Nutrition and Health Sciences, Department of


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A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy, Major: Nutrition, Under the Supervision of Professor Timothy P. Carr.
Lincoln, Nebraska: March, 2011

Copyright 2011 Andrew W. Brown


Phytosterols and their fatty acyl esters have been known for decades to lower LDL cholesterol, making them powerful nutraceuticals in lowering cardiovascular disease risk. The mechanisms by which phytosterols lower cholesterol, though, have been incompletely characterized. Three studies were executed to examine three aspects of cholesterol and phytosterol interactions in the intestinal lumen. In the first study, the ability of pancreatic cholesterol esterase to hydrolyze phytosterol esters was examined. Pancreatic cholesterol esterase hydrolyzed phytosterol esters, but the rate of hydrolysis proved sensitive to the structures of both the sterol and ester components. In the second study, cholesterol micellarization was challenged with phytosterols, phytosterol esters, and simulated hydrolysis products of phytosterol esters. Phytosterols inhibited cholesterol incorporation into micelles, but there was little difference in effects among the phytosterols. Investigation of the influence of fatty acids, simulating the effects of phytosterol ester hydrolysis, demonstrated a moderate increase in cholesterol micellarization in the presence of unsaturated, but not saturated, fatty acids. Intact esters, however, did not alter cholesterol micellarization, nor did the esters themselves incorporate into micelles. In the third study, phytosterol esters and ethers possessing differential stability towards hydrolysis were incorporated into diets administered to hamsters. The lipids in the intestinal lumen of the hamsters did not show a hydrolysis-dependent partitioning of cholesterol between aqueous and oily phases, as was hypothesized. The extent of hydrolysis of phytosterol esters, however, was strongly and negatively correlated with cholesterol absorption efficiency. Treatment-associated changes to lipid profiles of the intestinal contents were also observed. These studies thus demonstrated that pancreatic cholesterol esterase is likely responsible for phytosterol ester hydrolysis in the intestine; competition for micellarization by free phytosterols explains some of their efficacy, while the exclusion of phytosterol esters from micelles implies hydrolysis must first take place for esters to affect this mechanism; and the extent of hydrolysis of phytosterol esters is a strong determinant of phytosterol ester efficacy. These conclusions may be useful in guiding phytosterol formulations for maximizing cholesterol-lowering efficacy.