{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:53:31Z","timestamp":1790726011935,"version":"4.1.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>NAFLD is a growing public health burden. However, the pathogenesis of NAFLD has not yet been fully elucidated, and the importance of genetic factors has only recently been appreciated. Genomic studies have revealed a strong association between NAFLD progression and the I148M variant in patatin\u2010like phospholipase domain\u2010containing protein 3 (PNPLA3). Nonetheless, very little is known about the mechanisms by which this gene and its variants can influence disease development. To investigate these mechanisms, we have developed an <jats:italic toggle=\"yes\">in vitro<\/jats:italic> model that takes advantage of the unique properties of human\u2010induced pluripotent stem cells (hiPSCs) and the CRISPR\/CAS9 gene editing technology.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We used isogenic hiPSC lines with either a knockout (PNPLA3<jats:sup>KO<\/jats:sup>) of the PNPLA3 gene or with the I148M variant (PNPLA3<jats:sup>I148M<\/jats:sup>) to model PNPLA3\u2010associated NAFLD. The resulting hiPSCs were differentiated into hepatocytes, treated with either unsaturated or saturated free fatty acids to induce NAFLD\u2010like phenotypes, and characterized by various functional, transcriptomic, and lipidomic assays. PNPLA3<jats:sup>KO<\/jats:sup> hepatocytes showed higher lipid accumulation as well as an altered pattern of response to lipid\u2010induced stress. Interestingly, loss of PNPLA3 also caused a reduction in xenobiotic metabolism and predisposed PNPLA3<jats:sup>KO<\/jats:sup> cells to be more susceptible to ethanol\u2010induced and methotrexate\u2010induced toxicity. The PNPLA3<jats:sup>I148M<\/jats:sup> cells exhibited an intermediate phenotype between the wild\u2010type and PNPLA3<jats:sup>KO<\/jats:sup> cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Together, these results indicate that the I148M variant induces a loss of function predisposing to steatosis and increased susceptibility to hepatotoxins.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32063","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T15:30:42Z","timestamp":1626795042000},"page":"2998-3017","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":78,"title":["Modeling PNPLA3\u2010Associated NAFLD Using Human\u2010Induced Pluripotent Stem Cells"],"prefix":"10.1097","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6318-5784","authenticated-orcid":false,"given":"Samantha G.","family":"Tilson","sequence":"first","affiliation":[{"name":"Wellcome Sanger Institute,Hinxton,United Kingdom"},{"name":"Wellcome Medical Research Council Cambridge Stem Cell Institute,University of Cambridge,Cambridge,United Kingdom"},{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola M.","family":"Morell","sequence":"additional","affiliation":[{"name":"Wellcome Medical Research Council Cambridge Stem Cell Institute,University of Cambridge,Cambridge,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An\u2010Sofie","family":"Lenaerts","sequence":"additional","affiliation":[{"name":"Wellcome Medical Research Council Cambridge Stem Cell Institute,University of Cambridge,Cambridge,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Bum","family":"Park","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongyi","family":"Hu","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Wellcome Medical Research Council Institute of Metabolic Science,University of Cambridge,Cambridge,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9998-051X","authenticated-orcid":false,"given":"Albert","family":"Koulman","sequence":"additional","affiliation":[{"name":"Wellcome Medical Research Council Institute of Metabolic Science,University of Cambridge,Cambridge,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3828-702X","authenticated-orcid":false,"given":"T. Jake","family":"Liang","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Vallier","sequence":"additional","affiliation":[{"name":"Wellcome Medical Research Council Cambridge Stem Cell Institute,University of Cambridge,Cambridge,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"issue":"Suppl 1","key":"hep32063-bib-0001-20250824","first-page":"81","article-title":"The epidemiology of non\u2010alcoholic fatty liver disease","volume":"37","year":"2017","journal-title":"Liver Int"},{"key":"hep32063-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.cgh.2011.03.020","article-title":"Changes in the prevalence of the most common causes of chronic liver 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History"}},{"value":"2021-07-06","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}