Cholesterol Homeostasis in Human Brain: Evidence for an Age-dependent Flux of 24S-hydroxycholesterol from the Brain into the Circulation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1996 Sep 3

PMID 8790411

Citations 214

Authors

D Lutjohann

O Breuer

G Ahlborg

I Nennesmo

A Siden

U Diczfalusy

I Bjorkhem

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms.

Savulescu-Fiedler I, Dorobantu-Lungu L, Dragosloveanu S, Benea S, Dragosloveanu C, Caruntu A Curr Issues Mol Biol. 2025; 47(2).

PMID: 39996836 PMC: 11853762. DOI: 10.3390/cimb47020115.

The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease.

Dai L, Wang J, Meng L, Zhang X, Xiao T, Deng M PLoS Biol. 2025; 23(2):e3002974.

PMID: 39964974 PMC: 11835240. DOI: 10.1371/journal.pbio.3002974.

Comprehensive analysis reveals cholesterol metabolism-related signature for predicting prognosis and guiding individualized treatment of glioma.

Lu D, Wang F, Yang Y, Duan A, Ren Y, Feng Y Heliyon. 2025; 11(1):e41601.

PMID: 39866460 PMC: 11757779. DOI: 10.1016/j.heliyon.2024.e41601.

Fragment-based development of small molecule inhibitors targeting cholesterol metabolism.

Kavanagh M, McLean K, Gilbert S, Amadi C, Snee M, Tunnicliffe R bioRxiv. 2025; .

PMID: 39803573 PMC: 11722527. DOI: 10.1101/2024.10.28.620643.

SNPs in cytochromes P450 catalyzing cholesterol degradation in brain are associated with Parkinson's disease.

Petkova-Kirova P, Kolchina A, Baas S, Wagenpfeil G, Unger M, Schulze-Hentrich J Front Pharmacol. 2024; 15:1477009.

PMID: 39403150 PMC: 11472000. DOI: 10.3389/fphar.2024.1477009.

References

Gustafsson J, Sjovall J . Identification of 22-, 24- and 26-hydroxycholesterol in the steroid sulphage fraction of faeces from infants. Eur J Biochem. 1969; 8(4):467-72. DOI: 10.1111/j.1432-1033.1969.tb00550.x. View

Breuer O, Bjorkhem 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; 270(35):20278-84. DOI: 10.1074/jbc.270.35.20278. View

Dhar A, Teng J, Smith L . Biosynthesis of cholest-5-ene-3beta, 24-diol (cerebrosterol) by bovine cerebral cortical microsomes. J Neurochem. 1973; 21(1):51-60. DOI: 10.1111/j.1471-4159.1973.tb04224.x. View

Lin Y, Smith L . Sterol metabolism. 28. Biosynthesis and accumulation of cholest-5-ene-3beta, 24-diol (cerebrosterol) in developing rat brain. Biochim Biophys Acta. 1974; 348(2):189-96. DOI: 10.1016/0005-2760(74)90230-6. View

Teng J, Smith L . Sterol metabolism XXXVI. Hydroxy- cholesterol esters of the human aorta. Tex Rep Biol Med. 1975; 33(2):293-301. View

Lin Y, Smith L . The disposition of [24-3H]cerebrosterol in developing rat brain. J Neurochem. 1975; 25(5):659-65. DOI: 10.1111/j.1471-4159.1975.tb04385.x. View

Ramsey R, Nicholas H . Unusual urinary cholesterol metabolites following intracerebral injection of [4-14C]cholesterol into rats: I. The minor 14C-metabolite. Lipids. 1982; 17(3):263-7. DOI: 10.1007/BF02535114. View

Spady D, Dietschy J . Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res. 1983; 24(3):303-15. View

Prasad 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; 21(6):733-6. DOI: 10.1016/0022-4731(84)90038-4. View

10.

Saucier S, KANDUTSCH A, GAYEN A, Swahn D, Spencer T . Oxysterol regulators of 3-hydroxy-3-methylglutaryl-CoA reductase in liver. Effect of dietary cholesterol. J Biol Chem. 1989; 264(12):6863-9. View

11.

Pedersen J, Oftebro H, Bjorkhem I . Reconstitution of C27-steroid 26-hydroxylase activity from bovine brain mitochondria. Biochem Int. 1989; 18(3):615-22. View

12.

Jung-Testas I, Hu Z, Baulieu E, Robel P . Neurosteroids: biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. Endocrinology. 1989; 125(4):2083-91. DOI: 10.1210/endo-125-4-2083. View

13.

Kudo K, Emmons G, Casserly E, Via D, Smith L, St Pyrek J . Inhibitors of sterol synthesis. Chromatography of acetate derivatives of oxygenated sterols. J Lipid Res. 1989; 30(7):1097-111. View

14.

Andersson M, Elmberger P, Edlund C, Kristensson K, Dallner G . Rates of cholesterol, ubiquinone, dolichol and dolichyl-P biosynthesis in rat brain slices. FEBS Lett. 1990; 269(1):15-8. DOI: 10.1016/0014-5793(90)81107-y. View

15.

GORDON E, Danielsson P, Nguyen T, Winn H . A comparison of primary cultures of rat cerebral microvascular endothelial cells to rat aortic endothelial cells. In Vitro Cell Dev Biol. 1991; 27A(4):312-26. DOI: 10.1007/BF02630909. View

16.

Czubayko F, Beumers B, Lammsfuss S, Lutjohann 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; 32(11):1861-7. View

17.

Bjorkhem I . Mechanism of degradation of the steroid side chain in the formation of bile acids. J Lipid Res. 1992; 33(4):455-71. View

18.

Lund E, Breuer O, Bjorkhem 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; 267(35):25092-7. View

19.

Lund E, Bjorkhem 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; 1166(2-3):177-82. DOI: 10.1016/0005-2760(93)90094-p. View

20.

Dietschy J, Turley S, Spady D . Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res. 1993; 34(10):1637-59. View