Cited by 2,164Peroxisome Proliferator-Activated ReceptorsFatty Acid Research and HealthCholesterol and Lipid Metabolism

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

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Kliewer, Steven A., Sundseth, Scott S., Jones, Stacey A., Brown, Peter J., Wisely, G. Bruce, Koble, Cecilia S., Devchand, Pallavi, Wahli, Walter, Willson, Timothy M., Lenhard, James M., Lehmann, Jürgen M.·1997·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.94.9.4318PMC PMC20720

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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.

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Authors: 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.
Affiliations: University of Lausanne (CH)
ORCID: Kliewer, Steven A.
Sundseth, Scott S.
Brown, Peter J.
Wahli, Walter
Willson, Timothy M.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1997-04-29
Volume: 94
Issue: 9
Pages: 4318-4323
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.94.9.4318
PMC: PMC20720
OpenAlex: W2139002144
Cited by: 2,164
References: 41
Citations by year: 2026: 33 · 2025: 37 · 2024: 47 · 2023: 34 · 2022: 47 · 2021: 62 · 2020: 54 · 2019: 59 · 2018: 59 · 2017: 56 · 2016: 49 · 2015: 76 · 2014: 76 · 2013: 61 · 2012: 64
FWCI: 35.08
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords: peroxisome proliferator-activated receptors, PPARα, PPARγ, fatty acids, eicosanoids, fibrates, thiazolidinediones, 15-deoxy-Δ12,14-prostaglandin J2, ligand binding, lipid homeostasis, gene expression regulation, dietary fatty acids
MeSH terms: Animals, Hypolipidemic Agents, Binding, Competitive, Butyrates, Fatty Acids, Gene Expression Regulation, Humans, Ligands, Phenylurea Compounds, Recombinant Fusion Proteins, Species Specificity, Transcription Factors, Xenopus, Eicosanoids, Receptors, Cytoplasmic and Nuclear, Mice

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

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