Hepatocyte-Specific Deletion Of Ppar Alpha Promotes Nafld In The Context Of Obesity

Peroxisome proliferator activated receptor alpha (PPAR alpha) 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 alpha in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis 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. In the current study, we investigated the role of hepatocyte PPAR alpha in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body Ppar alpha (-) deficient mice (Ppar alpha (-/-)) and in mice lacking Ppar alpha only in hepatocytes (Ppar alpha (hep-/-)). We provide evidence that Ppar alpha deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPAR alpha activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPAR alpha as being essential to the prevention of NAFLD and that extra-hepatocyte PPAR alpha activity contributes to whole-body lipid homeostasis.