Establishment of CTX Model Animal and Survey of its Pathogenesis.

脑腱黄瘤病(CTX)是一种遗传性的类固醇蓄积性疾病，其特征是血清和各器官中胆固醇量的增加。为了阐明CTX的发病机制，给小鼠喂饲富含胆甾醇的饲料。用高效液相色谱法测定血清、肝脏和小脑中的甾醇浓度。(1)在灌胃胆甾醇的小鼠中，血清和肝脏中的胆甾醇浓度在最初的2~4周达到最大值。此后，胆甾醇浓度下降，最终降至最大值的50-60%。另一方面，小脑中的胆甾醇水平几乎与喂养时间呈线性增加，并且没有观察到下降。这些结果表明，长期摄入该化合物可提高肝脏清除或降解胆甾醇的能力，而小脑则没有这种反馈调节。电子显微镜下的组织学检查显示…增大喂饲胆固醇组小鼠肝脏内有较多溶酶体颗粒。(2)其中20%的小鼠可见两种类似人类角膜钙化带病的混浊。电子显微镜下可见上皮基底膜与浅基质之间有结晶颗粒。对这些物质进行了能量色散分析，推测是胆甾醇。这些结果表明，血清水平升高可能会使胆甾醇沉积在角膜中。CTX中角膜及相关区域的胆甾醇沉积可能是导致角膜营养不良的原因之一。(3)喂饲胆甾醇14个月后，20%的小鼠出现由55%的胆固醇和45%的胆甾醇组成的胆结石，并伴有胆囊炎和浆膜血管增厚。实验数据表明，胆甾醇替代了血清和肝脏中的胆固醇，导致胆固醇生物合成增加，但抑制了胆汁酸的合成。这些现象的结合促进了喂食胆甾醇的小鼠的胆结石形成。这三个发现证明了该模型动物在CTX致病机制研究中的有效性。较少

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