Establishment of CTX Model Animal and Survey of its Pathogenesis.

脑腱黄瘤病（CTX）是一种以血清及各器官胆固醇含量增高为特征的遗传性固醇贮藏病。为了阐明CTX的发病机制，我们给小鼠喂食富含胆固醇的食物。采用高效液相色谱法测定血清、肝脏和小脑中的甾醇浓度。(1)在胆固醇喂养的小鼠中，血清和肝脏中的胆固醇浓度在前2 ~ 4周达到最大值。胆固醇浓度随后下降，最后降至最大值的50- 60%。另一方面，小脑内胆固醇水平几乎与摄食时间呈线性平行增加，未见下降。这些结果表明，肝脏清除或降解胆固醇的能力通过长期摄入这种化合物而增加，而小脑没有这种反馈调节。电镜组织学检查显示，饲喂胆固醇的小鼠肝脏内溶酶体颗粒增多。(2) 20%的胆甾醇小鼠出现两种类似人类钙化带性角膜病变的角膜混浊。电镜观察到上皮基底膜与浅表间质之间有晶体颗粒。对物质进行能量色散分析，推测为胆固醇。这些结果表明胆固醇可能由于血清水平升高而沉积在角膜中。角膜及相关区域胆固醇沉积可能是CTX患者角膜营养不良的原因之一。(3)饲喂胆固醇饲料14个月后，20%的小鼠出现了由55%胆固醇和45%胆固醇组成的胆结石，并伴有胆囊黏膜炎症和浆膜血管增厚。实验数据表明，胆固醇在血清和肝脏中替代胆固醇，增加胆固醇的生物合成，但抑制胆汁酸的合成。这些现象的结合促进了胆固醇喂养小鼠胆石的形成。这三个结果证明了该模型动物在CTX发病机制研究中的实用性。少

Cerebrotendinous xanthomatosis (CTX) is a hereditary sterol storage disease which is characterized by the increase in the cholestanol content in the serum and various organs. In order to elucidate the pathogenesis of CTX, mice were fed with a diet rich in cholestanol. The concentrations of sterol in the serum, liver, and cerebellum were determined using HPLC. (1) In the cholestanol-fed mice, the cholestanol concentrations in the serum and liver reached maxima in the first 2 to 4 weeks. Cholestanol concentration declined thereafter, finally to 50-60 % of the maxima. On the other hand, the levels of cholestanol in the cerebellum increased almost linearly in parallel to the feeding time, and no decline was observed. These results suggest that the capacity of the liver to remove or degrade cholestanol was increased by long-term intake of this compound, whereas the cerebellum had no such feed-back regulation. Histological examinations using an electron microscops revealed the enlargement of … More lysosomal granules in the liver of the cholestanol-fed mice. (2) Two kinds of corneal opacities resembling calcific band keratopathy in human were also found in 20 % of these cholestanolfed mice. The crystal particles were observed between epithelial basement membrane and superficial stroma by the electron microscopy. Energy dispersive analysis of the materials, which was presumed to be cholestanol. These results suggest that the cholestanol may deposit in the cornea from elevated serum levels. Deposition of cholestanol in cornea and related area may be a cause of corneal dystrophy in CTX. (3) After feeding cholestanol diet for 14 months, gallstones composed of 55 % cholesterol and 45 % cholestanol developed in 20 % of the mice and were associated with gallbladder mucosal inflammation and serosal vessel thickening. Experimental data demonstrate that cholestanol replaces cholesterol in serum and liver, causes increased cholestanol biosynthesis, but inhibits bile acid synthesis. The combination of these phenomena promotes gallstone formation in cholestanol-fed mice. These three findings proof the usefulness of this model animal in the investigation of CTX pathogenesis. Less