On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis.
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| 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.
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| Authors | Ute Panzenboeck, Ulla Andersson, Magnus Hansson, Wolfgang Sattler, Steve Meaney, Ingemar Björkhem |
| Journal | Journal of lipid research (J Lipid Res) Vol. 48 Issue 5 Pg. 1167-74 (May 2007) ISSN: 0022-2275 [Print] United States |
| PMID | 17325385 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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