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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| Veröffentlicht in: | Journal of genetics and genomics 2023-12, Vol.50 (12), p.1004-1013 |
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| creator | Wu, Chaoying Zhang, Wenfeng Luo, Yiyu Cheng, Chaoqing Wang, Xinjuan Jiang, Yan Li, Shuang Luo, Lingfei Yang, Yun |
| description | 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. |
| doi_str_mv | 10.1016/j.jgg.2023.05.013 |
| format | Article |
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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.</description><identifier>ISSN: 1673-8527</identifier><identifier>DOI: 10.1016/j.jgg.2023.05.013</identifier><identifier>PMID: 37271428</identifier><language>eng</language><publisher>China: Elsevier Ltd</publisher><subject>apoptosis ; bile ; bile ducts ; Danio rerio ; dogs ; fibrosis ; genomics ; liver ; liver cirrhosis ; mutants ; pathogenesis ; pathophysiology ; PDC-E2 ; PI3K/AKT/mTOR pathway ; ppp1r21 ; Primary biliary cholangitis ; rapamycin ; Zebrafish mutant</subject><ispartof>Journal of genetics and genomics, 2023-12, Vol.50 (12), p.1004-1013</ispartof><rights>2023 The Authors</rights><rights>Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c429t-5c3574ff517cc60353874608524652b4044244bb66fe40a1a97c50ac39426e363</citedby><cites>FETCH-LOGICAL-c429t-5c3574ff517cc60353874608524652b4044244bb66fe40a1a97c50ac39426e363</cites><orcidid>0000-0002-5976-2259 ; 0000-0001-8009-5246 ; 0000-0002-6631-4649</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1673852723001236$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37271428$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Chaoying</creatorcontrib><creatorcontrib>Zhang, Wenfeng</creatorcontrib><creatorcontrib>Luo, Yiyu</creatorcontrib><creatorcontrib>Cheng, Chaoqing</creatorcontrib><creatorcontrib>Wang, Xinjuan</creatorcontrib><creatorcontrib>Jiang, Yan</creatorcontrib><creatorcontrib>Li, Shuang</creatorcontrib><creatorcontrib>Luo, Lingfei</creatorcontrib><creatorcontrib>Yang, Yun</creatorcontrib><title>Zebrafish ppp1r21 mutant as a model for the study of primary biliary cholangitis</title><title>Journal of genetics and genomics</title><addtitle>J Genet Genomics</addtitle><description>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. 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These findings implicate the potential role of the Ppp1r21-mediated PI3K/AKT/mTOR pathway in the pathophysiology of PBC.</description><subject>apoptosis</subject><subject>bile</subject><subject>bile ducts</subject><subject>Danio rerio</subject><subject>dogs</subject><subject>fibrosis</subject><subject>genomics</subject><subject>liver</subject><subject>liver cirrhosis</subject><subject>mutants</subject><subject>pathogenesis</subject><subject>pathophysiology</subject><subject>PDC-E2</subject><subject>PI3K/AKT/mTOR pathway</subject><subject>ppp1r21</subject><subject>Primary biliary cholangitis</subject><subject>rapamycin</subject><subject>Zebrafish mutant</subject><issn>1673-8527</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFkLtOwzAUQD2AaCl8AAvyyJLgtxMxoYqXhAQDLCyW4zito6QJtoPUv8dVCyNMdzn36N4DwAVGOUZYXLd5u1rlBBGaI54jTI_AHAtJs4ITOQOnIbQI8aLE_ATMqCQSM1LMweuHrbxuXFjDcRyxJxj2U9SbCHWAGvZDbTvYDB7GtYUhTvUWDg0cveu138LKdW43zXro9Gblogtn4LjRXbDnh7kA7_d3b8vH7Pnl4Wl5-5wZRsqYcUO5ZE3DsTRGIMppIZlA6VgmOKkYYowwVlVCNJYhjXUpDUfa0JIRYamgC3C1945--JxsiKp3wdgu3WGHKSiKk5KwMpn_Q0lBiEQC8TKheI8aP4TgbaMOryqM1K6zalXqrHadFeIqdU47lwf9VPW2_t34iZyAmz1gU48vZ70KxtmNsbXz1kRVD-4P_TcZJ40x</recordid><startdate>20231201</startdate><enddate>20231201</enddate><creator>Wu, Chaoying</creator><creator>Zhang, Wenfeng</creator><creator>Luo, Yiyu</creator><creator>Cheng, Chaoqing</creator><creator>Wang, Xinjuan</creator><creator>Jiang, Yan</creator><creator>Li, Shuang</creator><creator>Luo, Lingfei</creator><creator>Yang, Yun</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><orcidid>https://orcid.org/0000-0002-5976-2259</orcidid><orcidid>https://orcid.org/0000-0001-8009-5246</orcidid><orcidid>https://orcid.org/0000-0002-6631-4649</orcidid></search><sort><creationdate>20231201</creationdate><title>Zebrafish ppp1r21 mutant as a model for the study of primary biliary cholangitis</title><author>Wu, Chaoying ; Zhang, Wenfeng ; Luo, Yiyu ; Cheng, Chaoqing ; Wang, Xinjuan ; Jiang, Yan ; Li, Shuang ; Luo, Lingfei ; Yang, Yun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c429t-5c3574ff517cc60353874608524652b4044244bb66fe40a1a97c50ac39426e363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>apoptosis</topic><topic>bile</topic><topic>bile ducts</topic><topic>Danio rerio</topic><topic>dogs</topic><topic>fibrosis</topic><topic>genomics</topic><topic>liver</topic><topic>liver cirrhosis</topic><topic>mutants</topic><topic>pathogenesis</topic><topic>pathophysiology</topic><topic>PDC-E2</topic><topic>PI3K/AKT/mTOR pathway</topic><topic>ppp1r21</topic><topic>Primary biliary cholangitis</topic><topic>rapamycin</topic><topic>Zebrafish mutant</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Chaoying</creatorcontrib><creatorcontrib>Zhang, Wenfeng</creatorcontrib><creatorcontrib>Luo, Yiyu</creatorcontrib><creatorcontrib>Cheng, Chaoqing</creatorcontrib><creatorcontrib>Wang, Xinjuan</creatorcontrib><creatorcontrib>Jiang, Yan</creatorcontrib><creatorcontrib>Li, Shuang</creatorcontrib><creatorcontrib>Luo, Lingfei</creatorcontrib><creatorcontrib>Yang, Yun</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Journal of genetics and genomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Chaoying</au><au>Zhang, Wenfeng</au><au>Luo, Yiyu</au><au>Cheng, Chaoqing</au><au>Wang, Xinjuan</au><au>Jiang, Yan</au><au>Li, Shuang</au><au>Luo, Lingfei</au><au>Yang, Yun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Zebrafish ppp1r21 mutant as a model for the study of primary biliary cholangitis</atitle><jtitle>Journal of genetics and genomics</jtitle><addtitle>J Genet Genomics</addtitle><date>2023-12-01</date><risdate>2023</risdate><volume>50</volume><issue>12</issue><spage>1004</spage><epage>1013</epage><pages>1004-1013</pages><issn>1673-8527</issn><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 alleviates the PBC-like symptoms. 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| subjects | apoptosis bile bile ducts Danio rerio dogs fibrosis genomics liver liver cirrhosis mutants pathogenesis pathophysiology PDC-E2 PI3K/AKT/mTOR pathway ppp1r21 Primary biliary cholangitis rapamycin Zebrafish mutant |
| title | Zebrafish ppp1r21 mutant as a model for the study of primary biliary cholangitis |
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