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 (PPAR alpha) plays a key r ole in the transcriptional control of genes encoding mitochondrial fatty ac id beta-oxidation (FAO) enzymes. In this study we sought to determine wheth er the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of c oactivating 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 plasmi ds containing PPARa target elements. PGC-1 also enhanced the transactivatio n activity of a PPAR alpha-Gal4 DNA binding domain fusion protein. Retrovir al vector-mediated expression studies performed in 3T3-L1 cells demonstrate d that PPAR alpha and PGC-1 cooperatively induced the expression of PPAR al pha target genes and increased cellular palmitate oxidation rates. Glutathi one S-transferase "pulldown" studies revealed that in contrast to the previ ously reported ligand-independent interaction with PPAR gamma, PGC-1 binds PPAR alpha in a ligand influenced manner. Protein-protein interaction studi es and mammalian cell hybrid experiments demonstrated that the PGC-1-PPAR a lpha interaction involves an LXXLL domain in PGC-1 and the PPAR alpha AF2 r egion, consistent with the observed ligand influence. Last, the PGC-1 trans activation domain was mapped to within the NH2-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPAR alpha interacting domai ns. These results identify PGC-1 as a coactivator of PPAR alpha in the tran scriptional control of mitochondrial FAO capacity, define separable PPAR al pha. 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.