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

Fatima Djouadi, Carla J. Weinheimer, Jeffrey E. Saffitz, Clovis Pitchford, Jean Bastin, Frank J. Gonzalez, Daniel P. Kelly

Research output: Contribution to journalArticlepeer-review

350 Scopus citations

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.

Original languageEnglish
Pages (from-to)1083-1091
Number of pages9
JournalJournal of Clinical Investigation
Volume102
Issue number6
DOIs
StatePublished - Sep 15 1998

Keywords

  • Cytoplasmic and nuclear receptors
  • Estrogens
  • Fatty acids
  • Hypoglycemia
  • Myocardial diseases

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