Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation.
We have previously demonstrated that the brain contains about 80% of the 24S-hydroxycholesterol in the human body and that there is a net flux of this steroid from the brain into the circulation (Lütjohann, D. et al. 1996. Proc. Natl. Acad. Sci. USA. 93: 9799-9804). Combining previous data with new data on 12 healthy volunteers, the arteriovenous difference between levels of this oxysterol in the internal jugular vein and in a peripheral artery was found to be -10.2 +/- 2.8 ng/ml (mean +/- SEM) corresponding to a net flux of 24S-hydroxycholesterol from the brain of about 6.4 mg/24 h. The arteriovenous difference between levels of 24S-hydroxycholesterol in the hepatic vein and a peripheral artery of 12 other volunteers was found to be 7.4 +/- 2.2 ng/ml, corresponding to a hepatic uptake of about 7.6 mg/24 h. The concentrations of 24S-hydroxycholesterol in the renal vein were about the same as those in a peripheral artery, indicating that a renal elimination is not of importance. Intravenously injected deuterium-labeled racemic 24-hydroxycholesterol was eliminated from the circulation of two human volunteers with half-lives of 10 h and 14 h, respectively. A positive correlation was found between the levels of circulating cholesterol and 24S-hydroxycholesterol. The results are consistent with a cerebral origin of most of the circulating 24S-hydroxycholesterol and suggest that the liver is the major eliminating organ. It is concluded that conversion into 24S-hydroxycholesterol is a quantitatively important mechanism for elimination of cholesterol from human brain. The possibility is discussed that circulating levels of 24S-hydroxycholesterol can be used as a marker for pathological and/or developmental changes in the brain.
Division of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Sweden.
I
I
Björkhem
D
D
Lütjohann
U
U
Diczfalusy
L
L
Ståhle
G
G
Ahlborg
J
J
Wahren
D000328:Adult; D015415:Biomarkers; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D003903:Deuterium; D006207:Half-Life; D006706:Homeostasis; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood* / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D012016:Reference Values; D013152:Splanchnic Circulation; D013250:Steroid Hydroxylases / Q000378:metabolism
D015415:Biomarkers; D006888:Hydroxycholesterols; C044563:24-hydroxycholesterol; D002784:Cholesterol; D003903:Deuterium; D013250:Steroid Hydroxylases