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

J. Biol. Chem., Vol. 276, Issue 40, 37004-37010, October 5, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/40/37004    most recent M103828200v1 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 Einarsson, C. Search for Related Content PubMed PubMed Citation Articles by Björkhem, I. Articles by Einarsson, C. Social Bookmarking                      What's this?

From Brain to Bile
EVIDENCE THAT CONJUGATION AND -HYDROXYLATION ARE IMPORTANT FOR ELIMINATION OF 24S-HYDROXYCHOLESTEROL (CEREBROSTEROL) IN HUMANS^*

Ingemar Björkhem^§, Ulla Andersson, Ewa Ellis^¶, Gunvor Alvelius, Lars Ellegård, Ulf Diczfalusy, Jan Sjövall^**, and Curt Einarsson^¶

From the  Divisions of Clinical Chemistry and ^¶ Gastroenterology and Hepatology, Karolinska Institutet, Huddinge University Hospital, S-141 86 Huddinge, Sweden, the ^** Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden, and the  Division of Clinical Nutrition, Sahlgrenska University Hospital, University of Gothenburg, SE-41345 Gothenburg, Sweden

The brain is the almost exclusive site of formation of 24S-hydroxycholesterol in man, and there is a continuous flux of this oxysterol across the blood-brain barrier into the circulation. The hepatic metabolism of 24S-hydroxycholesterol was studied here by three different approaches: incubation of tritium-labeled 24S-hydroxycholesterol with human primary hepatocytes, administration of tritium-labeled 24S-hydroxycholesterol to a human volunteer, and quantitation of free and conjugated 24S-hydroxycholesterol and its neutral metabolites in ileocecal fluid from patients with ileal fistulae. 24S-Hydroxycholesterol as well as 24R-hydroxycholesterol were converted into bile acids by human hepatocytes at a rate of about 40% of that of the normal intermediate in bile acid synthesis, 7-hydroxycholesterol. There was also a conversion of 24S-hydroxycholesterol into conjugate(s) of 5-cholestene-3,24S,27-triol at a rate similar to the that of conversion into bile acids. When administered to a human volunteer, labeled 24S-hydroxycholesterol was converted into bile acids at about half the rate of simultaneously administered labeled 7-hydroxycholesterol. Free, sulfated, and glucuronidated 24S-hydroxycholesterol and 5-cholestene-3,24,27-triol were identified in ileocecal fluid. The excretion of these steroids was about 3.5 mg/24 h, amounting to more than 50% of the total estimated flux of 24S-hydroxycholesterol from the brain. It is concluded that 24S-hydroxycholesterol is a less efficient precursor to bile acids and that about half of it is conjugated and eliminated in bile as such or as a conjugate of a 27-hydroxylated metabolite. The less efficient metabolism of 24S-hydroxycholesterol may explain the surprisingly high levels of this oxysterol in the circulation and is of interest in relation to the suggested role of 24S-hydroxycholesterol as a regulator of cholesterol homeostasis.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

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. M. Thelen, R. Laaksonen, H. Paiva, T. Lehtimaki, and D. Lutjohann High-dose statin treatment does not alter plasma marker for brain cholesterol metabolism in patients with moderately elevated plasma cholesterol levels. J. Clin. Pharmacol., July 1, 2006; 46(7): 812 - 816. [Abstract] [Full Text] [PDF]

				T. J. Kotti, D. M. O. Ramirez, B. E. Pfeiffer, K. M. Huber, and D. W. Russell Brain cholesterol turnover required for geranylgeraniol production and learning in mice PNAS, March 7, 2006; 103(10): 3869 - 3874. [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]

				S. Ferdinandusse, S. Denis, H. Overmars, L. Van Eeckhoudt, P. P. Van Veldhoven, M. Duran, R. J. A. Wanders, and M. Baes Developmental Changes of Bile Acid Composition and Conjugation in L- and D-Bifunctional Protein Single and Double Knockout Mice J. Biol. Chem., May 13, 2005; 280(19): 18658 - 18666. [Abstract] [Full Text] [PDF]

				N. Mano, Y. Sato, M. Nagata, T. Goto, and J. Goto Bioconversion of 3{beta}-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems J. Lipid Res., September 1, 2004; 45(9): 1741 - 1748. [Abstract] [Full Text] [PDF]

				M. Norlin, S. von Bahr, I. Bjorkhem, and K. Wikvall On the substrate specificity of human CYP27A1: implications for bile acid and cholestanol formation J. Lipid Res., August 1, 2003; 44(8): 1515 - 1522. [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]

				M. Fuchs Bile Acid Regulation of Hepatic Physiology: III. Regulation of bile acid synthesis: past progress and future challenges Am J Physiol Gastrointest Liver Physiol, April 1, 2003; 284(4): G551 - G557. [Abstract] [Full Text] [PDF]

				S. Meaney, K. Bodin, U. Diczfalusy, and I. Bjorkhem On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function J. Lipid Res., December 1, 2002; 43(12): 2130 - 2135. [Abstract] [Full Text] [PDF]

				U. Panzenboeck, Z. Balazs, A. Sovic, A. Hrzenjak, S. Levak-Frank, A. Wintersperger, E. Malle, and W. Sattler ABCA1 and Scavenger Receptor Class B, Type I, Are Modulators of Reverse Sterol Transport at an in Vitro Blood-Brain Barrier Constituted of Porcine Brain Capillary Endothelial Cells J. Biol. Chem., November 1, 2002; 277(45): 42781 - 42789. [Abstract] [Full Text] [PDF]

				K. Meir, D. Kitsberg, I. Alkalay, F. Szafer, H. Rosen, S. Shpitzen, L. B. Avi, B. Staels, C. Fievet, V. Meiner, et al. Human Sterol 27-Hydroxylase (CYP27) Overexpressor Transgenic Mouse Model. EVIDENCE AGAINST 27-HYDROXYCHOLESTEROL AS A CRITICAL REGULATOR OF CHOLESTEROL HOMEOSTASIS J. Biol. Chem., September 6, 2002; 277(37): 34036 - 34041. [Abstract] [Full Text] [PDF]

				K. Bodin, U. Andersson, E. Rystedt, E. Ellis, M. Norlin, I. Pikuleva, G. Eggertsen, I. Bjorkhem, and U. Diczfalusy Metabolism of 4beta -Hydroxycholesterol in Humans J. Biol. Chem., August 23, 2002; 277(35): 31534 - 31540. [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]

				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]