Polyunsaturated Fatty Acids Including Docosahexaenoic and Arachidonic Acid Bind to the Retinoid X Receptor α Ligand-binding Domain
Open accessAbstract
Nuclear receptors (NRs) constitute a large and highly conserved family of ligand-activated transcription factors that regulate diverse biological processes such as development, metabolism, and reproduction. As such, NRs have become important drug targets, and the identification of novel NR ligands is a subject of much interest. The retinoid X receptor (RXR) belongs to a subfamily of NRs that bind vitamin A metabolites (i.e. retinoids), including 9-cis-retinoic acid (9-cis-RA). However, although 9-cis-RA has been described as the natural ligand for RXR, its endogenous occurrence has been difficult to confirm. Recently, evidence was provided for the existence of a different natural RXR ligand in mouse brain, the highly enriched polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) (Mata de Urquiza et al. (2000) Science 290, 2140-2144). However, the results suggested that supra-physiological levels of DHA were required for efficient RXR activation. Using a refined method for ligand addition to transfected cells, the current study shows that DHA is a more potent RXR ligand than previously observed, inducing robust RXR activation already at low micromolar concentrations. Furthermore, it is shown that other naturally occurring PUFAs can activate RXR with similar efficiency as DHA. In additional experiments, the binding of fatty acid ligands to RXRalpha is directly demonstrated by electrospray mass spectrometry of the noncovalent complex between the RXR ligand-binding domain (LBD) and its ligands. Data is presented that shows the noncovalent interaction between the RXR LBD and a number of PUFAs including DHA and arachidonic acid, corroborating the results in transfected cells. Taken together, these results show that RXR binds PUFAs in solution and that these compounds induce receptor activation, suggesting that RXR could function as a fatty acid receptor in vivo.
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Increased availability of PUFA ligand for nuclear receptor LXR alters LXR-mediated gene expression.
“In addition, increased availability of PUFA ligand for nuclear receptor LXR alters LXR-mediated gene expression47.”
From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [47]
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- Authors
- Lengqvist, J., Mata de Urquiza, A., Bergman, A.-C., Willson, T. M., Sjövall, J., Perlmann, T., & Griffiths, W. J.
- Affiliations
- Ludwig Cancer Research (BE)
- Karolinska University Hospital (SE)
- GlaxoSmithKline (United States) (US)
- Karolinska Institutet (SE)
- University of London (GB)
- Corresponding author
- Griffiths, William J.
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2004-07
- Volume
- 3
- Issue
- 7
- Pages
- 692-703
- ISSN
- 1535-9476 (ISSN-L)
- OpenAlex
- W2133639929
- Cited by
- 323
- References
- 4
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 13 · 2023: 12 · 2022: 6 · 2021: 17 · 2020: 14 · 2019: 12 · 2018: 13 · 2017: 18 · 2016: 14 · 2015: 14 · 2014: 19 · 2013: 13 · 2012: 16
- FWCI
- 16.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- retinoid X receptor alpha, docosahexaenoic acid, arachidonic acid, polyunsaturated fatty acids, ligand-binding domain, fatty acid receptor, nuclear receptor activation, electrospray ionization mass spectrometry, 9-cis-retinoic acid
- MeSH terms
- Cells, Cultured, Docosahexaenoic Acids, Fatty Acids, Unsaturated, Humans, Isotope Labeling, Mass Spectrometry, Arachidonic Acid, Protein Structure, Tertiary, Retinoid X Receptor alpha
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