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 7 alpha-hydroxy-4-cholesten-3-one, a precursor both to bile acids and cholestanol. Injection of a cyp27a1(-/-) mouse with H-2(7)-labeled 7 alpha-hydroxy-4-cholesten-3-one resulted in a signifi cant incorporation of H-2(7)-cholestanol in the brain. The results are consistent with a concentration-dependent flux of 7 alpha-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.-B ($) over circle vner, A., M. Shafaati, M. Hansson, M. Olin, S. Shpitzen, V. Meiner, E. Leitersdorf, and I. Bjorkhem. On the mechanism of accumulation of cholestanol in the brain of mice with a disruption of sterol 27-hydroxylase. J. Lipid Res. 2010. 51: 2722-2730