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In humans, the PNPLA3 I148M polymorphism of the phospholipase patatin\u2010like phospholipid domain containing protein 3 (PNPLA3) has a well\u2010documented impact on metabolic liver disease. In this study, we used a mouse model mimicking the human PNPLA3 I148M polymorphism in a long\u2010term high fat diet (HFD) experiment to better define its role for NAFLD progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male mice bearing wild\u2010type <jats:italic>Pnpla3<\/jats:italic> (<jats:italic>Pnpla3<\/jats:italic><jats:sup><jats:italic>WT<\/jats:italic><\/jats:sup>), or the human polymorphism PNPLA3 I148M (<jats:italic>Pnpla3<\/jats:italic><jats:sup><jats:italic>148M\/M<\/jats:italic><\/jats:sup>) were subjected to HFD feeding for 24 and 52\u2009weeks. Further analysis concerning basic phenotype, inflammation, proliferation and cell death, fibrosis and microbiota were performed in each time point.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After 52\u2009weeks HFD <jats:italic>Pnpla3<\/jats:italic><jats:sup><jats:italic>148M\/M<\/jats:italic><\/jats:sup> animals had more liver fibrosis, enhanced numbers of inflammatory cells as well as increased Kupffer cell activity. Increased hepatocyte cell turnover and ductular proliferation were evident in HFD <jats:italic>Pnpla3<\/jats:italic><jats:sup><jats:italic>148M\/M<\/jats:italic><\/jats:sup> livers. Microbiome diversity was decreased after HFD feeding, changes were influenced by HFD feeding (36%) and the PNPLA3 I148M genotype (12%). <jats:italic>Pnpla3<\/jats:italic><jats:sup><jats:italic>148M\/M<\/jats:italic><\/jats:sup> mice had more faecal bile acids. RNA\u2010sequencing of liver tissue defined an HFD\u2010associated signature, and a <jats:italic>Pnpla3<\/jats:italic><jats:sup><jats:italic>148M\/M<\/jats:italic><\/jats:sup> specific pattern, which suggests Kupffer cell and monocytes\u2010derived macrophages as significant drivers of liver disease progression in <jats:italic>Pnpla3<\/jats:italic><jats:sup><jats:italic>148M\/M<\/jats:italic><\/jats:sup> animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>With long\u2010term HFD feeding, mice with the PNPLA3 I148M genotype show exacerbated NAFLD. This finding is linked to PNPLA3 I148M\u2010specific changes in microbiota composition and liver gene expression showing a stronger inflammatory response leading to enhanced liver fibrosis progression.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15587","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T05:27:40Z","timestamp":1681882060000},"page":"1699-1713","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Long\u2010term hypercaloric diet exacerbates metabolic liver disease in PNPLA3 I148M animals"],"prefix":"10.1111","volume":"43","author":[{"given":"Huan","family":"Su","sequence":"first","affiliation":[{"name":"Department of Medicine III University Hospital RWTH Aachen  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhuri","family":"Haque","sequence":"additional","affiliation":[{"name":"Department of Medicine III University Hospital RWTH Aachen  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