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Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ
Open accessAbstract
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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“PPARs are nuclear hormone receptors that respond to binding of endogenous fatty acids and fatty acid derivatives such as eicosanoids, by regulating expression of genes within diverse cellular pathways including lipid metabolism and inflammation (Kliewer et al., 1997; Chinetti et al., 2000).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kliewer et al., 1997
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Metadata
- 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)
- 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
- 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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