title: On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis.
abstract: The most serious consequence of sterol 27-hydroxylase deficiency in humans [cerebrotendinous xanthomatosis (CTX)] is the development of cholestanol-containing brain xanthomas. The cholestanol in the brain may be derived from the circulation or from 7alpha-hydroxylated intermediates in bile acid synthesis, present at 50- to 250-fold increased levels in plasma. Here, we demonstrate a transfer of 7alpha-hydroxy-4-cholesten-3-one across cultured porcine brain endothelial cells (a model for the blood-brain barrier) that is approximately 100-fold more efficient than the transfer of cholestanol. Furthermore, there was an efficient conversion of 7alpha-hydroxy-4-cholesten-3-one to cholestanol in cultured neuronal and glial cells as well as in monocyte-derived macrophages of human origin. It is concluded that the continuous intracellular production of cholestanol from a bile acid precursor capable of rapidly passing biomembranes, including the blood-brain barrier, is likely to be of major importance for the accumulation of cholestanol in patients with CTX. Such a mechanism also fits well with the observation that treatment with chenodeoxycholic acid, which normalizes the level of the bile acid precursor, results in a reduction of cholestanol-containing xanthomas even in the brain.
authors.affiliation: Institute of Pathophysiology, Center of Molecular Medicine, Medical University of Graz, Graz, Austria, and Division of Clinical Chemistry, Karolinska University Hospital, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Ute
authors.initials: U
authors.lastname: Panzenboeck
authors.forename: Ulla
authors.initials: U
authors.lastname: Andersson
authors.forename: Magnus
authors.initials: M
authors.lastname: Hansson
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.forename: Steve
authors.initials: S
authors.lastname: Meaney
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004083:Cholestanol / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D013552:Swine; D019294:Xanthomatosis, Cerebrotendinous / Q000378:metabolism* / Q000473:pathology*
chemical_list: D004083:Cholestanol