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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M700027-JLR200 on February 26, 2007

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Journal of Lipid Research, Vol. 48, 1167-1174, May 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis

Ute Panzenboeck*, Ulla Andersson{dagger}, Magnus Hansson{dagger}, Wolfgang Sattler§, Steve Meaney{dagger} and Ingemar Björkhem1,{dagger}

* Institute of Pathophysiology, Center of Molecular Medicine, Medical University of Graz, Graz, Austria
§ Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria
{dagger} Division of Clinical Chemistry, Karolinska University Hospital, Karolinska Institutet, Huddinge, Sweden

Published, JLR Papers in Press, February 26, 2007.

1 To whom correspondence should be addressed. e-mail: 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 7{alpha}-hydroxylated intermediates in bile acid synthesis, present at 50- to 250-fold increased levels in plasma. Here, we demonstrate a transfer of 7{alpha}-hydroxy-4-cholesten-3-one across cultured porcine brain endothelial cells (a model for the blood-brain barrier) that is ~100-fold more efficient than the transfer of cholestanol. Furthermore, there was an efficient conversion of 7{alpha}-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.

Supplementary key words blood-brain barrier • brain xanthomas • brain endothelial cells


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