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

Regnier, M.; Polizzi, A.; Smati, S.; Lukowicz, C.; Fougerat, A.; Lippi, Y.; Fouche, E.; Lasserre, F.; Naylies, C.; Betoulieres, C.; Barquissau, V.; Mouisel, E.; Bertrand-Michel, J.; Batut, A.; Al Saati, T.; Canlet, C.; Tremblay-Franco, M.; Ellero-Simatos, S.; Langin, D.; Postic, C.; Wahli, W.; Loiseau, N.; Guillou, H.; Montagner, A.

doi:10.1101/488031

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bioRxiv · 10.1101/488031

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

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Abstract

ObjectivesPeroxisome proliferator activated receptor (PPAR) 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 Ppar 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 PPAR in a preclinical model of steatosis.\n\nMethods/ResultsWe have investigated the role of hepatocyte PPAR 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 (Ppar-/-) mice and in mice lacking Ppar in hepatocyte (Pparhep-/-). We provide evidence that Ppar 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 PPAR activity predominantly contributes to the metabolic response to HFD.\n\nConclusionTaken together, our data support hepatocyte PPAR as being essential to the prevention of steatosis progression to NASH and that extra-hepatocyte PPAR activity contributes to whole-body lipid homeostasis.\n\nHighlightsO_LIPpar deletion in hepatocytes promotes steatosis and inflammation in HFD-induced obesity\nC_LIO_LIHepatocyte-specific deletion of Ppar dissociates NAFLD from glucose intolerance in HFD-induced obesity obesity\nC_LIO_LIExtrahepatic PPAR activity contributes to the metabolic response to HFD-induced obesity\nC_LI

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Regnier, M., Polizzi, A., Smati, S., Lukowicz, C., Fougerat, A., Lippi, Y., Fouche, E., Lasserre, F., Naylies, C., Betoulieres, C., Barquissau, V., Mouisel, E., Bertrand-Michel, J., Batut, A., Al Saati, T., Canlet, C., Tremblay-Franco, M., Ellero-Simatos, S., Langin, D., Postic, C., Wahli, W., Loiseau, N., Guillou, H., Montagner, A.. 2018-12-06. Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity. https://doi.org/10.1101/488031

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