Long‐term hypercaloric diet exacerbates metabolic liver disease in PNPLA3 I148M animals

Liver International, vol. 43, pp. 1699–1713

Abstract

Abstract 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.

Authors 17

1. Huan Su Aachen Department of Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Medicine III University Hospital RWTH Aachen Aachen Germany

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

2. Svea Becker Aachen Department of Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Medicine III University Hospital RWTH Aachen Aachen Germany

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

3. Karolina Edlund

   TU Dortmund University · Leibniz Research Centre for Working Environment and Human Factors

   Affiliation as printed

   Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors Technical University Dortmund Dortmund Germany

   Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany

4. Julia Duda

   TU Dortmund University

   Affiliation as printed

   Department of Statistics TU Dortmund University Dortmund Germany

   Department of Statistics, TU Dortmund University, Dortmund, Germany

5. Qingbi Wang Aachen Department of Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Medicine III University Hospital RWTH Aachen Aachen Germany

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

6. Johanna Reißing Aachen Department of Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Medicine III University Hospital RWTH Aachen Aachen Germany

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

7. Hanns–Ulrich Marschall

   University of Gothenburg

   Affiliation as printed

   Department of Molecular and Clinical Medicine University of Gothenburg Gothenburg Sweden

   Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

8. Lena Susanna Candels Aachen Department of Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Medicine III University Hospital RWTH Aachen Aachen Germany

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

9. Mohamed Ramadan Mohamed Aachen Department of Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Department of Medicine III University Hospital RWTH Aachen Aachen Germany

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

10. Wilhelm Sjöland

    University of Gothenburg

    Affiliation as printed

    Department of Molecular and Clinical Medicine University of Gothenburg Gothenburg Sweden

    Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

11. Lijun Liao

    Tongji University · Shanghai East Hospital

    Affiliation as printed

    Department of Pain Management Shanghai East Hospital, School of Medicine, Tongji University Shanghai China

    Department of Pain Management, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

12. Stephan Drexler Aachen Department of Medicine III

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Department of Medicine III University Hospital RWTH Aachen Aachen Germany

    Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

13. Till Strowig

    Helmholtz Centre for Infection Research

    Affiliation as printed

    Helmholtz Centre for Infection Research Braunschweig Germany

    Helmholtz Centre for Infection Research, Braunschweig, Germany

14. Jörg Rahnenführer

    TU Dortmund University

    Affiliation as printed

    Department of Statistics TU Dortmund University Dortmund Germany

    Department of Statistics, TU Dortmund University, Dortmund, Germany

15. Jan Georg Hengstler

    TU Dortmund University · Leibniz Research Centre for Working Environment and Human Factors

    Affiliation as printed

    Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors Technical University Dortmund Dortmund Germany

    Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany

16. Maximilian Hatting corresponding Aachen Department of Medicine III

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Department of Medicine III University Hospital RWTH Aachen Aachen Germany

    Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

17. Christian Trautwein corresponding Aachen Department of Medicine III

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Department of Medicine III University Hospital RWTH Aachen Aachen Germany

    Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany