@article{e6d0573b40a2428d9e4d3f89efb7002b,
title = "Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice",
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",
author = "Mohammad Kabbani and Eleftherios Michailidis and Sandra Steensels and Fulmer, {Clifton G.} and Luna, {Joseph M.} and {Le Pen}, J{\'e}r{\'e}mie and Matteo Tardelli and Brandon Razooky and Inna Ricardo-Lax and Chenhui Zou and Briana Zeck and Stenzel, {Ansgar F.} and Corrine Quirk and Lander Foquet and Ashbrook, {Alison W.} and Schneider, {William M.} and Serkan Belkaya and Gadi Lalazar and Yupu Liang and Meredith Pittman and Lindsey Devisscher and Hiroshi Suemizu and Theise, {Neil D.} and Luis Chiriboga and Cohen, {David E.} and Robert Copenhaver and Markus Grompe and Philip Meuleman and Ersoy, {Baran A.} and Rice, {Charles M.} and {de Jong}, {Ype P.}",
note = "Funding Information: This work was supported by the National Institutes of Health grants R37DK048873, R01DK056626, and R01DK103046 (to D.E.C.); R01DK085713 (to C.M.R.); K08DK090576 and R01AA027327 (to Y.P.d.J.); and the Starr Foundation (to C.M.R.). P.M. was supported by grants from Ghent University (Special Research Fund—ICOH expert center) and the Research Foundation—Flanders (grants VirEOS 30981113 and G047417N). M.K. received funding from the Deutsche Forschungsgemeinschaft under grant no. KA4688/1-1. The project was co-sponsored by the Center for Basic and Translational Research on Disorders of the Digestive System through the generosity of the Leona M. and Harry B. Helmsley Charitable Trust (to E.M.). The NYULH Center for Biospecimen Research and Development, Histology and Immunohistochemistry Laboratory SCR_018304is supported in part by the Laura and Isaac Perlmutter Cancer Center Support Grant: NIH/NCI P30CA016087. The RU Center for Clinical and Translational Science Bioinformatics program is supported by the Clinical and Translational Award (CTSA) and the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health. We thank Branka Brukner Dabovic (NYULH—Department of Cell Biology Research) for help with imaging fluorescence samples. We thank the Rockefeller University High-Throughput, Bioimaging, and Genomics Resource Centers. M.K. E.M. S.S. B.A.E. and Y.P.d.J. designed the research. M.K. E.M. S.S. C.G.F. J.M.L. J.L.P. M.T. B.R. I.R.-L. C.Z. B.Z. A.F.S. C.Q. L.F. A.W.A. W.M.S. S.B. G.L. L.C. and Y.P.d.J. performed the experiments. M.K. E.M. S.S. C.G.F. J.M.L. J.L.P. M.T. B.R. I.R.-L. C.Z. B.Z. A.F.S. C.Q. L.F. A.W.A. Y.L. D.E.C. M.P. L.D. M.G. P.M. B.A.E. C.M.R. and Y.P.d.J. analyzed the data. H.S. N.D.T. and R.C. provided new reagents/analytic tools. D.E.C. P.M. C.M.R. and Y.P.d.J. secured funding. M.K. E.M. and Y.P.d.J. wrote the paper. Y.P.d.J. directed the study. L.F. R.C. and M.G. have financial interest in Yecuris Corporation. All others declare no competing interests. Funding Information: This work was supported by the National Institutes of Health grants R37DK048873 , R01DK056626 , and R01DK103046 (to D.E.C.); R01DK085713 (to C.M.R.); K08DK090576 and R01AA027327 (to Y.P.d.J.); and the Starr Foundation (to C.M.R.). P.M. was supported by grants from Ghent University (Special Research Fund—ICOH expert center) and the Research Foundation— Flanders (grants VirEOS 30981113 and G047417N ). M.K. received funding from the Deutsche Forschungsgemeinschaft under grant no. KA4688/1-1 . The project was co-sponsored by the Center for Basic and Translational Research on Disorders of the Digestive System through the generosity of the Leona M. and Harry B. Helmsley Charitable Trust (to E.M.). The NYULH Center for Biospecimen Research and Development, Histology and Immunohistochemistry Laboratory SCR_018304 is supported in part by the Laura and Isaac Perlmutter Cancer Center Support Grant: NIH / NCI P30CA016087 . The RU Center for Clinical and Translational Science Bioinformatics program is supported by the Clinical and Translational Award (CTSA) and the National Center for Advancing Translational Sciences ( NCATS ), part of the National Institutes of Health . We thank Branka Brukner Dabovic (NYULH—Department of Cell Biology Research) for help with imaging fluorescence samples. We thank the Rockefeller University High-Throughput, Bioimaging, and Genomics Resource Centers. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = sep,
day = "13",
doi = "10.1016/j.celrep.2022.111321",
language = "English (US)",
volume = "40",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}