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PMID:9113987

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Citation

Kliewer, SA, Sundseth, SS, Jones, SA, Brown, PJ, Wisely, GB, Koble, CS, Devchand, P, Wahli, W, Willson, TM, Lenhard, JM and Lehmann, JM (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. U.S.A. 94:4318-23

Abstract

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-Delta12, 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 GW2331, that is a high-affinity ligand for both PPARalpha and PPARgamma. Using GW2331 as 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-Delta12,14-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.

Links

PubMed PMC20720

Keywords

Animals; Binding, Competitive; Butyrates/metabolism; Eicosanoids/metabolism; Fatty Acids/metabolism; Gene Expression Regulation; Humans; Hypolipidemic Agents/metabolism; Ligands; Mice; Phenylurea Compounds/metabolism; Receptors, Cytoplasmic and Nuclear/classification; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism; Recombinant Fusion Proteins/metabolism; Species Specificity; Transcription Factors/classification; Transcription Factors/genetics; Transcription Factors/metabolism; Xenopus

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PPARA

enables

GO:0008144: drug binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPARD

enables

GO:0008144: drug binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPARG

enables

GO:0008144: drug binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPARG

involved_in

GO:0055088: lipid homeostasis

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete


See also

References

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