HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Björkhem, I. Articles by Wennmalm, A. Search for Related Content PubMed PubMed Citation Articles by Björkhem, I. Articles by Wennmalm, A. Social Bookmarking                      What's this?

Volume 272, Number 48, Issue of November 28, 1997 pp. 30178-30184
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Importance of a Novel Oxidative Mechanism for Elimination of Brain Cholesterol
TURNOVER OF CHOLESTEROL AND 24(S)-HYDROXYCHOLESTEROL IN RAT BRAIN AS MEASURED WITH ¹⁸O₂ TECHNIQUES IN VIVO AND IN VITRO

(Received for publication, July 14, 1997, and in revised form, September 17, 1997)

Ingemar Björkhem , Dieter Lütjohann , Olof Breuer , Augustinas Sakinis ^¶ and Åke Wennmalm ^¶

From the  Division of Clinical Chemistry, Karolinska Institutet, Huddinge Hospital, SE-141 86 Huddinge, Sweden and the ^¶ Division of Clinical Physiology, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden

The brain is the most cholesterol-rich organ in the body. Brain cholesterol is characterized by a very low turnover with very little exchange with lipoproteins in the circulation. Very recently we showed that there is a continuous age-dependent flux of 24(S)-hydroxycholesterol from the human brain into the circulation (Lütjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Sidén, Å., Diczfalusy, U., and Björkhem, I. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9799-9804). Here we measured the rate of synthesis of cholesterol as well as the conversion of cholesterol into 24(S)-hydroxycholesterol in rat brain in vivo with use of an ¹⁸O₂ inhalation technique and mass isotopomer distribution analysis. Cholesterol synthesis was found to correspond to 0.03 ± 0.01% of the pool per h. Conversion of cholesterol into 24(S)-hydroxycholesterol was of a similar magnitude, about 0.02% of the pool per h. Brain microsomes converted endogenous cholesterol into 24(S)-hydroxycholesterol at a similar rate when incubated in the presence of NADPH. When incubated with whole homogenate and subcellular fractions of rat brain, there was no significant conversion of tritium-labeled 24-hydroxycholesterol into more polar products. Plasma from ¹⁸O₂-exposed rats contained 24(S)-hydroxycholesterol with an enrichment of ¹⁸O similar to that in 24(S)-hydroxycholesterol in the brain.

The results suggest that the present 24(S)-hydroxylase mediated mechanism is most important for elimination of cholesterol from the brain of rats. There is a slow conversion of brain cholesterol into 24(S)-hydroxycholesterol with a rapid turnover of the small pool of the latter oxysterol due to leakage to the circulation (half-life of brain 24(S)-hydroxycholesterol is about 0.5 days as compared with 2-4 months for brain cholesterol). It is evident that the 24(S)-hydroxylation greatly facilitates transfer of cholesterol over the blood-brain barrier and that this hydroxylation may be critical for cholesterol homeostasis in the brain.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Kotti, D. D. Head, C. E. McKenna, and D. W. Russell Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation PNAS, August 12, 2008; 105(32): 11394 - 11399. [Abstract] [Full Text] [PDF]

				K. Karu, M. Hornshaw, G. Woffendin, K. Bodin, M. Hamberg, G. Alvelius, J. Sjovall, J. Turton, Y. Wang, and W. J. Griffiths Liquid chromatography-mass spectrometry utilizing multi-stage fragmentation for the identification of oxysterols J. Lipid Res., April 1, 2007; 48(4): 976 - 987. [Abstract] [Full Text] [PDF]

				S. Meaney, M. Heverin, U. Panzenboeck, L. Ekstrom, M. Axelsson, U. Andersson, U. Diczfalusy, I. Pikuleva, J. Wahren, W. Sattler, et al. Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7{alpha}-hydroxy-3-oxo-4-cholestenoic acid J. Lipid Res., April 1, 2007; 48(4): 944 - 951. [Abstract] [Full Text] [PDF]

				K. Abildayeva, P. J. Jansen, V. Hirsch-Reinshagen, V. W. Bloks, A. H. F. Bakker, F. C. S. Ramaekers, J. de Vente, A. K. Groen, C. L. Wellington,, F. Kuipers, et al. 24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux J. Biol. Chem., May 5, 2006; 281(18): 12799 - 12808. [Abstract] [Full Text] [PDF]

				Y. Ohyama, S. Meaney, M. Heverin, L. Ekstrom, A. Brafman, M. Shafir, U. Andersson, M. Olin, G. Eggertsen, U. Diczfalusy, et al. Studies on the Transcriptional Regulation of Cholesterol 24-Hydroxylase (CYP46A1): MARKED INSENSITIVITY TOWARD DIFFERENT REGULATORY AXES J. Biol. Chem., February 17, 2006; 281(7): 3810 - 3820. [Abstract] [Full Text] [PDF]

				M. Heverin, S. Meaney, D. Lutjohann, U. Diczfalusy, J. Wahren, and I. Bjorkhem Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain J. Lipid Res., May 1, 2005; 46(5): 1047 - 1052. [Abstract] [Full Text] [PDF]

				J.-i. Ito, Y. Nagayasu, R. Lu, A. Kheirollah, M. Hayashi, and S. Yokoyama Astrocytes produce and secrete FGF-1, which promotes the production of apoE-HDL in a manner of autocrine action J. Lipid Res., April 1, 2005; 46(4): 679 - 686. [Abstract] [Full Text] [PDF]

				R. K. Keller, M. Small, and S. J. Fliesler Enzyme blockade: a nonradioactive method to determine the absolute rate of cholesterol synthesis in the brain J. Lipid Res., October 1, 2004; 45(10): 1952 - 1957. [Abstract] [Full Text] [PDF]

				I. Bjorkhem and S. Meaney Brain Cholesterol: Long Secret Life Behind a Barrier Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 806 - 815. [Abstract] [Full Text]

				M. Heverin, N. Bogdanovic, D. Lutjohann, T. Bayer, I. Pikuleva, L. Bretillon, U. Diczfalusy, B. Winblad, and I. Bjorkhem Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease J. Lipid Res., January 1, 2004; 45(1): 186 - 193. [Abstract] [Full Text] [PDF]

				C. Xie, E. G. Lund, S. D. Turley, D. W. Russell, and J. M. Dietschy Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration J. Lipid Res., September 1, 2003; 44(9): 1780 - 1789. [Abstract] [Full Text] [PDF]

				R. L. Raffai and K. H. Weisgraber Cholesterol: from heart attacks to Alzheimer's disease J. Lipid Res., August 1, 2003; 44(8): 1423 - 1430. [Abstract] [Full Text] [PDF]

				E. G. Lund, C. Xie, T. Kotti, S. D. Turley, J. M. Dietschy, and D. W. Russell Knockout of the Cholesterol 24-Hydroxylase Gene in Mice Reveals a Brain-specific Mechanism of Cholesterol Turnover J. Biol. Chem., June 13, 2003; 278(25): 22980 - 22988. [Abstract] [Full Text] [PDF]

				G. L. Vega, M. F. Weiner, A. M. Lipton, K. von Bergmann, D. Lutjohann, C. Moore, and D. Svetlik Reduction in Levels of 24S-Hydroxycholesterol by Statin Treatment in Patients With Alzheimer Disease Arch Neurol, April 1, 2003; 60(4): 510 - 515. [Abstract] [Full Text] [PDF]

				A. Papassotiropoulos, J. R. Streffer, M. Tsolaki, S. Schmid, D. Thal, F. Nicosia, V. Iakovidou, A. Maddalena, D. Lutjohann, E. Ghebremedhin, et al. Increased Brain {beta}-Amyloid Load, Phosphorylated Tau, and Risk of Alzheimer Disease Associated With an Intronic CYP46 Polymorphism Arch Neurol, January 1, 2003; 60(1): 29 - 35. [Abstract] [Full Text] [PDF]

				D. Lutjohann, A. Brzezinka, E. Barth, D. Abramowski, M. Staufenbiel, K. von Bergmann, K. Beyreuther, G. Multhaup, and T. A. Bayer Profile of cholesterol-related sterols in aged amyloid precursor protein transgenic mouse brain J. Lipid Res., July 1, 2002; 43(7): 1078 - 1085. [Abstract] [Full Text] [PDF]

				K. D. Whitney, M. A. Watson, J. L. Collins, W. G. Benson, T. M. Stone, M. J. Numerick, T. K. Tippin, J. G. Wilson, D. A. Winegar, and S. A. Kliewer Regulation of Cholesterol Homeostasis by the Liver X Receptors in the Central Nervous System Mol. Endocrinol., June 1, 2002; 16(6): 1378 - 1385. [Abstract] [Full Text] [PDF]

				I. Bjorkhem and U. Diczfalusy Oxysterols: Friends, Foes, or Just Fellow Passengers? Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 734 - 742. [Abstract] [Full Text] [PDF]

				S. Locatelli, D. Lutjohann, H. H.-J. Schmidt, C. Otto, U. Beisiegel, and K. von Bergmann Reduction of Plasma 24S-Hydroxycholesterol (Cerebrosterol) Levels Using High-Dosage Simvastatin in Patients With Hypercholesterolemia: Evidence That Simvastatin Affects Cholesterol Metabolism in the Human Brain Arch Neurol, February 1, 2002; 59(2): 213 - 216. [Abstract] [Full Text] [PDF]

				M. Schwarz, D. W. Russell, J. M. Dietschy, and S. D. Turley Alternate pathways of bile acid synthesis in the cholesterol 7{alpha}-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding J. Lipid Res., October 1, 2001; 42(10): 1594 - 1603. [Abstract] [Full Text] [PDF]

				M. Lehto, S. Laitinen, G. Chinetti, M. Johansson, C. Ehnholm, B. Staels, E. Ikonen, and V. M. Olkkonen The OSBP-related protein family in humans J. Lipid Res., August 1, 2001; 42(8): 1203 - 1213. [Abstract] [Full Text] [PDF]

				I. Björkhem, L. Starck, U. Andersson, D. Lütjohann, S. von Bahr, I. Pikuleva, A. Babiker, and U. Diczfalusy Oxysterols in the circulation of patients with the Smith-Lemli-Opitz syndrome: abnormal levels of 24S- and 27-hydroxycholesterol J. Lipid Res., March 1, 2001; 42(3): 366 - 371. [Abstract] [Full Text]

				M. Norlin, A. Toll, I. Björkhem, and K. Wikvall 24-Hydroxycholesterol is a substrate for hepatic cholesterol 7{alpha}-hydroxylase (CYP7A) J. Lipid Res., October 1, 2000; 41(10): 1629 - 1639. [Abstract] [Full Text]

				M. Di Buono, P. J. H. Jones, L. Beaumier, and L. J. Wykes Comparison of deuterium incorporation and mass isotopomer distribution analysis for measurement of human cholesterol biosynthesis J. Lipid Res., September 1, 2000; 41(9): 1516 - 1523. [Abstract] [Full Text]

				P. E. Jira, R. A. Wevers, J. de Jong, E. Rubio-Gozalbo, F. S. M. Janssen-Zijlstra, A. F. J. van Heyst, R. C. A. Sengers, and J. A. M. Smeitink Simvastatin: a new therapeutic approach for Smith-Lemli-Opitz syndrome J. Lipid Res., August 1, 2000; 41(8): 1339 - 1346. [Abstract] [Full Text]

				N. Demeester, G. Castro, C. Desrumaux, C. De Geitere, J. C. Fruchart, P. Santens, E. Mulleners, S. Engelborghs, P. P. De Deyn, J. Vandekerckhove, et al. Characterization and functional studies of lipoproteins, lipid transfer proteins, and lecithin:cholesterol acyltransferase in CSF of normal individuals and patients with Alzheimer's disease J. Lipid Res., June 1, 2000; 41(6): 963 - 974. [Abstract] [Full Text]

				L. Bretillon, D. Lütjohann, L. Ståhle, T. Widhe, L. Bindl, G. Eggertsen, U. Diczfalusy, and I. Björkhem Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface J. Lipid Res., May 1, 2000; 41(5): 840 - 845. [Abstract] [Full Text]

				D. Lütjohann, A. Papassotiropoulos, I. Björkhem, S. Locatelli, M. Bagli, R. D. Oehring, U. Schlegel, F. Jessen, M. L. Rao, K. von Bergmann, et al. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients J. Lipid Res., February 1, 2000; 41(2): 195 - 198. [Abstract] [Full Text]

				G. J. Schroepfer Jr. Oxysterols: Modulators of Cholesterol Metabolism and Other Processes Physiol Rev, January 1, 2000; 80(1): 361 - 554. [Abstract] [Full Text] [PDF]

				S. Laitinen, V. M. Olkkonen, C. Ehnholm, and E. Ikonen Family of human oxysterol binding protein (OSBP) homologues: a novel member implicated in brain sterol metabolism J. Lipid Res., December 1, 1999; 40(12): 2204 - 2211. [Abstract] [Full Text] [PDF]

				E. G. Lund, J. M. Guileyardo, and D. W. Russell cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain PNAS, June 22, 1999; 96(13): 7238 - 7243. [Abstract] [Full Text] [PDF]

				I. Björkhem, D. Lütjohann, U. Diczfalusy, L. Ståhle, G. Ahlborg, and J. Wahren Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation J. Lipid Res., August 1, 1998; 39(8): 1594 - 1600. [Abstract] [Full Text]

				J. Li-Hawkins, E. G. Lund, A. D. Bronson, and D. W. Russell Expression Cloning of an Oxysterol 7alpha -Hydroxylase Selective for 24-Hydroxycholesterol J. Biol. Chem., May 26, 2000; 275(22): 16543 - 16549. [Abstract] [Full Text] [PDF]

				I. Bjorkhem, U. Andersson, E. Ellis, G. Alvelius, L. Ellegard, U. Diczfalusy, J. Sjovall, and C. Einarsson From Brain to Bile. EVIDENCE THAT CONJUGATION AND omega -HYDROXYLATION ARE IMPORTANT FOR ELIMINATION OF 24S-HYDROXYCHOLESTEROL (CEREBROSTEROL) IN HUMANS J. Biol. Chem., September 28, 2001; 276(40): 37004 - 37010. [Abstract] [Full Text] [PDF]

				J. M. Dietschy and S. D. Turley Thematic review series: Brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal J. Lipid Res., August 1, 2004; 45(8): 1375 - 1397. [Abstract] [Full Text] [PDF]