Ligand Selectivity of the Peroxisome Proliferator-Activated Receptor α
Abstract
Peroxisome proliferator-activated receptors (PPAR alpha, beta, and gamma) are nuclear hormone receptors that play critical roles in regulating lipid metabolism. It is well established that PPARs are the targets for the hypolipidemic synthetic compounds known as peroxisome proliferators, and it has been proposed that various long-chain fatty acids and metabolites of arachidonic acid serve as the physiological ligands that activate these receptors in vivo. However, a persistent problem is that reported values of the equilibrium dissociation constants (Kds) of complexes of PPARs with these ligands are in the micromolar range, at least an order of magnitude higher than the physiological concentrations of the ligands. Thus, the identity of the endogenous ligands for PPAR remains unclear. Here we report on a fluorescence-based method for investigating the interactions of PPAR with ligands. It is shown that the synthetic fluorescent long-chain fatty acid trans-parinaric acid binds to PPARalpha with high affinity and can be used as a probe to monitor protein-ligand interactions by the receptor. Measurements of Kds characterizing the interactions of PPARalpha with various ligands revealed that PPARalpha interacts with unsaturated C:18 fatty acids, with arachidonic acid, and with the leukotriene LTB4 with affinities in the nanomolar range. These data demonstrate the utility of the optical method in examining the ligand-selectivity of PPARs, and resolve a long-standing uncertainty in un…
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- Authors
- Lin, Q., Ruuska, S. E., Shaw, N. S., Dong, D., & Noy, N.
- Affiliations
- Cornell University (US)
- Corresponding author
- Noy, Noa
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1998-12-05
- Volume
- 38
- Issue
- 1
- Pages
- 185-190
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2034283257
- Cited by
- 263
- References
- 0
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 2 · 2018: 7 · 2017: 4 · 2016: 5 · 2015: 9 · 2014: 7 · 2013: 17 · 2012: 11
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 68150, R01CA068150)
- 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
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- PPARα, peroxisome proliferator-activated receptors, ligand selectivity, endogenous ligands, fluorescent probes, protein-ligand binding affinity, arachidonic acid metabolites, leukotriene B4, long-chain fatty acids, nuclear receptors, lipid metabolism
- MeSH terms
- Agar, Animals, Chemistry, Chromatography, DEAE-Cellulose, Chromatography, Gel, Creatine Kinase, Electrophoresis, Electrophoresis, Polyacrylamide Gel, Gels, Isoenzymes, Molecular Weight, Muscles, Columbidae, Ultracentrifugation, Chemical Phenomena
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