This application proposes to test the hypothesis that cholesterol absorption in the intestine is a key point of regulation for body cholesterol metabolism. Cholesterol absorption is viewed as important not only in limiting dietary cholesterol uptake but also in regulating the reverse transport of endogenous biliary cholesterol from the body through excretion in the bowel. Although important preliminary work has provided some evidence for both of these roles, surprisingly few studies of cholesterol absorption have been performed and little is known about the metabolic control of cholesterol absorption in normal subjects. This project will acquire basic descriptive data quantifying cholesterol absorption in normal adult subjects of all ages and both sexes and will test the hypothesis that the absolute absorption of cholesterol from the intestine (mg/day) is regulated in order to achieve a constant input into body cholesterol pools. Both the efficiency with which the intestine absorbs cholesterol (percent cholesterol absorption) and the endogenous biliary cholesterol load delivered to the intestine will be measured using tracer cholesterols and intestinal intubation. Since a major reason for the deficiency of data on cholesterol absorption has been the need to use radioactive isotopes in clinical studies, the current project will use and further develop methods for cholesterols labeled with stable isotopes. The recently synthesized non-radioactive tracers [23,24,2,26,27-13C5]cholesterol and [26,26,26,27,27,27- 2H6]cholesterol will be employed in the measurement of cholesterol absorption with detection by gas chromatography-mass spectrometry (GC/MS) and isotope ratio mass spectrometry (IR/MS). Measurements of cholesterol absorption made with these tracers will be Compared to results obtained by direct intestinal intubation. This project will provide new data relating measures of cholesterol absorption to age, sex, diet and common metabolic variables. The long- term goal of the project is to provide new insights into the regulation of body cholesterol by the absorption mechanism and to focus more precisely existing diet and drug therapies.
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