Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

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 PittmanLindsey 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

Research output: Contribution to journalArticlepeer-review

Abstract

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 broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.

Original languageEnglish (US)
Article number111321
JournalCell Reports
Volume40
Issue number11
DOIs
StatePublished - Sep 13 2022

Keywords

  • CP: Metabolism
  • human genetics
  • hypernutrition
  • NAFLD progression
  • NASH

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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