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. 2023 Jul 1;78(1):10-25.
doi: 10.1097/HEP.0000000000000317. Epub 2023 Feb 20.

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

Jun Zhang  1 , Zhuwan Lyu  1 , Bo Li  1 , Zhengrui You  1 , Nana Cui  1 , You Li  1 , Yikang Li  1 , Bingyuan Huang  1 , Ruiling Chen  1 , Yong Chen  1 , Yanshen Peng  1 , Jingyuan Fang  1 , Qixia Wang  1 , Qi Miao  1 , Ruqi Tang  1 , M Eric Gershwin  2 , Min Lian  1 , Xiao Xiao  1 , Xiong Ma  1
Affiliations

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

Jun Zhang et al. Hepatology. .

Abstract

Backgrounds: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases.

Methods: We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation.

Results: The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the 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 a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP.

Conclusions: P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.

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