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

Abstract

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