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.[1]References
- The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Vega, R.B., Huss, J.M., Kelly, D.P. Mol. Cell. Biol. (2000) [Pubmed]
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