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Gut. 2016 Jul;65(7):1202-14. doi: 10.1136/gutjnl-2015-310798. Epub 2016 Feb 1.

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

Author information

1
INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France.
2
INSERM UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France University of Toulouse, UMR1048, Paul Sabatier University, France.
3
INSERM U1016, Cochin Institute, Paris, France CNRS UMR 8104, Paris, France University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
INSERM/UPS-US006/CREFRE, Service d'Histopathologie, CHU Purpan, Toulouse, France.
5
INSERM U855, University of Lyon, Lyon, France.
6
INRA UMR1348 Pegase, Saint-Gilles, France Agrocampus Ouest, UMR1348 Pegase, Rennes, France Université Européenne de Bretagne, France.
7
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.
8
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.

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.

KEYWORDS:

GENE EXPRESSION; LIPID METABOLISM; NONALCOHOLIC STEATOHEPATITIS

PMID:
26838599
PMCID:
PMC4941147
DOI:
10.1136/gutjnl-2015-310798
[Indexed for MEDLINE]
Free PMC Article

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