On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis.
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.
Panzenboeck
Ute
U
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.
Andersson
Ulla
U
Hansson
Magnus
M
Sattler
Wolfgang
W
Meaney
Steve
S
Björkhem
Ingemar
I
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*
D004083:Cholestanol