Contributions of hepatic and intestinal pathways to cholesterol excretion

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7. Project Summary The elimination of excess cholesterol from the body is essential in maintaining homeostasis and opposing the development of a number of metabolic diseases, most notably atherosclerotic cardiovascular disease. Classically, cholesterol elimination is thought to be accomplished by hepatic metabolism of cholesterol to bile acids and the secretion of both bile acids and cholesterol in the bile. However, under a number of conditions in which biliary secretion of cholesterol is compromised fecal excretion is maintained, indicating the presence of a non-biliary, alternate pathway. Previously published and preliminary studies demonstrate that the proximal small intestine is capable of secreting cholesterol and that the rate of intestinal cholesterol secretion increases when biliary cholesterol secretion is reduced. The hypothesis of this proposal is that transintestinal cholesterol elimination (TICE) is regulated by biliary cholesterol output, by plasma lipoprotein donors, and by an enterohepatic signaling axis involving bile acids. To date, the contribution of the intestine to cholesterol excretion has largely been inferred by calculating differences in cholesterol concentrations in bile among strains of mice or in response to pharmacological agents relative to the changes in fecal neutral sterols. We have developed a novel surgical procedure to simultaneously measure rates of biliary and intestinal cholesterol secretion in mice. This will allow us to address, for the first time, the relative rates of biliary and intestinal cholesterol secretion, track the delivery of cholesterol from plasma lipoproteins to both the hepatic and intestinal pathway, and better understand how the intestine adapts to alterations in biliary cholesterol secretion. The aims are to: I) determine the impact of biliary cholesterol secretion on intestinal cholesterol secretion rates, II) determine the lipoprotein donors to both the biliary and intestinal pathway under conditions of high and low biliary cholesterol secretion, and III) determine the impact of bile acid signaling in the intestine on hepatic and intestinal cholesterol secretion. The accomplishment of these aims will further our understanding of the intestine as a regulator of cholesterol homeostasis and identify novel regulators of intestinal cholesterol secretion that may be targeted to promote cholesterol excretion and the removal of excess cholesterol from the body.