title: Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Polizzi
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Edwin
authors.initials: E
authors.lastname: Fouché
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Ducheix
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Lippi
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lasserre
authors.affiliation: INSERM UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Barquissau
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Régnier
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Lukowicz
authors.affiliation: INSERM U1016, Cochin Institute, Paris, France CNRS UMR 8104, Paris, France University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Fadila
authors.initials: F
authors.lastname: Benhamed
authors.affiliation: INSERM U1016, Cochin Institute, Paris, France CNRS UMR 8104, Paris, France University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Alison
authors.initials: A
authors.lastname: Iroz
authors.affiliation: INSERM UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.affiliation: INSERM/UPS-US006/CREFRE, Service d'Histopathologie, CHU Purpan, Toulouse, France.
authors.forename: Talal
authors.initials: T
authors.lastname: Al Saati
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Cano
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Laila
authors.initials: L
authors.lastname: Mselli-Lakhal
authors.affiliation: INSERM U855, University of Lyon, Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Mithieux
authors.affiliation: INSERM U855, University of Lyon, Lyon, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rajas
authors.affiliation: INRA UMR1348 Pegase, Saint-Gilles, France Agrocampus Ouest, UMR1348 Pegase, Rennes, France Université Européenne de Bretagne, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lagarrigue
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pineau
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Loiseau
authors.affiliation: INSERM U1016, Cochin Institute, Paris, France CNRS UMR 8104, Paris, France University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
authors.affiliation: INSERM UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, France Laboratory of Clinical Biochemistry, Toulouse University Hospitals, Toulouse, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore Center for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.affiliation: INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
mesh_terms: D017667:Adipocytes; D000375:Aging / Q000502:physiology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D004195:Disease Models, Animal; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D022781:Hepatocytes; D006706:Homeostasis / Q000235:genetics; D007003:Hypoglycemia / Q000235:genetics; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007035:Hypothermia / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008066:Lipolysis / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D050177:Overweight / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: C512110:Cyp4a10 protein, mouse; C436963:Cyp4a14 protein, mouse; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D011345:Fenofibrate
keywords: GENE EXPRESSION; LIPID METABOLISM; NONALCOHOLIC STEATOHEPATITIS
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