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

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