On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis |
| |
Authors: | Panzenboeck Ute Andersson Ulla Hansson Magnus Sattler Wolfgang Meaney Steve Björkhem Ingemar |
| |
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. |
| |
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. |
| |
Keywords: | blood-brain barrier brain xanthomas brain endothelial cells |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|