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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL050420-01A1
Application #
2226596
Study Section
Nutrition Study Section (NTN)
Project Start
1994-05-01
Project End
1997-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lin, Xiaobo; Racette, Susan B; Ma, Lina et al. (2015) Plasma biomarker of dietary phytosterol intake. PLoS One 10:e0116912
Lin, Xiaobo; Ma, Lina; Moreau, Robert A et al. (2011) Glycosidic bond cleavage is not required for phytosteryl glycoside-induced reduction of cholesterol absorption in mice. Lipids 46:701-8
Lin, Xiaobo; Racette, Susan B; Lefevre, Michael et al. (2011) Combined effects of ezetimibe and phytosterols on cholesterol metabolism: a randomized, controlled feeding study in humans. Circulation 124:596-601
Racette, Susan B; Lin, Xiaobo; Lefevre, Michael et al. (2010) Dose effects of dietary phytosterols on cholesterol metabolism: a controlled feeding study. Am J Clin Nutr 91:32-8
Lin, X; Racette, S B; Lefevre, M et al. (2010) The effects of phytosterols present in natural food matrices on cholesterol metabolism and LDL-cholesterol: a controlled feeding trial. Eur J Clin Nutr 64:1481-7
Lin, Xiaobo; Ma, Lina; Gopalan, Chaya et al. (2009) d- chiro-Inositol is absorbed but not synthesised in rodents. Br J Nutr 102:1426-34
Racette, Susan B; Spearie, Catherine Anderson; Phillips, Katherine M et al. (2009) Phytosterol-deficient and high-phytosterol diets developed for controlled feeding studies. J Am Diet Assoc 109:2043-51
Lin, Xiaobo; Ma, Lina; Fitzgerald, Robin L et al. (2009) Human sodium/inositol cotransporter 2 (SMIT2) transports inositols but not glucose in L6 cells. Arch Biochem Biophys 481:197-201
Westover, Emily J; Lin, Xiaobo; Riehl, Terrence E et al. (2006) Rapid transient absorption and biliary secretion of enantiomeric cholesterol in hamsters. J Lipid Res 47:2374-81
Lin, Xiaobo; Chen, Zhouji; Yue, Pin et al. (2006) A targeted apoB38.9 mutation in mice is associated with reduced hepatic cholesterol synthesis and enhanced lipid peroxidation. Am J Physiol Gastrointest Liver Physiol 290:G1170-6

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