Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement Access content directly
Journal Articles Gut Year : 2016

Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD

Alexandra Montagner
  • Function : Author
Simon Ducheix
  • Function : Author
Yannick Lippi
Frédéric Lasserre
  • Function : Author
  • PersonId : 1202853
Marion Régnier
  • Function : Author
  • PersonId : 1073447
Céline Lukowicz
  • Function : Author
  • PersonId : 1017606
Fadila Benhamed
Alison Iroz
  • Function : Author
Patricia Cano
  • Function : Author
Gilles Mithieux
Fabienne Rajas
Thierry Pineau
  • Function : Author
Nicolas Loiseau
Catherine Postic
  • Function : Author

Abstract

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 (Pparα(hep-/-)) 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 Pparα(hep-/-) 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 Pparα(hep-/-) remained lean. However, like Pparα(-/-) mice, Pparα(hep-/-) 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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Dates and versions

inserm-02339685 , version 1 (30-10-2019)

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Alexandra Montagner, Arnaud Polizzi, Edwin Fouché, Simon Ducheix, Yannick Lippi, et al.. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut, 2016, 65 (7), pp.1202-1214. ⟨10.1136/gutjnl-2015-310798⟩. ⟨inserm-02339685⟩
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