenin signaling is crucial in regulating cell differentiation. Our previous studies showed that Huang Qi Decoction (HQD) could ameliorate progression of cholestatic liver fibrosis (CLF) through inhibition of hepatic oval cells (HOCs) differentiation into cholangiocytes. However, the role of HQD in β-catenin signaling in cholangiocyte differentiation remains unclear. In this study, bile duct ligation (BDL) model was established in rats for in vivo experiment and hepatic oval cell line (WB-F344) via stimulation with sodium butyrate for in vitro experiment. Histology analysis showed that HQD ameliorated BDL-induced hepatic fibrosis (HF) with the reduction of alpha smooth muscle actin and collagen I expression. HQD inhibited CK-19 and EpCam protein expression and decreased hydroxyproline level in BDL rat liver. HQD inhibited Cyclin D1 and c-myc mRNA and protein expression levels and blocked β-catenin nuclear translocation in liver. Moreover, HQD inhibited Wnt3a expression in BDL rat liver. In vitro results showed that HQD inhibited differentiation of WB‑F344 cells into cholangiocyte with a decreased CK-19, Cyclin D1 and c-myc mRNA and protein expression. HQD blocked β-catenin nuclear translocation during hepatic oval cell differentiation to cholangiocytes in WB-F344 cells. In addition, overexpression of β-catenin promoted hepatic oval cell differentiation into cholangiocytes and abolished the inhibitory effect of HQD. Taken together, this study has highlighted that HQD could prevent CLF by inhibiting differentiation of HOCs into cholangiocytes via the β-catenin signaling pathway, which suggests that β-catenin may be considered as a potential target for HQD during CLF treatment.