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.
Highlights
The most serious consequence of sterol 27-hydroxylase deficiency in humans [cerebrotendinous xanthomatosis (CTX)] is the development of cholestanolcontaining brain xanthomas
Sterol 27-hydroxylase deficiency [cerebrotendinous xanthomatosis (CTX)] is a rare familial lipid storage disease characterized by the accumulation of cholesterol and cholestanol in most tissues, in particular in tendon and brain xanthomas
We have shown previously that the major part of the cholestanol present in the circulation of CTX patients is derived from 7a-hydroxylated intermediates in bile acid synthesis, such as 7a-hydroxycholesterol and 7a-hydroxy4-cholesten-3-one [1, 2]
Summary
The most serious consequence of sterol 27-hydroxylase deficiency in humans [cerebrotendinous xanthomatosis (CTX)] is the development of cholestanolcontaining brain xanthomas. 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 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, U., U. We have shown previously that the major part of the cholestanol present in the circulation of CTX patients is derived from 7a-hydroxylated intermediates in bile acid synthesis, such as 7a-hydroxycholesterol and 7a-hydroxy4-cholesten-3-one [1, 2]. This article is available online at http://www.jlr.org
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