TY - JOUR T1 - Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice JF - bioRxiv DO - 10.1101/2020.11.19.387613 SP - 2020.11.19.387613 AU - Mohammad Kabbani AU - Eleftherios Michailidis AU - Sandra Steensels AU - Clifton G. Fulmer AU - Joseph M. Luna AU - Jérémie Le Pen AU - Matteo Tardelli AU - Brandon Razooky AU - Inna Ricardo-Lax AU - Chenhui Zou AU - Briana Zeck AU - Ansgar F. Stenzel AU - Corrine Quirk AU - Lander Foquet AU - Alison W. Ashbrook AU - William M. Schneider AU - Serkan Belkaya AU - Gadi Lalazar AU - Yupu Liang AU - Meredith Pittman AU - Lindsey Devisscher AU - Hiroshi Suemizu AU - Neil D. Theise AU - Luis Chiriboga AU - David E. Cohen AU - Robert Copenhaver AU - Markus Grompe AU - Philip Meuleman AU - Baran A. Ersoy AU - Charles M. Rice AU - Ype P. de Jong Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/20/2020.11.19.387613.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -