A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator- activated receptor alpha- deficient mice.
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.
Djouadi
F
F
INSERM U319, Université Paris 7, Paris, France.
Weinheimer
C J
CJ
Saffitz
J E
JE
Pitchford
C
C
Bastin
J
J
Gonzalez
F J
FJ
Kelly
D P
DP
D000818:Animals; D002239:Carbohydrate Metabolism, Inborn Errors / Q000503:physiopathology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D004852:Epoxy Compounds / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005246:Feedback; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D007003:Hypoglycemia; D008052:Lipid Metabolism, Inborn Errors / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency*; D012737:Sex Factors; D014157:Transcription Factors / Q000172:deficiency*
D004852:Epoxy Compounds; D005227:Fatty Acids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004958:Estradiol; D006003:Glycogen; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; C054207:etomoxir