P4HA2 induces hepatic ductular reaction and biliary fibrosis in chronic cholestatic liver diseases.

The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. In cholestatic patients with more severe liver injury correlated with levels of P4HA2 in liver. In P4HA2-/- mice there was a significantly reduced level of ductular reaction and fibrosis compared with controls in DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2-/-/MDR2-/- mice compared with MDR2-/- mice. Cholangiocytes isolated from P4HA2-/-/MDR2-/- mice displayed higher level of YAP phosphorylation, resulted in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cells proliferation by inducing SAV1 degradation, eventually resulted in activation of YAP.Conclusions:P4HA2 promotes hepatic ductular reaction and biliary fibrosis through regulating SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.