METABOLISM OF CHOLESTANOL AND CHOLESTEROL IN MAN

这项调查的目的是检测胆甾醇， 慢性阻塞性肺疾病患者的胆固醇和胆汁酸代谢 脑腱黄瘤病(CTX)，谷固醇血症伴 黄瘤病、动脉粥样硬化和胆结石。具体来说，我们 应继续界定临床和生化异常 在罕见的遗传性脂质储存疾病中，CTX和 谷固醇血症。在环磷酰胺中，胆汁酸合成缺陷会导致 胆固醇的过度生产和积累以及 组织中的胆甾醇。一个主要目标是(1)抑制异常 鹅去氧胆酸合成胆汁酸及其评价 慢性粒细胞白血病临床和生化过程中的期别变化 疾病。与其他有希望的治疗方法进行比较，如 胆酸和HMG辅酶A还原酶抑制剂Mevinolin将 被创造出来。(2)关于侧向作用机理的定量信息。 胆酸生物合成中的链式氧化将使用3 阿尔法，7阿尔法，12阿尔法三羟基辅前列酸，C-27胆汁 酸，作为一种假定的前体。(3)通过界定数量上的 侧链(25-羟基或26-羟基)裂解机理 途径)在胆汁酸合成中，特定的胆汁酸酶 CTX中的缺陷将被确定。(4)胆甾醇的代谢途径 将对环磷酰胺和谷甾醇血症的生物合成进行研究。 为了确定胆汁酸前体，7α- 羟基胆固醇或4-胆固酮-3-酮是 胆固醇会积聚的这些疾病。(5) 植物甾醇(菜籽甾醇和谷甾醇)的代谢和 胆固醇症与胆固醇在谷甾醇血症中的比较 黄瘤病。在这种疾病中，植物对类固醇的吸收 肝脏类固醇和胆汁酸的升高和降低 分泌物。我们建议测定(A)谷甾醇和胆固醇 利用同位素动力学方法进行周转，(B)转化率 谷甾醇转化为胆汁酸；(C)植物甾醇可能 竞争性地阻止正常胆汁酸的合成(抑制 胆固醇7α-羟基酶活性)和(D)肠道 谷甾醇和胆固醇的吸收将通过以下方法测量 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.