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Molecular Endocrinology 11 (6): 779-791
Copyright © 1997 by The Endocrine Society

Fatty Acids, Eicosanoids, and Hypolipidemic Agents Identified as Ligands of Peroxisome Proliferator-Activated Receptors by Coactivator-Dependent Receptor Ligand Assay

Grigorios Krey, Olivier Braissant, Fabienne L’Horset, Eric Kalkhoven, Mai Perroud, Malcolm G. Parker and Walter Wahli

Institut de Biologie Animale (G.K., O.B., M.P., W.W.), Bâtiment de Biologie, Université de Lausanne, CH-1015 Lausanne, Switzerland,
Molecular Endocrinology Laboratory (F.L., E.K., M.G.P.), Imperial Cancer Research Fund, 44 Lincoln’s Inn Fields, London WC2A 3PX, U.K.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors controlling the expression of genes involved in lipid homeostasis. PPARs activate gene transcription in response to a variety of compounds including hypolipidemic drugs as well as natural fatty acids. From the plethora of PPAR activators, Scatchard analysis of receptor-ligand interactions has thus far identified only four ligands. These are the chemotactic agent leukotriene B4 and the hypolipidemic drug Wy 14,643 for the {alpha}-subtype and a prostaglandin J2 metabolite and synthetic antidiabetic thiazolidinediones for the {gamma}-subtype. Based on the hypothesis that ligand binding to PPAR would induce interactions of the receptor with transcriptional coactivators, we have developed a novel ligand sensor assay, termed coactivator-dependent receptor ligand assay (CARLA). With CARLA we have screened several natural and synthetic candidate ligands and have identified naturally occurring fatty acids and metabolites as well as hypolipidemic drugs as bona fide ligands of the three PPAR subtypes from Xenopus laevis. Our results suggest that PPARs, by their ability to interact with a number of structurally diverse compounds, have acquired unique ligand-binding properties among the superfamily of nuclear receptors that are compatible with their biological activity.




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T. Yoshikawa, T. Ide, H. Shimano, N. Yahagi, M. Amemiya-Kudo, T. Matsuzaka, S. Yatoh, T. Kitamine, H. Okazaki, Y. Tamura, et al.
Cross-Talk between Peroxisome Proliferator-Activated Receptor (PPAR) {alpha} and Liver X Receptor (LXR) in Nutritional Regulation of Fatty Acid Metabolism. I. PPARs Suppress Sterol Regulatory Element Binding Protein-1c Promoter through Inhibition of LXR Signaling
Mol. Endocrinol., July 1, 2003; 17(7): 1240 - 1254.
[Abstract] [Full Text] [PDF]

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T. Ide, H. Shimano, T. Yoshikawa, N. Yahagi, M. Amemiya-Kudo, T. Matsuzaka, M. Nakakuki, S. Yatoh, Y. Iizuka, S. Tomita, et al.
Cross-Talk between Peroxisome Proliferator-Activated Receptor (PPAR) {alpha} and Liver X Receptor (LXR) in Nutritional Regulation of Fatty Acid Metabolism. II. LXRs Suppress Lipid Degradation Gene Promoters through In