The role of the peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac lipid metabolism.
The postnatal mammalian heart uses mitochondrial fatty acid oxidation (FAO) as the chief source of energy to meet the high energy demands necessary for pump function. Flux through the cardiac FAO pathway is tightly controlled in accordance with energy demands dictated by diverse physiologic and dietary conditions. In this report, we demonstrate that the lipid-activated nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARalpha), regulates the expression of several key enzymes involved in cardiac mitochondrial FAO. In response to the metabolic stress imposed by pharmacologic inhibition of mitochondrial long-chain fatty acid import with etomoxir, PPARa serves as a molecular 'lipostat' factor by inducing the expression of target genes involved in fatty acid utilization including enzymes involved in mitochondrial and peroxisomal beta-oxidation pathways. In mice lacking PPARalpha (PPARalpha-/- mice), etomoxir precipitates a cardiac phenotype characterized by myocyte lipid accumulation. Surprisingly, this metabolic regulatory response is influenced by gender as demonstrated by the observation that male PPARalpha-/- mice are more susceptible to the metabolic stress compared to female animals. These results identify an important role for PPARalpha in the control of cardiac lipid metabolism.
Djouadi
F
F
INSERM U319, Université Paris 7, France.
Brandt
J M
JM
Weinheimer
C J
CJ
Leone
T C
TC
Gonzalez
F J
FJ
Kelly
D P
DP
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000096:biosynthesis / Q000502:physiology; D000102:Acetyl-CoA C-Acyltransferase / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D019748:Carbon-Carbon Double Bond Isomerases / Q000096:biosynthesis / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D004746:Enoyl-CoA Hydratase / Q000096:biosynthesis / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008830:Microbodies / Q000502:physiology*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology; D012313:RNA / Q000096:biosynthesis; D019998:Racemases and Epimerases / Q000096:biosynthesis / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D016335:Zinc Fingers / Q000502:physiology
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C038784:fatty acid oxidation complex; D012313:RNA; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases