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Mutations in NPC1 and cholesterol metabolism in the brain
Author(s) -
Dietschy John M.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.434.2
Subject(s) - npc1 , endosome , cholesterol , sterol , blood–brain barrier , endocytosis , liver x receptor , medicine , endocrinology , neurodegeneration , excretion , biology , apolipoprotein e , chemistry , dmt1 , myelin , receptor , microbiology and biotechnology , biochemistry , central nervous system , transporter , nuclear receptor , gene , disease , transcription factor
This presentation reviews the processes involved in cholesterol (C) homeostasis in the brain. The amount of C in an animal equals about 2100 mg/kg bw, and 15% and 23% of this sterol in the mouse and human, respectively, is found in the CNS. No uptake of C carried in plasma lipoproteins across the blood‐brain barrier can be detected. High rates of synthesis in glia and neurons provide the sterol necessary for early development. Sterol synthesized in oligodendrocytes (250 µg/day) in the newborn mouse supplies sufficient C for myelin formation. Cholesterol, along with apoE, is synthesized in astrocytes, released into the pericellular fluid, and taken up by neurons through receptor‐mediated endocytosis. Mutation of NPC1 leads to accumulation of this C in the late endosomal/lysosomal compartment. In the mature brain, the rate of excretion of C from the CNS must equal the rate of synthesis, and this excretion is accomplished by movement of both C and 24( S )‐hydroxycholesterol across the blood‐brain barrier. This excretion is partially controlled by a target gene of the LXR nuclear receptor. The neurodegeneration and glial activation that is seen with a mutation in NPC1 is ameliorated by agents that either facilitate C transport across the lysosomal membrane or that divert C away from neurons across the blood‐brain barrier. Cholesterol turnover in myelin is very slow while turnover in neurons may be very rapid. (NIH 5R01 HL09610).