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 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

doi:10.1016/j.celrep.2022.111321

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

Cell Rep. 2022 Sep 13;40(11):111321. doi: 10.1016/j.celrep.2022.111321.

Authors

Mohammad Kabbani¹, Eleftherios Michailidis², Sandra Steensels³, Clifton G Fulmer⁴, Joseph M Luna⁵, Jérémie Le Pen⁵, Matteo Tardelli³, Brandon Razooky⁵, Inna Ricardo-Lax⁵, Chenhui Zou⁶, Briana Zeck⁷, Ansgar F Stenzel⁸, Corrine Quirk⁵, Lander Foquet⁹, Alison W Ashbrook⁵, William M Schneider⁵, Serkan Belkaya¹⁰, Gadi Lalazar¹¹, Yupu Liang¹², Meredith Pittman¹³, Lindsey Devisscher¹⁴, Hiroshi Suemizu¹⁵, Neil D Theise⁷, Luis Chiriboga⁷, David E Cohen³, Robert Copenhaver⁹, Markus Grompe¹⁶, Philip Meuleman¹⁷, Baran A Ersoy³, Charles M Rice⁵, Ype P de Jong¹⁸

Affiliations

¹ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
² Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
³ Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA.
⁴ Department of Pathology, Weill Cornell Medicine, New York, NY 10065, USA; Robert J. Tomsich Pathology and Laboratory Medicine Institute, The Cleveland Clinic, Cleveland, OH 44195, USA.
⁵ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
⁶ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA.
⁷ Department of Pathology, NYU Langone, New York, NY 10028, USA.
⁸ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
⁹ Yecuris Corporation, Tualatin, OR 97062, USA.
¹⁰ St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA.
¹¹ Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA; Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065, USA.
¹² Center for Clinical and Translational Science, The Rockefeller University, New York, NY 10065, USA.
¹³ Department of Pathology, Weill Cornell Medicine, New York, NY 10065, USA.
¹⁴ Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.
¹⁵ Central Institute for Experimental Animals, Kanagawa, Japan.
¹⁶ Yecuris Corporation, Tualatin, OR 97062, USA; Department of Pediatrics, Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR 97239, USA.
¹⁷ Laboratory of Liver Infectious Diseases, Ghent University, Ghent, Belgium.
¹⁸ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA. Electronic address: ydj2001@med.cornell.edu.

PMID: 36103835
DOI: 10.1016/j.celrep.2022.111321

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.

Keywords: CP: Metabolism; NAFLD progression; NASH; human genetics; hypernutrition.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases
Animals
Hepatocytes / metabolism
Humans
Lipase / genetics
Lipase / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Non-alcoholic Fatty Liver Disease* / genetics
Phospholipases A2, Calcium-Independent

Substances

Membrane Proteins
Acyltransferases
Lipase
PNPLA3 protein, mouse
Phospholipases A2, Calcium-Independent

Grants and funding

R01 DK085713/DK/NIDDK NIH HHS/United States