Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha

J Biol Chem. 1998 Sep 11;273(37):23786-92. doi: 10.1074/jbc.273.37.23786.

Abstract

To explore the gene regulatory mechanisms involved in the metabolic control of cardiac fatty acid oxidative flux, the expression of muscle-type carnitine palmitoyltransferase I (M-CPT I) was characterized in primary cardiac myocytes in culture following exposure to the long-chain mono-unsaturated fatty acid, oleate. Oleate induced steady-state levels of M-CPT I mRNA 4.5-fold. The transcription of a plasmid construct containing the human M-CPT I gene promoter region fused to a luciferase gene reporter transfected into cardiac myocytes, was induced over 20-fold by long-chain fatty acid in a concentration-dependent and fatty acyl-chain length-specific manner. The M-CPT I gene promoter fatty acid response element (FARE-1) was localized to a hexameric repeat sequence located between 775 and 763 base pairs upstream of the initiator codon. Cotransfection experiments with expression vectors for the peroxisome proliferator-activated receptor alpha (PPARalpha) demonstrated that FARE-1 is a PPARalpha response element capable of conferring oleate-mediated transcriptional activation to homologous or heterologous promoters. Electrophoretic mobility shift assays demonstrated that PPARalpha bound FARE-1 with the retinoid X receptor alpha. The expression of M-CPT I in hearts of mice null for PPARalpha was approximately 50% lower than levels in wild-type controls. Moreover, a PPARalpha activator did not induce cardiac expression of the M-CPT I gene in the PPARalpha null mice. These results demonstrate that long-chain fatty acids regulate the transcription of a gene encoding a pivotal enzyme in the mitochondrial fatty acid uptake pathway in cardiac myocytes and define a role for PPARalpha in the control of myocardial lipid metabolism.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Base Sequence
  • Carnitine O-Palmitoyltransferase / biosynthesis
  • Carnitine O-Palmitoyltransferase / genetics*
  • Cells, Cultured
  • Cloning, Molecular
  • Epoxy Compounds / pharmacology
  • Fatty Acids, Nonesterified / pharmacology*
  • Genes, Reporter
  • Humans
  • Luciferases / biosynthesis
  • Luciferases / genetics
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / enzymology*
  • Myocardium / enzymology*
  • Oleic Acid / pharmacology
  • Promoter Regions, Genetic*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Recombinant Fusion Proteins / biosynthesis
  • Regulatory Sequences, Nucleic Acid
  • Repetitive Sequences, Nucleic Acid
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects*
  • Transcriptional Activation / drug effects*
  • Transfection

Substances

  • Epoxy Compounds
  • Fatty Acids, Nonesterified
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Oleic Acid
  • Luciferases
  • Carnitine O-Palmitoyltransferase
  • etomoxir