Examination of ligand-dependent coactivator recruitment by peroxisome proliferator-activated receptor-α (PPARα)

Eric S. Tien, Daniel B. Hannon, Jerry T. Thompson, John P. Vanden Heuvel

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The ligand-dependent recruitment of coactivators to peroxisome proliferator-activated receptor-α (PPARα) was examined. PPAR-binding protein (PBP), PPARγcoactivator-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 456 LHPLL to 456 LHPAA 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.

Original languageEnglish (US)
Article number69612
JournalPPAR Research
DOIs
StatePublished - 2006

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Pharmacology (medical)

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