The purpose of this research is to improve the dietary treatment of hypercholesterolemia by understanding more fully how dietary factors interact with mechanisms of cholesterol absorption. Cholesterol absorption is a critical control point for cholesterol metabolism because it affects both dietary and endogenous recirculating biliary cholesterol. The central hypothesis of this proposal is that certain lipids (phytosterols, squalene and oxysterols), in the quantities found in western diets, have physiologically important effects on cholesterol absorption and metabolism.
The aims i nvolve human subjects, animals and cultured cells and rely heavily on stable isotopic tracers and newly developed mass spectroscopic methods of analysis. Dietary supplementation with phytosterols is known to reduce cholesterol absorption. During the current funding period we have demonstrated that the quantity of phytosterols contained in normal diets is sufficient to reduce cholesterol absorption. Here we propose to use a novel phytosterol-deficient baseline diet in controlled feeding studies to test the hypothesis that natural food phytosterols lower LDL cholesterol. We will also explore the interaction of phytosterols with ezetimibe. Squalene is known to be a cholesterol precursor but whether dietary squalene contributes significantly to cholesterol synthesis in man has not been adequately addressed. We will measure squalene absorption and quantify its effect on cholesterol biosynthesis and LDL cholesterol. Oxysterols are known to regulate cholesterol absorption by binding to LXR/RXR nuclear receptors in enterocytes; however the effect of dietary oxysterols on cholesterol absorption has not been addressed. We propose to measure the metabolism of oxysterols in humans and to define their effects on cholesterol absorption. Finally we will use cholesterol enantiomer, a new synthetic probe which is not absorbed but which has identical physical properties as cholesterol, to trace absorption pathways. Successful completion of this work will provide new directions for improving circulating lipoproteins through dietary counseling as well as by changes in industrial food manufacturing.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050420-12
Application #
7192480
Study Section
Nutrition Study Section (NTN)
Program Officer
Ershow, Abby
Project Start
1994-05-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
12
Fiscal Year
2007
Total Cost
$521,636
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
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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