The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes.
Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid beta-oxidation (FAO) enzymes. In this study we sought to determine whether the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of coactivating PPARalpha in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demonstrated that PGC-1 enhanced PPARalpha-mediated transcriptional activation of reporter plasmids containing PPARalpha target elements. PGC-1 also enhanced the transactivation activity of a PPARalpha-Gal4 DNA binding domain fusion protein. Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPARalpha and PGC-1 cooperatively induced the expression of PPARalpha target genes and increased cellular palmitate oxidation rates. Glutathione S-transferase "pulldown" studies revealed that in contrast to the previously reported ligand-independent interaction with PPARgamma, PGC-1 binds PPARalpha in a ligand-influenced manner. Protein-protein interaction studies and mammalian cell hybrid experiments demonstrated that the PGC-1-PPARalpha interaction involves an LXXLL domain in PGC-1 and the PPARalpha AF2 region, consistent with the observed ligand influence. Last, the PGC-1 transactivation domain was mapped to within the NH(2)-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPARalpha interacting domains. These results identify PGC-1 as a coactivator of PPARalpha in the transcriptional control of mitochondrial FAO capacity, define separable PPARalpha interaction and transactivation domains within the PGC-1 molecule, and demonstrate that certain features of the PPARalpha-PGC-1 interaction are distinct from that of PPARgamma-PGC-1.
Vega
R B
RB
Center for Cardiovascular Research, Departments of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Huss
J M
JM
Kelly
D P
DP
D000818:Animals; D002460:Cell Line; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D004798:Enzymes; D005227:Fatty Acids; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1