The aim of this investigation is to examine cholesterol and cholestanol metabolism in patients with cerebrotendinous xanthomatosis (CTX), atherosclerosis and gallstones. Specially we shall continue to define the clinical and biochemical abnormalities in the rare inherited lipid storage diseases, CTX. In CTX, a defect in bile acid synthesis leads to excessive production and tissue accumulation of cholesterol and cholestanol. A major goal is to suppress the abnormal bile acid synthetic pathway with chenodeoxycholic acid and evaluate changes in the clinical and biochemical course of the disease. Further the site of cholestanol formation and its regulation will be investigated. In addition, the pathway of side chain oxidation of cholesterol to bile acid will be examined to determine whether the side chain cleavage proceeds via 26- or 25-hydroxylated derivatives. In other experiments, the metabolism of plant sterols (campesterol and sitosterol) and cholesterol will be evaluated in sitosterolemia with xanthomatosis, a newly discovered lipid storage disease in which plant sterols (campesterol and sitosterol) along with cholesterol accumulate in the body. We intend to measure sitosterol and cholesterol turnover by the isotope kinetic method, conversion of sitosterol to bile acids and to assess the intestinal absorption of both sitosterol and cholesterol by the plasma dual isotope ratio method, which is not dependent on fecal balance measurements.
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