Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity [article]

Marion Régnier, Arnaud Polizzi, Sarra Smati, Céline Lukowicz, Anne Fougerat, Yannick Lippi, Edwin Fouché, Frédéric Lasserre, Claire Naylies, Colette Bétoulières, Valentin Barquissau, Etienne Mouisel (+12 others)
2018 bioRxiv   pre-print
AbstractObjectivesPeroxisome 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.
more » ... 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/ResultsWe 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.ConclusionTaken 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 obesity obesityExtrahepatic PPARα activity contributes to the metabolic response to HFD-induced obesity
doi:10.1101/488031 fatcat:c4pk6urs2fdtlnydwakdmppzzm