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      • Record: found
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      Cholesterol metabolites exported from human brain

      a , b , 1 , a , c , b , d ,   b , * , b , *

      Steroids

      Elsevier

      MS, mass spectrometry, GC, gas chromatography, LC, liquid chromatography, BBB, blood brain barrier, CYP, cytochrome P450, 24S-HC, 24S-hydroxycholesterol, 26-HC, (25R)26-hydroxycholesterol, 7αH,3O-CA, 7α-hydroxy-3-oxocholest-4-enoic acid, 3β,5α-diHC-6O, 3β,5α-dihydroxycholestan-6-one, C-triol, cholestane-3β,5α,6β-triol, 4α-HC, 4α-hydroxycholesterol, 4β-HC, 4β-hydroxycholesterol, GP, Girard P, 7β-HC, 7β-hydroxycholesterol, 7O-C, 7-oxocholesterol, 25-D3, 25-hydroxyvitamin D3, 7α,25-diHCO, 7α,25-dihydroxycholest-4-en-3-one, 7α,26-diHCO, 7α,(25R)26-hydroxycholest-4-en-3-one, ROS, reactive oxygen species, 7α,26-diHC, 7α,(25R)26-dihydroxycholesterol, 7α,25-diHC, 7α,25-dihydroxycholesterol, HSD3B7, hydroxysteroid dehydrogenase 3B7, 3β-HCA, 3β-hydroxycholest-5-en-(25R)26-oic acid, 3β,7α-diHCA, 3β,7α-dihydroxycholest-5-enoic acid, CHD, coronary heart disease, Oxysterol, LC–MS, GC–MS, 24S-hydroxycholesterol

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          Graphical abstract

          Highlights

          • Flux of more than 20 sterols into and out from human brain measured.

          • 24S-hydroxycholesterol confirmed to be exported from brain at about 2–3 mg/24 h.

          • Other sterols exported from brain include 5α-hydroxy-6-oxo-, 7β-hydroxy- and 7-oxo-cholesterol.

          Abstract

          The human brain contains approximately 25% of the body’s cholesterol. The brain is separated from the circulation by the blood brain barrier. While cholesterol will not passes this barrier, oxygenated forms of cholesterol can cross the barrier. Here by measuring the difference in the oxysterol content of blood plasma in the jugular vein and in a forearm vein by mass spectrometry (MS) we were able to determine the flux of more than 20 cholesterol metabolites between brain and the circulation. We confirm that 24S-hydroxycholesterol is exported from brain at a rate of about 2–3 mg/24 h. Gas chromatography (GC)–MS data shows that the cholesterol metabolites 5α-hydroxy-6-oxocholesterol (3β,5α-dihydroxycholestan-6-one), 7β-hydroxycholesterol and 7-oxocholesterol, generally considered to be formed through reactive oxygen species, are similarly exported from brain at rates of about 0.1, 2 and 2 mg/24 h, respectively. Although not to statistical significance both GC–MS and liquid chromatography (LC)–MS methods indicate that (25R)26-hydroxycholesterol is imported to brain, while LC–MS indicates that 7α-hydroxy-3-oxocholest-4-enoic acid is exported from brain.

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          Most cited references 19

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          Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.

          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.
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            Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain.

             I Björkhem (2006)
            A normal brain function requires constant levels of cholesterol, and the need for constancy seems to be higher here than in any other organ. Nature has met this need by isolation of brain cholesterol by a highly efficient blood-brain barrier. As a low synthesis of cholesterol is present in the brain, a mechanism for compensatory elimination is required. A decade ago we made the unexpected finding that the favoured mechanism for this involves conversion into 24S-hydroxycholesterol, followed by diffusion over the blood-brain barrier. Recent studies by us and others on this new pathway have given new insights into the mechanisms by which cholesterol homeostasis is maintained in the brain. We recently demonstrated a flux of another oxygenated product of cholesterol, 27-hydroxycholesterol, in the opposite direction. The latter flux may be important for neurodegeneration, and may be the link between hypercholesterolaemia and Alzheimer's disease. An overview of the above studies is presented and the possibility that the cholesterol 24S-hydroxylase in the brain may be important for memory and learning and that it may be a new drug target is discussed.
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              • Article: not found

              Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry.

              A method based on isotope dilution-mass spectrometry was developed for the determination of nine cholesterol oxidation products in human plasma. The cholesterol oxidation products determined were cholest-5-ene-3 beta,7 alpha-diol, cholest-5-ene-3 beta,7 beta-diol (7 alpha- and 7 beta-hydroxycholesterol, respectively), 3 beta-hydroxycholest-5-en-7-one(7-oxocholesterol),5,6 alpha-epoxy-5 alpha- cholestan-3 beta-ol (cholesterol-5 alpha,6 alpha-epoxide),5,6 beta-epoxy-5 beta-cholestan-3 beta-ol (cholesterol-5 beta,6 beta-epoxide), (cholesterol-5 beta,6 beta-epoxide), cholestane-3 beta,5 alpha,6 beta-triol, cholest-5-ene-3 beta,24-diol (24-hydroxycholesterol), cholest-5-ene-3 beta,25-diol (25-hydroxycholesterol), and cholest-5-ene-3 beta,27-diol (27-hydroxycholesterol). A corresponding deuterium-labeled internal standard, containing 3 to 6 deuterium atoms, was synthesized for each cholesterol oxidation product except 5 beta,6 beta-epoxycholesterol which was determined using the internal standard for 5 alpha,6 alpha-epoxycholesterol. Plasma from 31 healthy volunteers was analyzed by the new method and 27-, 24-, and 7 alpha-hydroxycholesterol were the most abundant cholesterol oxidation products (mean values 154, 64, and 43 ng/ml, respectively). The other oxysterols determined were present in concentrations lower than 30 ng/ml. Males had higher 27-hydroxycholesterol concentrations in plasma than females. The 5,6-oxygenated products were present mainly unesterified while the other oxidation products were mostly in esterified form.
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                Author and article information

                Contributors
                Journal
                Steroids
                Steroids
                Steroids
                Elsevier
                0039-128X
                1878-5867
                1 July 2015
                July 2015
                : 99
                : 189-193
                Affiliations
                [a ]Department of Medico-Surgical Sciences and Biotechnology, Sapienza University of Rome, corso della Repubblica 79, Latina 04100, Italy
                [b ]College of Medicine, Grove Building, Swansea University, Singleton Park, Swansea SA2 8PP, UK
                [c ]Department of Anesthesiology and Intensive Care, Sapienza University of Rome, vial del Policlinico 163, Rome 00161, Italy
                [d ]UMR 1037 INSERM-University Toulouse III, Cancer Research Center of Toulouse, and Institut Claudius Regaud, 31052 Toulouse, France
                Author notes
                [* ]Corresponding authors. Tel.: +44 1792 602730 (Y. Wang). Tel.: +44 1792 295562; mob.: +44 7796 776363 (W.J. Griffiths). y.wang@ 123456swansea.ac.uk w.j.griffiths@ 123456swansea.ac.uk
                [1]

                Present address: Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.

                Article
                S0039-128X(15)00055-0
                10.1016/j.steroids.2015.01.026
                4503873
                25668615
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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