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Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice
bioRxiv - Pathology Pub Date : 2020-11-20 , DOI: 10.1101/2020.11.19.387613
Mohammad Kabbani , Eleftherios Michailidis , Sandra Steensels , Clifton G. Fulmer , Joseph M. Luna , Jérémie Le Pen , Matteo Tardelli , Brandon Razooky , Inna Ricardo-Lax , Chenhui Zou , Briana Zeck , Ansgar F. Stenzel , Corrine Quirk , Lander Foquet , Alison W. Ashbrook , William M. Schneider , Serkan Belkaya , Gadi Lalazar , Yupu Liang , Meredith Pittman , Lindsey Devisscher , Hiroshi Suemizu , Neil D. Theise , Luis Chiriboga , David E. Cohen , Robert Copenhaver , Markus Grompe , Philip Meuleman , Baran A. Ersoy , Charles M. Rice , Ype P. de Jong

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of chimeric mice respond to a hypercaloric Western-style diet. As early as 4 weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatohepatitis selectively in the human graft, followed by pericellular fibrosis after 8 weeks of hypercaloric feeding. The PNPLA3 148M variant, either from a homozygous 148M human donor or overexpressed in a homozygous 148I donor background, caused widespread microvesicular steatosis and even more severe steatohepatitis. We conclude that PNPLA3 148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variants associated with advanced fatty liver diseases.

中文翻译:

人肝细胞PNPLA3 148M加重了嵌合小鼠的快速非酒精性脂肪性肝炎发展

晚期非酒精性脂肪性肝病(NAFLD)是与易感基因多态性相关的快速出现的全球性健康问题,其中最显着的是在含有patatin样磷脂酶结构域的蛋白3(PNPLA3-I148M)中将异亮氨酸替换为蛋氨酸。在这里,我们研究了嵌合小鼠肝脏中植入的具有PNPLA3 148I和148M变体的人肝细胞如何响应高热量的西式饮食。早在4周时,高热量喂养8周后,小鼠的移植物中小鼠选择性地发生了血脂异常,葡萄糖耐量降低和脂肪性肝炎,随后出现细胞周围纤维化。PNPLA3 148M变体来自纯合的148M人类供体或在纯合的148I供体背景中过表达,引起广泛的微囊性脂肪变性,甚至更严重的脂肪性肝炎。我们得出的结论是,人肝细胞中的PNPLA3 148M使NAFLD恶化。这些模型将有助于对与晚期脂肪肝疾病相关的人类遗传变异进行机理研究。
更新日期:2020-11-22
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