Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a major health burden associated with the metabolic syndrome leading to liver fibrosis, cirrhosis and ultimately liver cancer. In humans, the PNPLA3 I148M polymorphism of the phospholipase patatin‐like phospholipid domain containing protein 3 (PNPLA3) has a well‐documented impact on metabolic liver disease. In this study, we used a mouse model mimicking the human PNPLA3 I148M polymorphism in a long‐term high fat diet (HFD) experiment to better define its role for NAFLD progression. Methods Male mice bearing wild‐type Pnpla3 (Pnpla3WT), or the human polymorphism PNPLA3 I148M (Pnpla3148M/M) were subjected to HFD feeding for 24 and 52 weeks. Further analysis concerning basic phenotype, inflammation, proliferation and cell death, fibrosis and microbiota were performed in each time point. Results After 52 weeks HFD Pnpla3148M/M 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 Pnpla3148M/M livers. Microbiome diversity was decreased after HFD feeding, changes were influenced by HFD feeding (36%) and the PNPLA3 I148M genotype (12%). Pnpla3148M/M mice had more faecal bile acids. RNA‐sequencing of liver tissue defined an HFD‐associated signature, and a Pnpla3148M/M specific pattern, which suggests Kupffer cell and monocytes‐derived macrophages as significant drivers of liver disease progression in Pnpla3148M/M animals. Conclusion With long‐term HFD feeding, mice with the PNPLA3 I148M genotype show exacerbated NAFLD. This finding is linked to PNPLA3 I148M‐specific changes in microbiota composition and liver gene expression showing a stronger inflammatory response leading to enhanced liver fibrosis progression.

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