Mechanisms Regulating Non-biliary Fecal Sterol Loss

胆固醇平衡失调是导致冠心病(CHD)的重要原因，冠心病是 在美国的死因。调节胆固醇进入和转运的分子机制 已经被很好地定义了出来。人们普遍认为，胆固醇是通过 肠道吸收或内源性合成，并通过肝胆途径排出体外， 作为游离的甾醇或在肝脏转化为胆汁酸之后。尽管人们认为 我们最近发现，肝胆途径是人类排泄粪便胆固醇的主要途径 对于不能将胆固醇分泌到胆汁中的小鼠来说，粪便中的类固醇丢失是正常的。此外，我们还拥有 证明新生的肝脏衍生的脂蛋白可以将胆固醇输送到肠道，这表明 存在基于非胆汁血浆的排泄物类固醇丢失途径。我们的发现以及其他发现表明， 肠道可能在直接消除胆固醇的过程中发挥重要作用。这样做的目的是 工作是了解调节非胆汁性粪便类固醇丢失的分子机制。 肠道，一条被理解得很差的通路，可能在整个身体中扮演着数量上重要的角色 胆固醇平衡。在该项目的指导阶段，我们建议：1)量化胆汁和非胆汁 胆道功能不全的外科和遗传学模型对粪便胆固醇损失的贡献，以及 2)确定血浆脂蛋白介导的胆固醇向肠道的输送是否取决于 载脂蛋白E的存在在独立研究阶段，我们建议：3)鉴定 负责胆固醇跨肠细胞基侧膜转运的携带者(S)，以及4) 确定负责将心尖胆固醇转运到小肠腔的携带者(S)。

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 pooriy 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 nonbiliary 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.