| First Author | Montagner A | Year | 2016 |
| Journal | Gut | Volume | 65 |
| Issue | 7 | Pages | 1202-14 |
| PubMed ID | 26838599 | Mgi Jnum | J:268779 |
| Mgi Id | MGI:6273267 | Doi | 10.1136/gutjnl-2015-310798 |
| Citation | Montagner A, et al. (2016) Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65(7):1202-14 |
| abstractText | OBJECTIVE: Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARalpha on non-alcoholic fatty liver disease (NAFLD). DESIGN: We constructed a novel hepatocyte-specific PPARalpha knockout (Pparalpha(hep-/-)) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARalpha. Moreover, we measured the contribution of hepatocytic PPARalpha activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARalpha deficiency in different models of steatosis and during ageing. RESULTS: Hepatocyte PPARalpha deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARalpha-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparalpha(hep-/-) mice when compared with Pparalpha(-/-) mice implying a role of PPARalpha activity in non-hepatic tissues. In agreement with this observation, Pparalpha(-/-) mice became overweight during ageing while Pparalpha(hep-/-) remained lean. However, like Pparalpha(-/-) mice, Pparalpha(hep-/-) fed a standard diet developed hepatic steatosis in ageing. CONCLUSIONS: Altogether, these findings underscore the potential of hepatocyte PPARalpha as a drug target for NAFLD. |
