Zebrafish ppp1r21 mutant as a model for the study of primary biliary cholangitis

Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, 400715 Chongqing, China

Funds: We thank Parsons, M. J. and Lieschke, G. J. for the transgenic lines and Luo lab members of Southwest University for technical help. This work was supported by the National Natural Science Foundation of China (32270859 and 32192400) and the National Key R&D Program of China (2021YFA0805000).

摘要

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Abstract: Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease that progresses to fibrosis and cirrhosis, resulting from the gradual destruction of intrahepatic bile ducts. Exploring genetic variants associated with PBC is essential to understand the pathogenesis of PBC. Here we identify a zebrafish balloon dog (blg) mutant with intrahepatic bile duct branching defects, exhibiting several key pathological PBC-like features, including immunodominant autoantigen PDC-E2 production, cholangiocyte apoptosis, immune cell infiltration, inflammatory activation, and liver fibrosis. blg encodes the protein phosphatase 1 regulatory subunit 21 (Ppp1r21), which is enriched in the liver and its peripheral tissues and plays a vital role in the early intrahepatic bile duct formation stage. Further studies show an excessive activation of the PI3K/AKT/mTOR pathway in the hepatic tissues in the mutant, while treatment with the pathway inhibitor LY294002 and rapamycin partially rescues intrahepatic bile duct branching defects and alleviate the PBC-like symptoms. These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.
- Zebrafish mutant /
- ppp1r21 /
- primary biliary cholangitis /
- PDC-E2 /
- PI3K/AKT/mTOR pathway

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