出版社：American Society for Biochemistry and Molecular Biology
摘要：The most serious consequence of sterol 27-hydroxylase deficiencyin humans [cerebrotendinous xanthomatosis (CTX)] is the developmentof cholestanol-containing brain xanthomas. The cholestanol inthe brain may be derived from the circulation or from 7-hydroxylatedintermediates in bile acid synthesis, present at 50- to 250-foldincreased levels in plasma. Here, we demonstrate a transferof 7-hydroxy-4-cholesten-3-one across cultured porcine brainendothelial cells (a model for the blood-brain barrier) thatis 100-fold more efficient than the transfer of cholestanol.Furthermore, there was an efficient conversion of 7-hydroxy-4-cholesten-3-oneto cholestanol in cultured neuronal and glial cells as wellas in monocyte-derived macrophages of human origin. It is concludedthat the continuous intracellular production of cholestanolfrom a bile acid precursor capable of rapidly passing biomembranes,including the blood-brain barrier, is likely to be of majorimportance for the accumulation of cholestanol in patients withCTX. Such a mechanism also fits well with the observation thattreatment with chenodeoxycholic acid, which normalizes the levelof the bile acid precursor, results in a reduction of cholestanol-containingxanthomas even in the brain.Supplementary key words blood-brain barrier • brain xanthomas • brain endothelial cells
-hydroxylated intermediates in bile acid synthesis, present at 50- to 250-fold increased levels in plasma. Here, we demonstrate a transfer of 7
100-fold more efficient than the transfer of cholestanol. Furthermore, there was an efficient conversion of 7
