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.
Båvner
Ann
A
Department of Laboratory Medicine, Division of Clincial Chemistry, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Shafaati
Marjan
M
Hansson
Magnus
M
Olin
Maria
M
Shpitzen
Shoshi
S
Meiner
Vardiella
V
Leitersdorf
Eran
E
Björkhem
Ingemar
I
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