Submitted on December 13, 2006
Revised on January 23, 2007
Accepted on January 24, 2007
A novel route for the elimination of brain oxysterols: Elimination of 27-hydroxycholesterol via conversion to 7
-hydroxy-3-oxo-4-cholestenoic acid
Steve Meaney, Maura Heverin, Ute Panzenboeck, Lena Ekström, Magnus Axelsson, Ulla Andersson, Ulf Diczfalusy, Irina Pikuleva, John Wahren, Wolfgang Sattler, and Ingemar Björkhem
Laboratory Medicine, Karolinska Institutet, Stockholm
Corresponding Author: ingemar.bjorkhem{at}karolinska.se
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/mg brain tissue, we hypothesised that it is metabolised 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 metabolise 27-hydroxycholesterol. We show here that 27-hydroxycholesterol is metabolized into the known C27 steroidal acid 7a-hydroxy-3-oxo-4-cholestenoic acid by neuronal cell models only. Using an in vitro model of the blood-brain barrier, we demonstrate that 7a-hydroxy-3-oxo-4-cholestenoic acid is efficiently transferred across monolayers of primary brain microvascular endothelial cells. Finally, we measured the concentration of 7a-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 man. Taken together these studies identify a novel metabolic route for 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.
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