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.
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