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

TLDR

PPARα is a nuclear receptor highly expressed in oxidative tissues and central to metabolism. The study aimed to determine how hepatocyte PPARα influences NAFLD, metabolic responses, and aging‑related steatosis using a hepatocyte‑specific knockout mouse. Using a hepatocyte‑specific PPARα knockout mouse, the authors performed fenofibrate‑stimulated transcriptomics, assessed metabolic and FGF21 responses during fasting, and evaluated steatosis and aging phenotypes. Loss of hepatocyte PPARα impaired fatty‑acid catabolism, caused hepatic lipid build‑up during fasting and steatosis models, and led to metabolic disturbances such as increased free fatty acids, hypoglycaemia, and hyp.

Abstract

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).We constructed a novel hepatocyte-specific PPARα knockout (Pparα(hep-/-)) 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.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 Pparα(hep-/-) 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 Pparα(hep-/-) remained lean. However, like Pparα(-/-) mice, Pparα(hep-/-) fed a standard diet developed hepatic steatosis in ageing.Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.