On the mechanism of accumulation of cholestanol in the brain of mice with a disruption of sterol 27-hydroxylase

J Lipid Res. 2010 Sep;51(9):2722-30. doi: 10.1194/jlr.M008326. Epub 2010 May 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain Chemistry
  • Cholestanetriol 26-Monooxygenase / genetics
  • Cholestanetriol 26-Monooxygenase / metabolism*
  • Cholestanol / chemistry
  • Cholestanol / metabolism*
  • Cholestenones / metabolism
  • Cholestyramine Resin
  • Cholic Acid / metabolism
  • Female
  • Humans
  • Liver / chemistry
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Tendons / chemistry
  • Tendons / metabolism
  • Xanthomatosis, Cerebrotendinous / enzymology
  • Xanthomatosis, Cerebrotendinous / pathology

Substances

  • Cholestenones
  • Cholestyramine Resin
  • 7 alpha-hydroxy-4-cholesten-3-one
  • Cholestanol
  • Cholestanetriol 26-Monooxygenase
  • Cholic Acid