Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 9; pp. 4318 - 4323
• Main Authors: Kliewer, S.A. (Glaxo Wellcome Research and Development, Research Triangle Park, NC.), Sundseth, S.S, Jones, S.A, Brown, P.J, Wisely, G.B, Koble, C.S, Devchand, P, Walhi, W, Willson, T.M, Lenhard, J.M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 29-04-1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: ACIDE GRAS; ACIDE GRAS POLYINSATURE; ACIDOS GRASOS; ACIDOS GRASOS POLIINSATURADOS; ADN; Amino acids; AMPHIBIEN; ANFIBIOS; Animals; Binding, Competitive; Biochemistry; Biological Sciences; Butyrates - metabolism; CHIMIORECEPTEUR; EICOSANOIDE; EICOSANOIDES; Eicosanoids; Eicosanoids - metabolism; Fatty acids; Fatty Acids - metabolism; Fibric acids; Gene Expression Regulation; GENERO HUMANO; GENETICA; GENETIQUE; GENRE HUMAIN; Humans; Hypolipidemic Agents - metabolism; LIGAND; LIGANDOS; Ligands; Lipids; MEDICAMENT; MEDICAMENTOS; Metabolism; Mice; Molecules; Phenylurea Compounds - metabolism; Plasmids; PROSTAGLANDINAS; PROSTAGLANDINE; PROTEINAS AGLUTINANTES; PROTEINE DE LIAISON; QUIMIORECEPTORES; RATON; Receptors; Receptors, Cytoplasmic and Nuclear - classification; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Recombinant Fusion Proteins - metabolism; SOURIS; Species Specificity; TRANSCRIPCION; TRANSCRIPTION; Transcription Factors - classification; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Xenopus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.9.4318

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma 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-delta(12,14)-prostaglandin J2 have been shown to bind to PPARgamma, 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 G2331, that is a high-affinity ligand for both PPARalpha and PPARgamma. Using GW2331 us a radioligand in competition binding assays, we show that certain mono- and polyunsaturated fatty acids bind directly to PPARalpha and PPARgamma at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-delta(12,14)-prostaglandin J2 can function as subtype-selective ligands for PPARalpha and PPARgamma, 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