A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor α-deficient mice

The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPAR alpha is activated as a component of the cellular lipid homeostatic response, the expression of PPAR alpha 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 alpha target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPAR alpha (PPAR alpha-/-), 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 alpha-/- mice. The metabolic phenotype of male PPAR alpha-/- mice was rescued by a 2-wk pretreatment with beta-estradiol. These results demonstrate a pivotal role for PPAR alpha in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism.