METABOLISM OF CHOLESTANOL AND CHOLESTEROL IN MAN

本研究的目的是检查胆甾烷醇， 胆固醇和胆汁酸代谢 腱性黄瘤病（CTX）、谷甾醇血症伴 黄瘤病、动脉粥样硬化和胆结石。 我们特别 应继续定义临床和生化异常 在罕见的遗传性脂质储存疾病中，CTX和 谷甾醇血症 在CTX中，胆汁酸合成的缺陷导致 胆固醇的过度生产和积累， 组织中的胆固醇。 一个主要目标是（1）抑制异常 鹅去氧胆酸合成胆汁酸及长时间评价 在临床和生化过程中的长期变化 疾病 与其他有前途的治疗方法比较，如 胆酸和HMG CoA还原酶抑制剂Mevinolin将 被制造。 (2)关于侧- 胆酸生物合成中的链氧化将使用3 α，7 α，12 α-三羟基粪甾烷酸，一种C-27胆汁 酸，作为假定的前体。 (3)通过定义定量 侧链裂解机制（25-或26-羟基 胆汁酸合成中，特异性胆汁酸酶促 将确定CTX中的缺陷。 (4)胆甾烷醇途径 将在CTX和谷甾醇血症中研究生物合成 以确定是否胆汁酸代谢酶，7 α- 羟基胆固醇或4-胆甾烯-3-酮是 这些疾病中胆甾烷醇的积累。 (5)的 植物甾醇（菜油甾醇和谷甾醇）的代谢， 胆甾烷醇将与谷甾醇血症中的胆固醇进行比较， 黄瘤病 在这种疾病中，植物甾醇的吸收是 增加并伴有肝固醇和胆汁酸减少 分泌物 我们建议测量（a）谷甾醇和胆固醇 （B）通过同位素动力学方法的转换， 谷甾醇转化为胆汁酸，（c）植物甾醇可能 竞争性阻断正常胆汁酸合成（抑制 胆固醇7 α-羟化酶活性）和（d）肠 谷甾醇和胆固醇的吸收将通过 不依赖粪便的血浆双同位素比值法 测量.

The aim of this investigation is to examine cholestanol, cholesterol, and bile acid metabolism in patients with cerebrotendinous xanthomatosis (CTX), sitosterolemia with xanthomatosis, atherosclerosis and gallstones. Specifically, we shall continue to define the clinical and biochemical abnormalities in the rare inherited lipid storage diseases, CTX and sitosterolemia. In CTX, a defect in bile acid synthesis leads to the overproduction and accumulation of cholesterol and cholestanol in tissues. A major goal is (1) to suppress abnormal bile acid synthesis with chenodeoxycholic acid and evaluate long term changes in the clinical and biochemical course of the disease. Comparison with other promising treatments such as cholic acid and the HMG CoA reductase inhibitor Mevinolin will be made. (2) Quantitative information on the mechanism of side- chain oxidation in cholic acid biosynthesis will be sought using 3 alpha, 7 alpha, 12 alpha-trihydroxycoprostanoic acid, a C-27 bile acid, as a putative precursor. (3) By defining the quantitative mechanism of side chain cleavage (either 25- or 26 hydroxy pathways) in bile acid synthesis, the specific bile acid enzymatic defect in CTX will be ascertained. (4) The pathway of cholestanol biosynthesis will be investigated in both CTX and sitosterolemia to determine if the bile acid precurcors, 7 alpha- hydroxycholesterol or 4-cholesten-3-one, are intermediates in these diseases where cholestanol accumulates. (5) The metabolism of plant sterols (campesterol and sitosterol) and cholestanol will be compared to cholesterol in sitosterolemia with xanthomatosis. In this disease, plant sterol absorption is increased and coupled to decreased hepatic sterol and bile acid secretion. We propose to measure (a) sitosterol and cholesterol turnover by isotope kinetic methods, (b) the conversion of sitosterol to bile acids, (c) the possibility that plant sterols may competitively block normal bile acid synthesis (suppress cholesterol 7 alpha-hydroxylase activity) and (d) intestinal absorption of sitosterol and cholesterol will be measured by plasma dual isotope ratio method which is independent of fecal measurements.