A Gender-related Defect in Lipid Metabolism and Glucose Homeostasis in Peroxisome Proliferator- Activated Receptor Alpha- Deficient Mice

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1998 Sep 17

PMID 9739042

Citations 133

Authors

F Djouadi

C J Weinheimer

J E Saffitz

C Pitchford

J Bastin

F J Gonzalez

D P Kelly

Affiliations

Soon will be listed here.

Abstract

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

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