An intronic peroxisome proliferator-activated receptor-binding sequence mediates fatty acid induction of the human carnitine palmitoyltransferase 1A.
The liver plays a central role in the response to fasting. The hormonal profile in this condition, low insulin, and high concentrations of glucagon in plasma, induce the release of large amounts of fatty acids from adipose tissue. Prolonged starvation can therefore induce a dramatic change in the fatty acid oxidative capacity of liver metabolism. Modulation of gene expression by PPARalpha plays a crucial role in this response. While a major role for PPARalpha in the liver is to produce ketone bodies as fuel through beta-oxidation for peripheral tissues during fast, its participation in the control of CPT1A, the rate-limiting step of the pathway, remains controversial. Using Web-based software (VISTA) combining transcription factor binding site database searches with comparative sequence analyses, we have localized a conserved functional PPAR responsive element downstream of the transcriptional start site of the human CPT1A gene. We have shown that this sequence is fundamental for fatty acids or PGC1-induced transcriptional activation of the CPT1A gene. These results corroborate the hypothesis that PPARalpha regulates the limiting step in the oxidation of fatty acids in liver mitochondria.
Napal
Laura
L
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, 08028 Barcelona, Spain.
Marrero
Pedro F
PF
Haro
Diego
D
D000595:Amino Acid Sequence; D001665:Binding Sites; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D019295:Computational Biology; D030561:Databases, Nucleic Acid; D004790:Enzyme Induction; D005227:Fatty Acids / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007438:Introns; D019787:Linoleic Acid / Q000494:pharmacology; D008099:Liver / Q000166:cytology; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000502:physiology*; D020218:Response Elements; D014157:Transcription Factors / Q000494:pharmacology; D014162:Transfection
D005227:Fatty Acids; D047493:PPAR alpha; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D019787:Linoleic Acid; D002334:Carnitine O-Palmitoyltransferase