DOI: 10.1073/pnas.94.9.4318. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ

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

10.1073/pnas.94.9.4318

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

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-Δ 12,14 -prostaglandin J 2 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-Δ 12,14 -prostaglandin J 2 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.

Bibliography

Kliewer, S. A., Sundseth, S. S., Jones, S. A., Brown, P. J., Wisely, G. B., Koble, C. S., Devchand, P., Wahli, W., Willson, T. M., Lenhard, J. M., & Lehmann, J. M. (1997). Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors Î± andâÎ³. Proceedings of the National Academy of Sciences, 94(9), 4318â4323.

Authors 11

Steven A. Kliewer (first)
Scott S. Sundseth (additional)
Stacey A. Jones (additional)
Peter J. Brown (additional)
G. Bruce Wisely (additional)
Cecilia S. Koble (additional)
Pallavi Devchand (additional)
Walter Wahli (additional)
Timothy M. Willson (additional)
James M. Lenhard (additional)
Jürgen M. Lehmann (additional)

References 40 Referenced 1,741

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:31 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 3:55 p.m.)
Indexed	2 days, 22 hours ago (Aug. 27, 2025, 11:34 a.m.)
Issued	28 years, 4 months ago (April 29, 1997)
Published	28 years, 4 months ago (April 29, 1997)
Published Online	28 years, 4 months ago (April 29, 1997)
Published Print	28 years, 4 months ago (April 29, 1997)

Funders 0

None

BibTeX

@article{Kliewer_1997, title={Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ}, volume={94}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.94.9.4318}, DOI={10.1073/pnas.94.9.4318}, number={9}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Kliewer, Steven A. and Sundseth, Scott S. and Jones, Stacey A. and Brown, Peter J. and Wisely, G. Bruce and Koble, Cecilia S. and Devchand, Pallavi and Wahli, Walter and Willson, Timothy M. and Lenhard, James M. and Lehmann, Jürgen M.}, year={1997}, month=apr, pages={4318–4323} }

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