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Journal of Lipid Research, Vol. 44, 1780-1789, September 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology
Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration
* Departments of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8887
Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8887
2 To whom correspondence should be addressed. e-mail: john.dietschy{at}utsouthwestern.edu
Although the pool of cholesterol in the adult central nervous system (CNS) is large and of constant size, little is known of the process(es) involved in regulation of sterol turnover in this pool. In 7-week-old mice, net excretion of cholesterol from the brain equaled 1.4 mg/day/kg body weight, and from the whole animal was 179 mg/day/kg. Deletion of cholesterol 24-hydroxylase, an enzyme highly expressed in the CNS, did not alter brain growth or myelination, but reduced sterol excretion from the CNS 64% to 0.5 mg/day/kg. In mice with a mutation in the Niemann-Pick C gene that had ongoing neurodegeneration, sterol excretion from the CNS was increased to 2.3 mg/day/kg. Deletion of cholesterol 24-hydroxylase activity in these animals reduced net excretion only 22% to 1.8 mg/day/kg.
Thus, at least two different pathways promote net sterol excretion from the CNS. One uses cholesterol 24-hydroxylase and may reflect sterol turnover in large neurons in the brain. The other probably involves the movement of cholesterol or one of its metabolites across the blood-brain barrier and may more closely mirror sterol turnover in pools such as glial cell membranes and myelin.
Abbreviations: CNS, central nervous system; LDLR, LDL receptor; NPC1, Niemann-Pick type C; SR-BI, scavenger receptor class B, type I
Supplementary key words Niemann-Pick type C disease • dementia • glial cells • oxysterols • cholesterol 24-hydroxylase • sterol 27-hydroxylase • neurons
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