Western diet induces severe nonalcoholic steatohepatitis, ductular reaction, and hepatic fibrosis in liver CGI-58 knockout mice
Western diet induces severe nonalcoholic steatohepatitis, ductular reaction, and hepatic fibrosis in liver CGI-58 knockout mice
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西方饮食导致 CGI-58 基因敲除小鼠出现严重的非酒精性脂肪性肝炎、导管反应和肝纤维化
DOI：
10.1038/s41598-020-61473-6
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发表时间：
2020-03
影响因子：
4.6
通讯作者：
Liqing Yu
中科院分区：
文献类型：
--
作者：
Pan Yang;Youlin Wang;Weiqing Tang;Weiwei Sun;Yinyan Ma;Shu Lin;Jia Jing;Long Jiang;Hang Shi;Zhiyuan Song;Liqing Yu
具有比较基因鉴定-58 （CGI-58）突变的人类和啮齿动物表现为非酒精性脂肪性肝病（NAFLD）。本研究表明，喂食西方饮食的肝脏CGI-58敲除（LivKO）小鼠迅速发展为晚期NAFLD，包括非酒精性脂肪性肝炎（NASH）和肝纤维化。经过14周的饮食挑战，从6周龄开始，LivKO小鼠显示肝脏炎症细胞浸润和促炎基因表达增加，这与血浆转氨酶水平升高有关。肝小管反应、细胞周围纤维化和桥式纤维化仅在LivKO小鼠中观察到。与此一致的是，KO小鼠的肝脏纤维化基因mrna显著增加。此外，LivKO小鼠在肝细胞中显示大量脂滴（ld）积聚。在LivKO小鼠的胆管细胞中也观察到ld，但在floxed对照组中没有。5种LD外壳蛋白中的4种，包括perilipins 2、3、4和5，在CGI-58 KO肝脏中增加。CRISPR/ cas9介导的敲除Huh7人肝癌细胞中CGI-58可诱导LD沉积和perilipin表达，提示细胞自主作用。我们的研究结果建立了西方饮食喂养的LivKO小鼠作为NASH和肝纤维化的动物模型。这些动物可能有助于临床前筛选对抗NAFLD进展的治疗药物。
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.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
6.5
作者：
Kien B;Grond S;Haemmerle G;Lass A;Eichmann TO;Radner FPW
通讯作者：
Radner FPW
影响因子：
4.5
作者：
Speliotes EK;Yerges-Armstrong LM;Wu J;Hernaez R;Kim LJ;Palmer CD;Gudnason V;Eiriksdottir G;Garcia ME;Launer LJ;Nalls MA;Clark JM;Mitchell BD;Shuldiner AR;Butler JL;Tomas M;Hoffmann U;Hwang SJ;Massaro JM;O'Donnell CJ;Sahani DV;Salomaa V;Schadt EE;Schwartz SM;Siscovick DS;NASH CRN;GIANT Consortium;MAGIC Investigators;Voight BF;Carr JJ;Feitosa MF;Harris TB;Fox CS;Smith AV;Kao WH;Hirschhorn JN;Borecki IB;GOLD Consortium
通讯作者：
GOLD Consortium
DOI：
10.1002/hep.30150
发表时间：
2019-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Sato K;Marzioni M;Meng F;Francis H;Glaser S;Alpini G
通讯作者：
Alpini G
影响因子：
1.3
作者：
B. Straub;P. Stöffel;H. Heid;R. Zimbelmann;P. Schirmacher
通讯作者：
B. Straub;P. Stöffel;H. Heid;R. Zimbelmann;P. Schirmacher