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 mug/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 C(27) steroidal acid 7alpha-hydroxy-3-oxo-4-cholestenoic acid by neuronal cell models only. Using an in vitro model of the blood-brain barrier, we demonstrate that 7alpha-hydroxy-3-oxo-4-cholestenoic acid is efficiently transferred across monolayers of primary brain microvascular endothelial cells. Finally, we measured the concentration of 7alpha-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.
Highlights
We demonstrated a net blood-to-brain passage of the oxysterol 27-hydroxycholesterol corresponding to 4–5 mg/day
RT-PCR-based profiling of enzymes known to be involved in the metabolism of 27-hydroxycholesterol (i.e., CYP27A1, CYP7B1, and HSD3B7) in different cell types revealed that SH-SH5Y, D-384, and CHME-3 cells had expression profiles consistent with those described in vivo [15,16,17] (Fig. 1A)
It is well established that conversion of cholesterol into 24S-hydroxycholesterol is of importance for cholesterol homeostasis in the brain. This mechanism appears to be responsible for the removal of only two-thirds of newly synthesized cholesterol in rodents [19, 20]
Summary
We demonstrated a net blood-to-brain passage of the oxysterol 27-hydroxycholesterol corresponding to 4–5 mg/day. 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. Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7a-hydroxy-3-oxo-4-cholestenoic acid. Using established physiological methods to investigate blood-to-brain transport, we recently made the surprising discovery that 27-hydroxycholesterol passes from the circulation into the central nervous system [3]. This finding is in agreement with our previous observations that labeled 27-hydroxycholesterol passed from the circulation into cerebrospinal fluid in a healthy volunteer and that the levels of 27-hydroxycholesterol in the circulation and the cerebrospinal fluid were correlated [4]. Heverin contributed to this work. 2 To whom correspondence should be addressed
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