出版社：American Society for Biochemistry and Molecular Biology
摘要：Recently, we demonstrated a net blood-to-brain passage of theoxysterol 27-hydroxycholesterol corresponding to 4–5 mg/day.As the steady-state levels of this sterol are only 1–2µg/g brain tissue, we hypothesized that it is metabolizedand subsequently eliminated from the brain. To explore thisconcept, we first measured the capacity of in vitro systemsrepresenting the major cell populations found in the brain tometabolize 27-hydroxycholesterol. We show here that 27-hydroxycholesterolis metabolized into the known C27 steroidal acid 7-hydroxy-3-oxo-4-cholestenoicacid by neuronal cell models only. Using an in vitro model ofthe blood-brain barrier, we demonstrate that 7-hydroxy-3-oxo-4-cholestenoicacid is efficiently transferred across monolayers of primarybrain microvascular endothelial cells. Finally, we measuredthe concentration of 7-hydroxy-3-oxo-4-cholestenoic acid inplasma from the internal jugular vein and brachial artery ofhealthy volunteers. Calculation of the arteriovenous concentrationdifference revealed a significant in vivo flux of this steroidfrom the brain into the circulation in human. Together, thesestudies identify a novel metabolic route for the eliminationof 27-hydroxylated sterols from the brain. Given the emergingconnections between cholesterol and neurodegeneration, thispathway may be of importance for the development of these conditions.Supplementary key words brain cholesterol homeostasis • 27-hydroxycholesterol • CYP7B1 • CYP27
-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
