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

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 identi...

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Bibliographic Details
Published in:Journal of genetics and genomics 2023-12, Vol.50 (12), p.1004-1013
Main Authors: Wu, Chaoying, Zhang, Wenfeng, Luo, Yiyu, Cheng, Chaoqing, Wang, Xinjuan, Jiang, Yan, Li, Shuang, Luo, Lingfei, Yang, Yun
Format: Article
Language:English
Subjects:
Animals
Dogs
Liver Cirrhosis, Biliary - metabolism
Liver Cirrhosis, Biliary - pathology
PDC-E2
Phosphatidylinositol 3-Kinases - genetics
PI3K/AKT/mTOR pathway
ppp1r21
Primary biliary cholangitis
Protein Phosphatase 1 - genetics
Proto-Oncogene Proteins c-akt - genetics
TOR Serine-Threonine Kinases
Zebrafish
Zebrafish mutant
Zebrafish Proteins - genetics
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Summary: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 alleviates the PBC-like symptoms. These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.
ISSN:1673-8527
DOI:10.1016/j.jgg.2023.05.013