Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor-α (PPARα)

The ligand-dependent recruitment of coactivators to peroxisome proliferator-activated receptor-alpha (PPAR alpha) was examined. PPAR-binding protein (PBP), PPAR gamma coactivator-1 alpha (PGC-1 alpha), steroid receptor coactivator-1 (SRC-1), and CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) affected PPAR alpha activity in the presence of Wy-14,643. The effects on PPAR alpha activity in light of increased or decreased expression of these coactivators were qualitatively different depending on the ligand examined. Diminished expression of PGC-1 alpha, SRC-1, or PBP by RNAi plasmids affected natural or synthetic agonist activity whereas only Wy-14,643 was affected by decreased PGC-1 alpha. The interaction of PPAR alpha with an LXXLL-containing peptide library showed ligand-specific patterns, indicative of differences in conformational change. The association of coactivators to PPAR alpha occurs predominantly via the carboxyl-terminus and mutating (LHPLL)-L-456 to (456)LHPAA resulted in a dominant-negative construct. This research confirms that coactivator recruitment to PPAR alpha is ligand-dependent and that selective receptor modulators (SRMs) of this important protein are likely. Copyright (C) 2006 Eric S. Tien et al.