Hepatic and Cardiac Metabolism in PPAR

The peroxisome proliferator–activated receptor a (PPAR a ) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPAR a is activated as a component of the cellular lipid homeostatic response, the expression of PPAR a target genes was characterized in response to a perturbation in cellular lipid oxidative flux caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition of fatty acid oxidative flux caused a feedback induction of PPAR a target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPAR a (PPAR a2 / 2 ), inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of male, but only 25% of female PPAR a2 / 2 mice. The metabolic phenotype of male PPAR a2 / 2 mice was rescued by a 2-wk pretreatment with b -estradiol. These results demonstrate a pivotal role for PPAR a in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism. ( J. Clin. Invest. 1998. 102:1083–1091.)