Contributions of hepatic and intestinal pathways to cholesterol excretion

7.项目总结 从体内消除多余的胆固醇对于维持体内平衡和 反对一些代谢性疾病的发展，尤其是动脉粥样硬化 心血管疾病。传统上，胆固醇的清除被认为是由肝脏完成的。 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，在一些胆汁胆固醇分泌受到损害的情况下，粪便 排泄维持，表明存在非胆道的替代途径。先前 已发表的和初步的研究表明，近端小肠能够 胆汁中胆固醇的分泌和肠道胆固醇分泌的增加 胆固醇分泌减少。这项提议的假设是，通过肠道的胆固醇 胆汁胆固醇排泄(TICE)受血浆脂蛋白供体和胆汁胆固醇排泄的调节。 胆汁酸参与的肠肝信号轴。到目前为止，肠道对 胆固醇排泄在很大程度上是通过计算胆固醇浓度的差异来推断的。 在小鼠品系之间的胆汁或对药物的反应与粪便的变化有关 中性的甾醇。我们已经开发了一种新的外科手术程序来同时测量 小鼠胆汁和肠道胆固醇分泌。这将使我们能够第一次解决 胆汁和肠道胆固醇分泌的相对速率，跟踪胆固醇从 血浆脂蛋白到肝脏和肠道的途径，并更好地了解 肠道适应胆汁胆固醇分泌的变化。目标是：i)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 高胆汁和低胆汁胆固醇条件下胆道和肠道的供体 分泌物，以及iii)确定肠道中胆汁酸信号对肝脏和肠道的影响 胆固醇分泌。这些目标的实现将加深我们对 肠道作为胆固醇动态平衡的调节器和发现新的肠道调节器 胆固醇分泌可能是促进胆固醇排泄和清除多余胆固醇的靶点 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.