Department of Laboratory Medicine, Division of Clincial Chemistry, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
J Lipid Res. 2010 Sep;51(9):2722-30. doi: 10.1194/jlr.M008326. Epub 2010 May 28.
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.
罕见病脑腱黄瘤病（CTX）是由于固醇 27-羟化酶（CYP27A1）缺乏引起的，其特征是脑和肌腱中含有胆甾醇的黄色瘤。具有相同缺陷的小鼠不会产生黄色瘤。黄色瘤发展的驱动力可能是将胆汁酸前体转化为胆甾醇。脑黄色瘤背后的机制尚未阐明。我们在这里证明，雌性 cyp27a1(-/-) 小鼠的血浆中胆甾醇增加了约 2.5 倍，肌腱中增加了 6 倍，脑内增加了 12 倍。用 0.05%胆酸治疗 cyp27a1(-/-) 小鼠可使肌腱和血浆中的胆甾醇水平正常化，并减少脑内含量。上述变化与血浆中 7α-羟基-4-胆甾-3-酮水平的变化平行发生，7α-羟基-4-胆甾-3-酮既是胆汁酸又是胆甾醇的前体。向 cyp27a1(-/-) 小鼠注射（2）H（7）标记的 7α-羟基-4-胆甾-3-酮，导致脑内显著掺入（2）H（7）-胆甾醇。结果与 cyp27a1(-/-) 小鼠中 7α-羟基-4-胆甾-3-酮穿过血脑屏障的浓度依赖性通量以及随后形成胆甾醇的结果一致。这表明，相同的机制导致 CTX 患者脑内胆甾醇的积累。
