| First Author | Régnier M | Year | 2020 |
| Journal | Sci Rep | Volume | 10 |
| Issue | 1 | Pages | 6489 |
| PubMed ID | 32300166 | Mgi Jnum | J:289796 |
| Mgi Id | MGI:6433899 | Doi | 10.1038/s41598-020-63579-3 |
| Citation | Regnier M, et al. (2020) Hepatocyte-specific deletion of Pparalpha promotes NAFLD in the context of obesity. Sci Rep 10(1):6489 |
| abstractText | Peroxisome proliferator activated receptor alpha (PPARalpha) 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 Pparalpha 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 PPARalpha in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6 J male Wild-Type mice (WT), in whole-body Pparalpha(-) deficient mice (Pparalpha(-/-)) and in mice lacking Pparalpha only in hepatocytes (Pparalpha(hep-/-)). We provide evidence that Pparalpha 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 PPARalpha activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPARalpha as being essential to the prevention of NAFLD and that extra-hepatocyte PPARalpha activity contributes to whole-body lipid homeostasis. |
