Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 recruitment regulates PPAR subtype specificity.
The peroxisome proliferator-activated receptors (PPAR) alpha and gamma play key roles in the transcriptional control of contrasting metabolic pathways such as adipogenesis and fatty acid beta-oxidation. Both ligand-activated nuclear receptors bind to common target gene response elements and interact with distinct domains of the transcriptional coactivator PGC-1 to attain their full transcriptional potency. Thus, PPAR subtype specificity may be determined by ligand availability and transcription factor or coactivator expression levels. To identify other, perhaps more precise mechanisms contributing to PPAR subtype specificity, we studied PGC-1 recruitment by PPARs using a previously described hormone response element in the human UCP1 promoter and a human brown adipocyte cell line as our model system. As in rodents, PGC-1 is involved in the transcriptional regulation of the UCP1 gene in humans and mediates the effects of PPARalpha and PPARgamma agonists and retinoic acid. Interestingly, a previously postulated PGC-1 repressor selectively affects the PPARalpha-mediated activation of UCP1 gene expression. Furthermore, inhibition of p38 MAPK signaling, known to regulate the PGC-1/repressor interaction, decreases the stimulatory effect of PPARalpha agonist treatment without reducing the response to thiazolidinedione or retinoic acid. These data support a model whereby PPAR subtype specificity is regulated by recruitment of PGC-1.
Oberkofler
Hannes
H
Department of Laboratory Medicine, Landeskliniken Salzburg, A-5020 Austria.
Esterbauer
Harald
H
Linnemayr
Veronika
V
Strosberg
A Donny
AD
Krempler
Franz
F
Patsch
Wolfgang
W
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007473:Ion Channels; D008024:Ligands; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D000071256:Uncoupling Protein 1; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007473:Ion Channels; D008024:Ligands; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D014212:Tretinoin; C089946:2,4-thiazolidinedione; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D010100:Oxygen