24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux
Open accessAbstract
Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose- and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10-20-fold higher basal LXRalpha and -beta expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases.
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Expression of APOE is controlled by LXRs in a human astrocytoma cell line (CCF-STTG1), where synthetic LXR agonists as well as oxysterols promote ApoE gene expression.
“Expression of APOE is controled by LXRs (51) in a human astrocytoma cell line (CCF-STTG1), where synthetic LXR agonists as well as oxysterols promote ApoE gene expression (52,53).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [53]
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- Authors
- Abildayeva, K., Jansen, P. J., Hirsch-Reinshagen, V., Bloks, V. W., Bakker, A. H. F., Ramaekers, F. C. S., de Vente, J., Groen, A. K., Wellington, Kuipers, F., & Mulder, M.
- Affiliations
- Maastricht University (NL)
- University Medical Center Groningen (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- University of British Columbia (CA)
- Corresponding author
- Mulder, Monique
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 281
- Issue
- 18
- Pages
- 12799-12808
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2114806174
- Cited by
- 267
- References
- 6
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 13 · 2023: 17 · 2022: 10 · 2021: 10 · 2020: 18 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 9 · 2015: 11 · 2014: 12 · 2013: 11 · 2012: 11
- FWCI
- 20.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Pure Amsterdam UMC (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-sa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Alzheimer's Society
- Alzheimer Society
- Rheinische Friedrich-Wilhelms-Universität Bonn
- Internationale Stichting Alzheimer Onderzoek
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- 24S-hydroxycholesterol, apolipoprotein E, cholesterol efflux, astrocytes, liver X receptor, Alzheimer's disease, ABCA1, ABCG1, ABCG4, SREBP2, astrocytoma cells, neuroblastoma cells, cholesterol metabolism
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Liver X Receptors, Animals, Apolipoproteins E, Astrocytes, Cholesterol, DNA-Binding Proteins, Humans, Hydroxycholesterols, Hydroxymethylglutaryl CoA Reductases, Mice, Inbred C57BL, Receptors, LDL, Receptors, Cytoplasmic and Nuclear, ATP-Binding Cassette Transporters, Mice, Rats, Sterol Regulatory Element Binding Protein 2, Orphan Nuclear Receptors
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