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    Western diet induces severe nonalcoholic steatohepatitis, ductular reaction, and hepatic fibrosis in liver CGI-58 knockout mice

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    Author
    Yang, P.
    Wang, Y.
    Yu, L.
    Date
    2020
    Journal
    Scientific Reports
    Publisher
    Nature Research
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1038/s41598-020-61473-6
    Abstract
    Humans and rodents with Comparative Gene Identification-58 (CGI-58) mutations manifest nonalcoholic fatty liver disease (NAFLD). Here we show that liver CGI-58 knockout (LivKO) mice fed a Western diet rapidly develop advanced NAFLD, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. After 14 weeks of diet challenge, starting at 6 weeks of age, LivKO mice showed increased inflammatory cell infiltration and proinflammatory gene expression in the liver, which was associated with elevated plasma levels of aminotransferases. Hepatic ductular reactions, pericellular fibrosis, and bridging fibrosis were observed only in the LivKO mice. Consistently, the KO mice had a significant increase in hepatic mRNAs for fibrogenic genes. In addition, LivKO mice displayed massive accumulation of lipid droplets (LDs) in hepatocytes. LDs were also observed in the cholangiocytes of the LivKO mice, but not the floxed controls. Four of the five LD coat proteins, including perilipins 2, 3, 4, and 5, were increased in the CGI-58 KO liver. CRISPR/Cas9-mediated knockout of CGI-58 in Huh7 human hepatoma cells induced LD deposition and perilipin expression, suggesting a cell autonomous effect. Our findings establish the Western diet-fed LivKO mice as an animal model of NASH and hepatic fibrosis. These animals may facilitate preclinical screening of therapeutic agents that counter against NAFLD progression. Copyright 2020, The Author(s).
    Sponsors
    This work was supported in part by Award Number DK111052 (L.Y.) from the National Institute of Diabetes and Digestive and Kidney Diseases, and the grant number 81570300 (Z.S) from the National Natural Science Foundation of China.
    Keyword
    gastrointestinal models
    LivKO mice
    Non-alcoholic Fatty Liver Disease
    Models, Animal
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85081921146&doi=10.1038%2fs41598-020-61473-6&partnerID=40&md5=e97717b2802179b8c76b91198c08161b; http://hdl.handle.net/10713/12457
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41598-020-61473-6
    Scopus Count
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