The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes

Peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 PPAR alpha in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demonstrated that PGC-1 enhanced PPAR alpha-mediated transcriptional activation of reporter plasmids containing PPARa target elements. PGC-1 also enhanced the transactivation activity of a PPAR alpha-Gal4 DNA binding domain fusion protein. Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPAR alpha and PGC-1 cooperatively induced the expression of PPAR alpha 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 PPAR gamma, PGC-1 binds PPAR alpha in a ligand influenced manner. Protein-protein interaction studies and mammalian cell hybrid experiments demonstrated that the PGC-1-PPAR alpha interaction involves an LXXLL domain in PGC-1 and the PPAR alpha AF2 region, consistent with the observed ligand influence. Last, the PGC-1 transactivation domain was mapped to within the NH2-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPAR alpha interacting domains. These results identify PGC-1 as a coactivator of PPAR alpha in the transcriptional control of mitochondrial FAO capacity, define separable PPAR alpha. interaction and transactivation domains within the PGC-1 molecule, and demonstrate that certain features of the PPAR gamma-PGC-1 interaction are distinct from that of PPAR gamma-PGC-1.