Dysregulation of cholesterol balance contributes significantly to coronary heart disease (CHD), the leading cause of death in the United States. Molecular mechanisms regulating the transport of cholesterol into and out of the body have been well defined. It is generally accepted that cholesterol enters the body via intestinal absorption or endogenous synthesis, and is excreted out of the body via a hepatobiliary route, either as free sterol or following hepatic conversion to bile acids. Although it is believed that the hepatobiliary route is the major pathway for fecal cholesterol excretion in humans, we have recently found that fecal sterol loss is normal in mice unable to secrete cholesterol into bile. Furthermore, we have demonstrated that nascent liver-derived lipoproteins can deliver cholesterol to the intestine, indicating the presence of a non-biliary plasma-based route for fecal sterol loss. Our findings, along with others, suggest that the intestine may play an important role in the direct elimination of cholesterol. The objective of this work is to understand the molecular mechanisms regulating non-biliary fecal sterol loss through the intestine, a poorly understood pathway that may play a quantitatively important role in whole body cholesterol balance. During the mentored phase of this project, we propose to: 1) quantify biliary and non-biliary contributions to fecal cholesterol loss using surgical and genetic models of biliary insufficiency, and 2) determine whether plasma lipoprotein-mediated delivery of cholesterol to the intestine depends on the presence of apolipoprotein E. During the independent research phase, we propose to: 3) identify the carrier(s) responsible for cholesterol transport across the basolateral membrane of the enterocyte, and 4) identify the carrier(s) responsible for apical cholesterol transport into the small intestine lumen. Data obtained from these studies are expected to define molecular mechanisms regulating non-biliary fecal sterol loss, an obvious gap in the current knowledge base. By elucidating the molecular mechanisms regulating the excretory function of the small intestine, these studies may lead to the development of novel therapeutic approaches for modulating cholesterol balance in humans.
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