Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation
Open accessAbstract
We have investigated whether side chain-hydroxylated cholesterol species are important for elimination of cholesterol from the brain. Plasma concentrations of 24-hydroxycholesterol (24-OH-Chol) in the internal jugular vein and the brachial artery in healthy volunteers were consistent with a net flux of this steroid from the brain into the circulation, corresponding to elimination of approximately 4 mg cholesterol during a 24-h period in adults. Results of experiments with rats exposed to 18O2 were also consistent with a flux of 24-OH-Chol from the brain into the circulation. No other oxysterol measured showed a similar behavior as 24-OH-Chol. These results and the finding that the concentration of 24-OH-Chol was 30- to 1500-fold higher in the brain than in any other organ except the adrenals indicate that the major part of 24-OH-Chol present in the circulation originates from the brain. Both the 24-OH-Chol present in the brain and in the circulation were the 24S-stereoisomer. In contrast to other oxysterols, levels of plasma 24-OH-Chol were found to be markedly dependent upon age. The ratio between 24-OH-Chol and cholesterol in plasma was approximately 5 times higher during the first decade of life than during the sixth decade. There was a high correlation between levels of 24-OH-Chol in plasma and cerebrospinal fluid. It is suggested that the flux of 24-OH-Chol from the brain is important for cholesterol homeostasis in this organ.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The catabolic pathway facilitated by cholesterol 24-hydroxylase (CYP46A1) is the major route for eliminating cholesterol from the CNS and is a key player in the maintenance of cholesterol homeostasis in the brain.
“This catabolic pathway, which is facilitated by cholesterol 24-hydroxylase (CYP46A1), is the major route for eliminating cholesterol from the CNS, and is therefore a key player in the maintenance of cholesterol homeostasis in the brain (Lütjohann et al., 1996; Russell et al., 2009).”
From Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis (2017) · cites this paper as Lütjohann et al., 1996
The Abstract (page not specified in our copy) reports a flux of 24S-hydroxycholesterol from the brain into circulation and suggests that this flux is important for brain cholesterol homeostasis. It does not identify CYP46A1 as the enzyme or establish that this is the major route for eliminating cholesterol from the CNS. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 30
- Andersson M., Elmberger P. G., Edlund C., Kristensson K., Dallner G. Rates of cholesterol, ubiquinone, dolichol and dolichyl-P biosynthesis in rat brain slices. FEBS Lett. 1990 Aug 20;269(1):15–18. doi: 10.1016/0014-5793(90)81107-y. [DOI] [PubMed] [Google Scholar] · DOI
- Björkhem I., Andersson O., Diczfalusy U., Sevastik B., Xiu R. J., Duan C., Lund E. Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8592–8596. doi: 10.1073/pnas.91.18.8592. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Björkhem I. Mechanism of degradation of the steroid side chain in the formation of bile acids. J Lipid Res. 1992 Apr;33(4):455–471. [PubMed] [Google Scholar]
- Bladin C. F., Burns P. N. Doppler ultrasound measurement of cerebral blood flow. Stroke. 1994 Jul;25(7):1524–1525. doi: 10.1161/01.str.25.7.1524. [DOI] [PubMed] [Google Scholar] · DOI
- Breuer O., Björkhem I. Use of an 18O2 inhalation technique and mass isotopomer distribution analysis to study oxygenation of cholesterol in rat. Evidence for in vivo formation of 7-oxo-, 7 beta-hydroxy-, 24-hydroxy-, and 25-hydroxycholesterol. J Biol Chem. 1995 Sep 1;270(35):20278–20284. doi: 10.1074/jbc.270.35.20278. [DOI] [PubMed] [Google Scholar] · DOI
- Czubayko F., Beumers B., Lammsfuss S., Lütjohann D., von Bergmann K. A simplified micro-method for quantification of fecal excretion of neutral and acidic sterols for outpatient studies in humans. J Lipid Res. 1991 Nov;32(11):1861–1867. [PubMed] [Google Scholar]
- DI FRISCO S., DE RUGGIERI P., ERCOLI A. Isolamento del cerebrosterolo dal cervello umano. Boll Soc Ital Biol Sper. 1953 Jul;29(7):1351–1352. [PubMed] [Google Scholar]
- Dhar A. K., Teng J. I., Smith L. L. Biosynthesis of cholest-5-ene-3beta, 24-diol (cerebrosterol) by bovine cerebral cortical microsomes. J Neurochem. 1973 Jul;21(1):51–60. doi: 10.1111/j.1471-4159.1973.tb04224.x. [DOI] [PubMed] [Google Scholar] · DOI
- Dietschy J. M., Turley S. D., Spady D. K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res. 1993 Oct;34(10):1637–1659. [PubMed] [Google Scholar]
- Dzeletovic S., Breuer O., Lund E., Diczfalusy U. Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal Biochem. 1995 Feb 10;225(1):73–80. doi: 10.1006/abio.1995.1110. [DOI] [PubMed] [Google Scholar] · DOI
- Gordon E. L., Danielsson P. E., Nguyen T. S., Winn H. R. A comparison of primary cultures of rat cerebral microvascular endothelial cells to rat aortic endothelial cells. In Vitro Cell Dev Biol. 1991 Apr;27A(4):312–326. doi: 10.1007/BF02630909. [DOI] [PubMed] [Google Scholar] · DOI
- Gustafsson J. A., Sjövall J. Identification of 22-, 24- and 26-hydroxycholesterol in the steroid sulphage fraction of faeces from infants. Eur J Biochem. 1969 Apr;8(4):467–472. doi: 10.1111/j.1432-1033.1969.tb00550.x. [DOI] [PubMed] [Google Scholar] · DOI
- Jung-Testas I., Hu Z. Y., Baulieu E. E., Robel P. Neurosteroids: biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. Endocrinology. 1989 Oct;125(4):2083–2091. doi: 10.1210/endo-125-4-2083. [DOI] [PubMed] [Google Scholar] · DOI
- Kudo K., Emmons G. T., Casserly E. W., Via D. P., Smith L. C., St Pyrek J., Schroepfer G. J., Jr Inhibitors of sterol synthesis. Chromatography of acetate derivatives of oxygenated sterols. J Lipid Res. 1989 Jul;30(7):1097–1111. [PubMed] [Google Scholar]
- Lange Y., Ye J., Strebel F. Movement of 25-hydroxycholesterol from the plasma membrane to the rough endoplasmic reticulum in cultured hepatoma cells. J Lipid Res. 1995 May;36(5):1092–1097. [PubMed] [Google Scholar]
- Lin Y. Y., Smith L. L. Sterol metabolism. 28. Biosynthesis and accumulation of cholest-5-ene-3beta, 24-diol (cerebrosterol) in developing rat brain. Biochim Biophys Acta. 1974 May 29;348(2):189–196. doi: 10.1016/0005-2760(74)90230-6. [DOI] [PubMed] [Google Scholar] · DOI
- Lin Y. Y., Smith L. L. The disposition of [24-3H]cerebrosterol in developing rat brain. J Neurochem. 1975 Nov;25(5):659–665. doi: 10.1111/j.1471-4159.1975.tb04385.x. [DOI] [PubMed] [Google Scholar] · DOI
- Lund E., Andersson O., Zhang J., Babiker A., Ahlborg G., Diczfalusy U., Einarsson K., Sjövall J., Björkhem I. Importance of a novel oxidative mechanism for elimination of intracellular cholesterol in humans. Arterioscler Thromb Vasc Biol. 1996 Feb;16(2):208–212. doi: 10.1161/01.atv.16.2.208. [DOI] [PubMed] [Google Scholar] · DOI
- Lund E., Björkhem I., Furster C., Wikvall K. 24-, 25- and 27-hydroxylation of cholesterol by a purified preparation of 27-hydroxylase from pig liver. Biochim Biophys Acta. 1993 Feb 24;1166(2-3):177–182. doi: 10.1016/0005-2760(93)90094-p. [DOI] [PubMed] [Google Scholar] · DOI
- Lund E., Breuer O., Björkhem I. Evidence that 24- and 27-hydroxylation are not involved in the cholesterol-induced down-regulation of hydroxymethylglutaryl-CoA reductase in mouse liver. J Biol Chem. 1992 Dec 15;267(35):25092–25097. [PubMed] [Google Scholar]
- Mellon S. H., Deschepper C. F. Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res. 1993 Dec 3;629(2):283–292. doi: 10.1016/0006-8993(93)91332-m. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- Pedersen J. I., Oftebro H., Björkhem I. Reconstitution of C27-steroid 26-hydroxylase activity from bovine brain mitochondria. Biochem Int. 1989 Mar;18(3):615–622. [PubMed] [Google Scholar]
- Prasad V. V., Ponticorvo L., Lieberman S. Identification of 24-hydroxycholesterol in bovine adrenals in both free and esterified forms and in bovine brains as its sulfate ester. J Steroid Biochem. 1984 Dec;21(6):733–736. doi: 10.1016/0022-4731(84)90038-4. [DOI] [PubMed] [Google Scholar] · DOI
- Ramsey R. B., Nicholas H. J. Unusual urinary cholesterol metabolites following intracerebral injection of [4-14C]cholesterol into rats: I. The minor 14C-metabolite. Lipids. 1982 Mar;17(3):263–267. doi: 10.1007/BF02535114. [DOI] [PubMed] [Google Scholar] · DOI
- Saucier S. E., Kandutsch A. A., Gayen A. K., Swahn D. K., Spencer T. A. Oxysterol regulators of 3-hydroxy-3-methylglutaryl-CoA reductase in liver. Effect of dietary cholesterol. J Biol Chem. 1989 Apr 25;264(12):6863–6869. [PubMed] [Google Scholar]
- Smith L. L., Ray D. R., Moody J. A., Wells J. D., Van Lier J. E. 24-hydroxycholesterol levels in human brain. J Neurochem. 1972 Mar;19(3):899–904. doi: 10.1111/j.1471-4159.1972.tb01406.x. [DOI] [PubMed] [Google Scholar] · DOI
- Spady D. K., Dietschy J. M. Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res. 1983 Mar;24(3):303–315. [PubMed] [Google Scholar]
- Stapleton G., Steel M., Richardson M., Mason J. O., Rose K. A., Morris R. G., Lathe R. A novel cytochrome P450 expressed primarily in brain. J Biol Chem. 1995 Dec 15;270(50):29739–29745. doi: 10.1074/jbc.270.50.29739. [DOI] [PubMed] [Google Scholar] · DOI
- Teng J. I., Smith L. L. Sterol metabolism XXXVI. Hydroxy- cholesterol esters of the human aorta. Tex Rep Biol Med. 1975;33(2):293–301. [PubMed] [Google Scholar]
- Zhang J., Akwa Y., Baulieu E. E., Sjövall J. 7 Alpha-hydroxylation of 27-hydroxycholesterol in rat brain microsomes. C R Acad Sci III. 1995 Mar;318(3):345–349. [PubMed] [Google Scholar]
Cited by
Sorted by citations
The glymphatic system: a beginner's guide
Jessen, N. A., Munk, A. S. F., Lundgaard, I., & Nedergaard, M. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1581-6 · Cited by 2,075 · see citing works
Brain Cholesterol: Long Secret Life Behind a Barrier
Björkhem, I., & Meaney, S. (2004) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000120374.59826.1b · Cited by 1,044 · see citing works
Cholesterol metabolism in neurons and astrocytes
Pfrieger, F. W., & Ungerer, N. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2011.06.002 · Cited by 500 · see citing works
Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms
Sastre, M., Klockgether, T., & Heneka, M. T. (2006) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2005.11.014 · Cited by 426 · see citing works
Lund, E. G., Xie, C., Kotti, T., Turley, S. D., Dietschy, J. M., & Russell, D. W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303415200 · Cited by 421 · see citing works
Central nervous system: cholesterol turnover, brain development and neurodegeneration
Dietschy, J. M. (2009) · bchm · doi:10.1515/bc.2009.035 · Cited by 394 · see citing works
Cholesterol 24-Hydroxylase: an enzyme of cholesterol turnover in the brain
Russell, D. W., Halford, R. W., Ramirez, D. M. O., Shah, R., & Kotti, T. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.072407.103859 · Cited by 317 · see citing works
Oxysterols are allosteric activators of the oncoprotein Smoothened
Nachtergaele, S., Mydock, L. K., Krishnan, K., Rammohan, J., Schlesinger, P. H., Covey, D. F., & Rohatgi, R. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.765 · Cited by 284 · see citing works
Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
Feringa, F. M., & van der Kant, R. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.690372 · Cited by 226 · see citing works
Djelti, F., Braudeau, J., Hudry, E., Dhenain, M., Varin, J., Bièche, I., Marquer, C., Chali, F., Ayciriex, S., Auzeil, N., et al. (2015) · Brain · doi:10.1093/brain/awv166 · Cited by 223 · see citing works
The biosynthesis, signaling, and neurological functions of bile acids
Kiriyama, Y., & Nochi, H. (2019) · Biomolecules · doi:10.3390/biom9060232 · Cited by 204 · see citing works
Statins for the prevention of dementia
McGuinness, B., Craig, D., Bullock, R., & Passmore, P. (2009) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003160.pub2 · Cited by 193 · see citing works
Apolipoprotein E and cholesterol in aging and disease in the brain
de Chaves, E. P., Narayanaswami, V., Christoffersen, C., & Nielsen, L. B. (2008) · Future Lipidology · doi:10.2217/17460875.3.5.505 · Cited by 164 · see citing works
Brain cholesterol in normal and pathological aging
Martin, M., Dotti, C. G., & Ledesma, M. D. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.03.011 · Cited by 162 · see citing works
Profile of cholesterol-related sterols in aged amyloid precursor protein transgenic mouse brain
Lütjohann, D., Brzezinka, A., Barth, E., Abramowski, D., Staufenbiel, M., von Bergmann, K., Beyreuther, K., Multhaup, G., & Bayer, T. A. (2002) · Journal of Lipid Research · doi:10.1194/jlr.m200071-jlr200 · Cited by 158 · see citing works
Self-citationAltered cholesterol and fatty acid metabolism in Huntington disease
Block, R. C., Dorsey, E. R., Beck, C. A., Brenna, J. T., & Shoulson, I. (2010) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2009.11.003 · Cited by 152 · see citing works
Kim, H.-J., Fan, X., Gabbi, C., Yakimchuk, K., Parini, P., Warner, M., & Gustafsson, J.-Å. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711599105 · Cited by 136 · see citing works
Liver X receptors (LXR) as therapeutic targets in dyslipidemia
Bełtowski, J. (2008) · Cardiovascular Therapeutics · doi:10.1111/j.1755-5922.2008.00062.x · Cited by 132 · see citing works
Circulating Biomarkers of Cognitive Decline and Dementia
Solfrizzi, V., D'Introno, A., Colacicco, A. M., Capurso, C., Todarello, O., Pellicani, V., Capurso, S. A., Pietrarossa, G., Santamato, V., Capurso, A., et al. (2006) · Clinica Chimica Acta · doi:10.1016/j.cca.2005.06.015 · Cited by 120 · see citing works
Identification of disease markers in human cerebrospinal fluid using lipidomic and proteomic methods
Fonteh, A. N., Harrington, R. J., Huhmer, A. F., Biringer, R. G., Riggins, J. N., & Harrington, M. G. (2006) · Disease Markers · doi:10.1155/2006/202938 · Cited by 113 · see citing works
Shibuya, Y., Chang, C. C. Y., Huang, L.-H., Bryleva, E. Y., & Chang, T.-Y. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2567-14.2014 · Cited by 108 · see citing works
“In addition to synthesizing cholesterol, the brain also synthesizes a small amount of oxysterols, with 24S-hydroxycholesterol (24S-OH) being the major oxysterol (Lütjohann et al., 1996).”
BackgroundCholesterol synthesis rate in human hippocampus declines with aging
Thelen, K. M., Falkai, P., Bayer, T. A., & Lütjohann, D. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.04.034 · Cited by 107 · see citing works
Self-citationSavolainen, K., Kotti, T. J., Schmitz, W., Savolainen, T. I., Sormunen, R. T., Ilves, M., Vainio, S. J., Conzelmann, E., & Hiltunen, J. K. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh107 · Cited by 83 · see citing works
Can Cholesterol Metabolism Modulation Affect Brain Function and Behavior?
Cartocci, V., Servadio, M., Trezza, V., & Pallottini, V. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25488 · Cited by 77 · see citing works
A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice
Wiesmann, M., Zerbi, V., Jansen, D., Haast, R., Lütjohann, D., Broersen, L. M., Heerschap, A., & Kiliaan, A. J. (2016) · Neural Plasticity · doi:10.1155/2016/6846721 · Cited by 60 · see citing works
Self-citationA New Hypothesis for Alzheimer’s Disease: The Lipid Invasion Model
Rudge, J. D. (2022) · Journal of Alzheimer's Disease Reports · doi:10.3233/adr-210299 · Cited by 58 · see citing works
Noradrenergic Hypothesis Linking Neurodegeneration-Based Cognitive Decline and Astroglia
Leanza, G., Gulino, R., & Zorec, R. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00254 · Cited by 54 · see citing works
What dictates the accumulation of desmosterol in the developing brain?
Jansen, M., Wang, W., Greco, D., Bellenchi, G. C., di Porzio, U., Brown, A. J., & Ikonen, E. (2013) · The FASEB Journal · doi:10.1096/fj.12-211235 · Cited by 42 · see citing works
The steroidogenic acute regulatory protein is expressed in steroidogenic cells of the day-old brain
King, S. R., Ginsberg, S. D., Ishii, T., Smith, R. G., Parker, K. L., & Lamb, D. J. (2004) · Endocrinology · doi:10.1210/en.2003-1740 · Cited by 34 · see citing works
High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease
Pedrini, S., Chatterjee, P., Hone, E., & Martins, R. N. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15170 · Cited by 22 · see citing works
Lopez, A. M., Chuang, J.-C., Posey, K. S., & Turley, S. D. (2017) · Brain Research · doi:10.1016/j.brainres.2016.10.021 · Cited by 24 · see citing works
Lütjohann, D., Lopez, A. M., Chuang, J., Kerksiek, A., & Turley, S. D. (2018) · Lipids · doi:10.1002/lipd.12041 · Cited by 11 · see citing works
Self-citation
- Authors
- Lütjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Sidén, A., Diczfalusy, U., & Björkhem, I.
- Affiliations
- Karolinska Institutet (SE)
- Division of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Sweden.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1996-09-03
- Volume
- 93
- Issue
- 18
- Pages
- 9799-9804
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC38509
- OpenAlex
- W2057365200
- Cited by
- 682
- References
- 0
- Citations by year
- 2026: 12 · 2025: 27 · 2024: 14 · 2023: 23 · 2022: 28 · 2021: 24 · 2020: 22 · 2019: 39 · 2018: 20 · 2017: 17 · 2016: 18 · 2015: 36 · 2014: 25 · 2013: 30 · 2012: 31
- FWCI
- 13.32
- 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)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- cholesterol homeostasis, 24S-hydroxycholesterol, oxysterols, cerebrospinal fluid, human brain
- MeSH terms
- Adolescent, Adult, Aged, Aging, Animals, Brain, Child, Child, Preschool, Circadian Rhythm, Female, Homeostasis, Humans, Hydroxycholesterols, Infant, Male, Middle Aged, Oxygen, Reference Values, Stereoisomerism, Tissue Distribution, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
