Open AccessFatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ
Author(s) -
Steven A. Kliewer,
Scott S. Sundseth,
Stacey A. Jones,
Peter J. Brown,
G. Bruce Wisely,
Cecilia S. Koble,
Pallavi R. Devchand,
Walter Wahli,
Timothy M. Willson,
James M. Lenhard,
Jürgen Lehmann
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.9.4318
Subject(s) - fibrate , peroxisome proliferator activated receptor , peroxisome , receptor , peroxisome proliferator activated receptor alpha , polyunsaturated fatty acid , biochemistry , nuclear receptor , eicosanoid , chemistry , prostaglandin , lipid signaling , biology , transcription factor , fatty acid , arachidonic acid , cholesterol , gene , enzyme
Peroxisome proliferator-activated receptors (PPARs) α and γ are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-Δ12,14 -prostaglandin J2 have been shown to bind to PPARγ, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, we describe a novel fibrate, designated GW2331, that is a high-affinity ligand for both PPARα and PPARγ. Using GW2331 as a radioligand in competition binding assays, we show that certain mono- and polyunsaturated fatty acids bind directly to PPARα and PPARγ at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-Δ12,14 -prostaglandin J2 can function as subtype-selective ligands for PPARα and PPARγ, respectively. These data provide evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis.