24-hydroxycholesterol sulfation by human cytosolic sulfotransferases: formation of monosulfates and disulfates, molecular modeling, sulfatase sensitivity, and inhibition of liver x receptor activation
Open accessAbstract
24-Hydroxycholesterol (24-OHChol) is a major cholesterol metabolite and the form in which cholesterol is secreted from the brain. 24-OHChol is transported by apolipoprotein E to the liver and converted into bile acids or excreted. In both brain and liver, 24-OHChol is a liver X receptor (LXR) agonist and has an important role in cholesterol homeostasis. 24-OHChol sulfation was examined to understand its role in 24-OHChol metabolism and its effect on LXR activation. 24-OHChol was conjugated by three isoforms of human cytosolic sulfotransferase (SULT). SULT2A1 and SULT1E1 sulfated both the 3- and 24-hydroxyls to form the 24-OHChol-3, 24-disulfate. SULT2B1b formed only 24-OHChol-3-sulfate. The 3-sulfate as a monosulfate or as the disulfate was hydrolyzed by human placental steroid sulfatase, whereas the 24-sulfate was resistant. At physiological 24-OHChol concentrations, SULT2A1 formed the 3-monosulfate and the 3, 24-disulfate as a result of a high affinity for sulfation of the 3-OH in 24-OHChol-24-sulfate. Molecular docking simulations indicate that 24-OHChol-24-sulfate binds in an active configuration in the SULT2A1 substrate binding site with high affinity only when the SULT2A1 homodimer structure was used. 24-OHChol is an LXR activator. In contrast, the 24-OHChol monosulfates were not LXR agonists in a fluorescence resonance energy transfer coactivator recruitment assay. However, both the 24-OHChol-3-sulfate and 24-sulfate were antagonists of LXR activation by N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trif-luoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) with an IC(50) of 0.15 and 0.31 muM, respectively. Inhibition of LXR activation by the 24-OHChol monosulfates at low nanomolar concentrations indicates that sulfation has a role in LXR regulation by oxysterols.
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The formation of distinct di-sulfates is described for the synthetic androgen tibolone and cholesterol.
“The formation of distinct di-sulfates is described for the synthetic androgen tibolone (Falany et al., 2004) and cholesterol (Cook et al., 2009).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Cook et al., 2009
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Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105439 · Cited by 450 · see citing works
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“The formation of distinct di-sulfates is described for the synthetic androgen tibolone (Falany et al., 2004) and cholesterol (Cook et al., 2009).”
- Authors
- Cook, I. T., Duniec-Dmuchowski, Z., Kocarek, T. A., Runge-Morris, M., & Falany, C. N.
- Affiliations
- University of Alabama at Birmingham (US)
- Wayne State University (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 37
- Issue
- 10
- Pages
- 2069-2078
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC2769038
- OpenAlex
- W2128655210
- Cited by
- 86
- References
- 42
- Citations by year
- 2026: 4 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 8 · 2016: 5 · 2015: 6 · 2014: 8 · 2013: 8 · 2012: 6
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01es006636-03, GM38953, HL050710, ES05823)
- National Heart, Lung, and Blood Institute (HL050710, R01HL050710)
- National Institute of General Medical Sciences (R01GM038953, GM-38953)
- National Institute of Environmental Health Sciences (ES 06636, R01ES005823, F32ES005823, ES05823)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- 24S-hydroxycholesterol, sulfation, cytosolic sulfotransferases, SULT2A1, SULT1E1, SULT2B1b, liver X receptor, LXR agonists, monosulfate, steroid sulfatase, cholesterol metabolism, apolipoprotein E, molecular docking
- MeSH terms
- Liver X Receptors, Cytosol, Enzyme Inhibitors, Humans, Hydroxycholesterols, Liver, Models, Molecular, Sulfatases, Sulfates, Sulfotransferases, Orphan Nuclear Receptors
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