Zebrafish ppp1r21 mutant as a model for the study of primary biliary cholangitis
作者机构：Institute of Developmental Biology and Regenerative MedicineSouthwest UniversityBeibeiChongqing 400715China
出 版 物：《Journal of Genetics and Genomics》 (遗传学报（英文版）)
年 卷 期：2023年第50卷第12期
页 面：1004-1013页
核心收录：
学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学]
基 金：This work was supported by the National Natural Science Foundation of China(32270859 and 32192400) the National Key R&D Program of China(2021YFA0805000)
主 题：Zebrafish mutant ppp1r21 Primary biliary cholangitis PDC-E2 PI3K/AKT/mTOR pathway
摘 要：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.
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