Contributions of hepatic and intestinal pathways to cholesterol excretion

肝脏和肠道途径对胆固醇排泄的贡献

• 批准号: 9447975
• 负责人: Gregory A Graf
• 金额: $ 46.96万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447975
• 关键词: Address; Antisense Oligonucleotides; Atherosclerosis; Bile Acids; Bile fluid; Biliary; Cells; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol Homeostasis; Data; Development; Distal; Event; Excision; Excretory function; GPBAR1 gene; Gallbladder; Genetic Complementation Test; Hepatic; Hepatobiliary; High Density Lipoprotein Cholesterol; Homeostasis; Intestines; Investigation; LDL Cholesterol Lipoproteins; Lipids; Lipoproteins; Liver; Measures; Metabolic Diseases; Metabolism; Methods; Micelles; Modeling; Mouse Strains; Mus; Operative Surgical Procedures; Organ; Output; Parabiosis; Pathway interactions; Peripheral; Pharmacology; Plasma; Play; Prevention; Process; Publishing; Regulation; Rodent; Role; Signal Transduction; Small Intestines; Sterols; Time; adeno-associated viral vector; liver metabolism; low density lipoprotein inhibitor; man; novel; receptor; response; reverse cholesterol transport; synergism; uptake

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.

七、项目概要 消除体内多余的胆固醇对于维持体内平衡和 对抗许多代谢疾病的发展，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完成的 胆固醇代谢为胆汁酸以及胆汁酸和胆汁中胆固醇的分泌。 然而，在胆汁分泌胆固醇受到损害的许多情况下，粪便 排泄得以维持，表明存在非胆汁替代途径。之前 已发表的初步研究表明，近端小肠能够 分泌胆固醇，胆汁分泌胆固醇时，肠道胆固醇分泌率增加 胆固醇分泌减少。该提案的假设是，经肠胆固醇 消除（TICE）受胆汁胆固醇输出、血浆脂蛋白供体和 涉及胆汁酸的肠肝信号轴。迄今为止，肠道对 胆固醇排泄很大程度上是通过计算胆固醇浓度的差异来推断的 小鼠品系的胆汁中或对与粪便变化相关的药物的反应 中性甾醇。我们开发了一种新颖的外科手术，可以同时测量 小鼠胆汁和肠道胆固醇分泌。这将使我们能够首次解决 胆汁和肠道胆固醇分泌的相对速率，跟踪胆固醇的输送 血浆脂蛋白进入肝脏和肠道途径，并更好地了解 肠道适应胆汁胆固醇分泌的变化。目的是： 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 高胆胆固醇和低胆胆固醇条件下胆道和肠道途径的供体 III) 确定肠道内胆汁酸信号传导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 肠道作为胆固醇稳态的调节剂并确定肠道的新型调节剂 胆固醇分泌，可能有针对性地促进胆固醇排泄和去除多余的胆固醇 排出体内的胆固醇。