Contributions of hepatic and intestinal pathways to cholesterol excretion

7.项目摘要 从体内消除多余的胆固醇对于维持体内平衡和 对抗许多代谢性疾病的发展，尤其是动脉粥样硬化 心血管疾病传统上，胆固醇的消除被认为是通过肝脏来完成的。 胆固醇代谢为胆汁酸以及胆汁中胆汁酸和胆固醇的分泌。 然而，在胆固醇的胆汁分泌受到损害的许多情况下， 维持排泄，表明存在非胆汁替代途径。先前 已发表的和初步的研究表明，近端小肠能够 分泌胆固醇和肠道胆固醇分泌率增加时，胆汁 胆固醇分泌减少。这项提议的假设是， 胆固醇清除（TICE）受胆汁胆固醇排出量、血浆脂蛋白供体和 涉及胆汁酸的肝肠信号轴。到目前为止，肠道对 胆固醇排泄主要是通过计算胆固醇浓度的差异来推断的 小鼠品系之间的胆汁中或对药物的反应相对于粪便中的变化 中性固醇我们已经开发了一种新的外科手术方法， 胆汁和肠胆固醇分泌。这将使我们能够第一次解决 胆固醇和肠胆固醇分泌的相对速率，跟踪胆固醇从 血浆脂蛋白的肝脏和肠道途径，并更好地了解如何 肠道适应胆汁胆固醇分泌的改变。目的是：（一）确定影响 胆汁胆固醇分泌对肠道胆固醇分泌率的影响，II）测定脂蛋白 在高胆固醇和低胆固醇条件下，胆和肠途径的供体 III）确定肠中胆汁酸信号传导对肝和肠分泌的影响， 胆固醇分泌这些目标的实现将进一步加深我们对 肠作为胆固醇体内平衡调节剂并鉴定新的肠调节剂 胆固醇分泌，可能有针对性地促进胆固醇排泄和清除多余的 体内的胆固醇。

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.