On the mechanism of accumulation of cholestanol in the brain of mice with a disruption of sterol 27-hydroxylase.
The rare disease cerebrotendinous xanthomatosis (CTX) is due to a lack of sterol 27-hydroxylase (CYP27A1) and is characterized by cholestanol-containing xanthomas in brain and tendons. Mice with the same defect do not develop xanthomas. The driving force in the development of the xanthomas is likely to be conversion of a bile acid precursor into cholestanol. The mechanism behind the xanthomas in the brain has not been clarified. We demonstrate here that female cyp27a1(-/-) mice have an increase of cholestanol of about 2.5- fold in plasma, 6-fold in tendons, and 12-fold in brain. Treatment of cyp27a1(-/-) mice with 0.05% cholic acid normalized the cholestanol levels in tendons and plasma and reduced the content in the brain. The above changes occurred in parallel with changes in plasma levels of 7alpha-hydroxy-4-cholesten-3-one, a precursor both to bile acids and cholestanol. Injection of a cyp27a1(-/-) mouse with (2)H(7)-labeled 7alpha-hydroxy-4-cholesten-3-one resulted in a significant incorporation of (2)H(7)-cholestanol in the brain. The results are consistent with a concentration-dependent flux of 7alpha-hydroxy-4-cholesten-3-one across the blood-brain barrier in cyp27a1(-/-) mice and subsequent formation of cholestanol. It is suggested that the same mechanism is responsible for accumulation of cholestanol in the brain of patients with CTX.
Department of Laboratory Medicine, Division of Clincial Chemistry, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Ann
A
Båvner
Marjan
M
Shafaati
Magnus
M
Hansson
Maria
M
Olin
Shoshi
S
Shpitzen
Vardiella
V
Meiner
Eran
E
Leitersdorf
Ingemar
I
Björkhem
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D004083:Cholestanol / Q000737:chemistry / Q000378:metabolism*; D002783:Cholestenones / Q000378:metabolism; D002792:Cholestyramine Resin; D019826:Cholic Acid / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D013710:Tendons / Q000737:chemistry / Q000378:metabolism; D019294:Xanthomatosis, Cerebrotendinous / Q000201:enzymology / Q000473:pathology
D002783:Cholestenones; D002792:Cholestyramine Resin; C002656:7 alpha-hydroxy-4-cholesten-3-one; D004083:Cholestanol; D053493:Cholestanetriol 26-Monooxygenase; D019826:Cholic Acid