PT  - JOURNAL ARTICLE
AU  - Marion Régnier
AU  - Arnaud Polizzi
AU  - Sarra Smati
AU  - Céline Lukowicz
AU  - Anne Fougerat
AU  - Yannick Lippi
AU  - Edwin Fouché
AU  - Frédéric Lasserre
AU  - Claire Naylies
AU  - Colette Bétoulières
AU  - Valentin Barquissau
AU  - Etienne Mouisel
AU  - Justine Bertrand-Michel
AU  - Aurélie Batut
AU  - Talal Al Saati
AU  - Cécile Canlet
AU  - Marie Tremblay-Franco
AU  - Sandrine Ellero-Simatos
AU  - Dominique Langin
AU  - Catherine Postic
AU  - Walter Wahli
AU  - Nicolas Loiseau
AU  - Hervé Guillou
AU  - Alexandra Montagner
TI  - Hepatocyte-specific deletion of <em>Pparα</em> promotes NASH in the context of obesity
AID  - 10.1101/488031
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 488031
4099  - http://biorxiv.org/content/early/2019/01/18/488031.short
4100  - http://biorxiv.org/content/early/2019/01/18/488031.full
AB  - Objectives Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Altough steatosis is a benign condition it can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. Several drugs are being tested in clinical trials, including pharmacological agonists for the different PPAR isotypes. In current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis.Methods/Results We have investigated the role of hepatocyte PPARα in a preclinical model of steatosis using High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body (Pparα-/-) mice and in mice lacking Pparα in hepatocyte (Pparαhep-/-). We provide evidence that Pparα deletion in hepatocytes promotes NASH in mice fed an HFD. This enhanced NASH susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD.Conclusion Taken together, our data support hepatocyte PPARα as being essential to the prevention of steatosis progression to NASH and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis.HighlightsPparα deletion in hepatocytes promotes steatosis and inflammation in HFD-induced obesityHepatocyte-specific deletion of Pparα dissociates NAFLD from glucose intolerance in HFD-induced obesityExtrahepatic PPARα activity contributes to the metabolic response to HFD-induced obesity