Submitted on January 18, 2007
Revised on February 23, 2007
Accepted on February 25, 2007
On the mechanism of cerebral accumulation of cholestanol in patients with Cerebrotendinous Xanthomatosis
Ute Panzenboeck, Ulla Andersson, Magnus Hansson, Wolfgang Sattler, Steve Meaney, and Ingemar Björkhem
Laboratory Medicine, Karolinska Institutet, Stockholm, Huddinge 14186
Corresponding Author: ingemar.bjorkhem{at}karolinska.se
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 7a-hydroxylated intermediates in bile acid synthesis, present at 50-250 fold elevated levels in plasma. Here we demonstrate a transfer of 7a-hydroxy-4-cholesten-3-one across cultured porcine brain endothelial cells (a model for the blood-brain barrier) that is about 100-fold more efficient than the transfer of cholestanol. Furthermore, there was an efficient conversion of 7a-hydroxy-4-cholesten-3-one into 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 normalises the level of the bile acid precursor, results in reduction of cholestanol-containing xanthomas even in the brain.
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