The coactivator PGC-1 is involved in the regulation of the liver carnitine palmitoyltransferase I gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB).
Liver carnitine palmitoyltransferase I catalyzes the transfer of long-chain fatty acids into mitochondria. L-CPT I is considered the rate-controlling enzyme in fatty acid oxidation. Expression of the L-CPT I gene is induced by starvation in response to glucagon secretion from the pancreas, an effect mediated by cAMP. Here, the molecular mechanisms underlying the induction of L-CPT I gene expression by cAMP were characterized. We demonstrate that the cAMP response unit of the L-CPT I gene is composed of a cAMP-response element motif and a DR1 sequence located 3 kb upstream of the transcription start site. Our data strongly suggest that the coactivator PGC-1 is involved in the regulation of this gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). Indeed, (i) cotransfection of CREB or HNF4 alpha dominant negative mutants completely abolishes the effect of cAMP on the L-CPT I promoter, and (ii) the cAMP-responsive unit binds HNF4 alpha and CREB through the DR1 and the cAMP-response element sequences, respectively. Moreover, cotransfection of PGC-1 strongly activates the L-CPT I promoter through HNF4 alpha bound at the DR1 element. Finally, we show that the transcriptional induction of the PGC-1 gene by glucagon through cAMP in hepatocytes precedes that of L-CPT-1. In addition to the key role that PGC-1 plays in glucose homeostasis, it may also be critical for lipid homeostasis. Taken together these observations suggest that PGC-1 acts to coordinate the process of metabolic adaptation in the liver.
Louet
Jean-François
JF
Institut Cochin, Département d'Endocrinologie, 24 rue du Faubourg Saint Jacques, 75014 Paris, France.
Hayhurst
Graham
G
Gonzalez
Frank J
FJ
Girard
Jean
J
Decaux
Jean-François
JF
D000818:Animals; D000831:Animals, Newborn; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D005934:Glucagon / Q000494:pharmacology; D051557:Hepatocyte Nuclear Factor 4; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; C496594:Hnf4a protein, rat; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D005934:Glucagon; D000242:Cyclic AMP; D002334:Carnitine O-Palmitoyltransferase