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PPAR Research
Volume 2006, Article ID 69612, 9 pages
http://dx.doi.org/10.1155/PPAR/2006/69612
Research Article

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

1Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, 201 Life Sciences Building, University Park, 16802, PA, USA
2NIEHS, MD E4-07, PO Box 12233, Research Triangle Park, 27709, NC, USA

Received 28 December 2005; Revised 30 March 2006; Accepted 25 April 2006

Copyright © 2006 Eric S. Tien et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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