Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD

Objective Peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 PPAR alpha on non-alcoholic fatty liver disease (NAFLD). Design We constructed a novel hepatocyte-specific PPAR alpha knockout (PPAR alpha(hep-/-)) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPAR alpha. Moreover, we measured the contribution of hepatocytic PPAR alpha activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPAR alpha deficiency in different models of steatosis and during ageing. Results Hepatocyte PPAR alpha deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPAR alpha-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 PPAR alpha(hep-/-) mice when compared with PPAR alpha(-/-) mice implying a role of PPAR alpha activity in non-hepatic tissues. In agreement with this observation, PPAR alpha(-/-) mice became overweight during ageing while PPAR alpha(hep-/-) remained lean. However, like PPAR alpha(-/-) mice, PPAR alpha(hep-/-) fed a standard diet developed hepatic steatosis in ageing. Conclusions Altogether, these findings underscore the potential of hepatocyte PPAR alpha as a drug target for NAFLD.