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Original article
Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD
  1. Alexandra Montagner1,
  2. Arnaud Polizzi1,
  3. Edwin Fouché1,
  4. Simon Ducheix1,
  5. Yannick Lippi1,
  6. Frédéric Lasserre1,
  7. Valentin Barquissau2,3,
  8. Marion Régnier1,
  9. Céline Lukowicz1,
  10. Fadila Benhamed4,5,6,
  11. Alison Iroz4,5,6,
  12. Justine Bertrand-Michel2,3,
  13. Talal Al Saati7,
  14. Patricia Cano1,
  15. Laila Mselli-Lakhal1,
  16. Gilles Mithieux8,
  17. Fabienne Rajas8,
  18. Sandrine Lagarrigue9,10,11,
  19. Thierry Pineau1,
  20. Nicolas Loiseau1,
  21. Catherine Postic4,5,6,
  22. Dominique Langin2,3,12,
  23. Walter Wahli1,13,14,
  24. Hervé Guillou1
  1. 1INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
  2. 2INSERM UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
  3. 3University of Toulouse, UMR1048, Paul Sabatier University, France
  4. 4INSERM U1016, Cochin Institute, Paris, France
  5. 5CNRS UMR 8104, Paris, France
  6. 6University of Paris Descartes, Sorbonne Paris Cité, Paris, France
  7. 7INSERM/UPS-US006/CREFRE, Service d'Histopathologie, CHU Purpan, Toulouse, France
  8. 8INSERM U855, University of Lyon, Lyon, France
  9. 9INRA UMR1348 Pegase, Saint-Gilles, France
  10. 10Agrocampus Ouest, UMR1348 Pegase, Rennes, France
  11. 11Université Européenne de Bretagne, France
  12. 12Laboratory of Clinical Biochemistry, Toulouse University Hospitals, Toulouse, France
  13. 13Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
  14. 14Center for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, Switzerland
  1. Correspondence to Dr Hervé Guillou, INRA UMR1331, ToxAlim, Chemin de Tournefeuille, Toulouse 31027, France; herve.guillou{at} or Prof. Walter Wahli Lee Kong Chian School of Medicine Nanyang Technological University The Academia, 20 College Road, Singapore 169856; walter.wahli{at}


Objective Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD).

Design We constructed a novel hepatocyte-specific PPARα knockout (Pparαhep−/−) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing.

Results Hepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparαhep−/− mice when compared with Pparα−/− mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα−/− mice became overweight during ageing while Pparαhep−/− remained lean. However, like Pparα−/− mice, Pparαhep−/− fed a standard diet developed hepatic steatosis in ageing.

Conclusions Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.


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