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Journal of Lipid Research, Vol. 48, 944-951, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Patient-Oriented Research

Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7-hydroxy-3-oxo-4-cholestenoic acid

Steve Meaney^1,*, Maura Heverin^1,*, Ute Panzenboeck, Lena Ekström, Magnus Axelsson^**, Ulla Andersson^*, Ulf Diczfalusy^*, Irina Pikuleva, John Wahren, Wolfgang Sattler^*** and Ingemar Björkhem^2,*

^* Division of Clinical Chemistry, Karolinska University Hospital, Huddinge, Sweden
Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, Sweden
^** Division of Clinical Chemistry, Karolinska University Hospital, Solna, Sweden
Division of Surgical Sciences, Karolinska University Hospital, Solna, Sweden
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX
Institute of Pathophysiology, Medical University Graz, Graz, Austria
^*** Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University Graz, Graz, Austria

Published, JLR Papers in Press, January 24, 2007.

¹ S. Meaney and M. Heverin contributed equally to this work.

² To whom correspondence should be addressed. e-mail: ingemar.bjorkhem{at}karolinska.se

ABSTRACT

Recently, we demonstrated a net blood-to-brain passage of the oxysterol 27-hydroxycholesterol corresponding to 4–5 mg/day. As the steady-state levels of this sterol are only 1–2 µg/g brain tissue, we hypothesized that it is metabolized and subsequently eliminated from the brain. To explore this concept, we first measured the capacity of in vitro systems representing the major cell populations found in the brain to metabolize 27-hydroxycholesterol. We show here that 27-hydroxycholesterol is metabolized into the known C₂₇ steroidal acid 7-hydroxy-3-oxo-4-cholestenoic acid by neuronal cell models only. Using an in vitro model of the blood-brain barrier, we demonstrate that 7-hydroxy-3-oxo-4-cholestenoic acid is efficiently transferred across monolayers of primary brain microvascular endothelial cells. Finally, we measured the concentration of 7-hydroxy-3-oxo-4-cholestenoic acid in plasma from the internal jugular vein and brachial artery of healthy volunteers. Calculation of the arteriovenous concentration difference revealed a significant in vivo flux of this steroid from the brain into the circulation in human. Together, these studies identify a novel metabolic route for the elimination of 27-hydroxylated sterols from the brain. Given the emerging connections between cholesterol and neurodegeneration, this pathway may be of importance for the development of these conditions.

Supplementary key words brain cholesterol homeostasis • 27-hydroxycholesterol • CYP7B1 • CYP27

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