Targeting the gut-liver axis in cardiovascular disease

针对心血管疾病的肠肝轴

• 批准号: 10606375
• 负责人: Elizabeth Joanna Tarling
• 金额: $ 74.53万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606375
• 关键词: Acceleration; Acids; Adult; Adverse event; Affect; Atherosclerosis; Bacterial Toxins; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biological Assay; CYP2C19 gene; CYP7A1 gene; CYP8B1 gene; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Cells; Chemical Structure; Chenodeoxycholic Acid; Cholesterol; Cholesterol Esters; Cholic Acids; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Detergents; Development; Diet; Dietary Fats; Dietary Fatty Acid; Disease; Enzymes; Fatty Acids; Gene Expression; Genes; Genetic study; Health system; Hepatic; Human Genetics; Immune; Inflammation; Inflammatory; Intake; Intestinal permeability; Intestines; LDL Cholesterol Lipoproteins; Leaky Gut; Lipids; Liver; Low-Density Lipoproteins; Mass Spectrum Analysis; Measures; Mediating; Metabolism; Mus; Nutrient; Pathogenesis; Pathway interactions; Plasma; Property; Public Health; Role; Signal Transduction; Signaling Molecule; System; Testing; Therapeutic; Therapeutic Intervention; Triglycerides; United States; absorption; atheroprotective; bile acid metabolism; burden of illness; cardiovascular disorder risk; cholesterol absorption; design; early onset; ezetimibe; gut-liver axis; hypercholesterolemia; improved; in vivo; lipid metabolism; muricholic acid; novel; protective pathway; tool; transcriptome sequencing; uptake

ABSTRACT Cardiovascular Disease (CVD) is the leading cause of death in the United States. Atherosclerosis is a hallmark of CVD and underlies many adverse events. Increased dietary lipid intake is a major contributor to the increased CVD disease burden. Elevated plasma lipids, particularly in the form of LDL cholesterol, accelerate atherosclerosis, the major cause of CVD. Emerging evidence suggests that other lipids, such as triglycerides (TAG), play a role in the development of CVD, independent of LDL cholesterol. To date, lipid lowering therapies have mostly focused on lowering LDL cholesterol, yet adverse events continue to rise. In this application we put forth the framework and hypothesis that modulating bile acids, the body’s natural detergents, can be protective against the onset of atherosclerosis. Dietary lipids such as TAG and cholesterol ester (CE) are insoluble and require detergents (bile acids) for absorption. Bile acids are synthesized from cholesterol in the liver. There are many different bile acids which differ in their chemical structure which results in different properties as detergents and also as signaling molecules. Therefore, the liver is a central hub that coordinately regulates the bile acids, and by extension, the metabolism of many nutrients, including lipids. We have developed a central hypothesis that lipid absorption is regulated by the type and amount of bile acid that is secreted into the intestine following a meal. We hypothesize that bile acids are the key conduits that drive a gut-liver communication axis to regulate lipid absorption. We have selectively targeted enzymes in the bile acid synthetic pathway to elicit specific changes to bile acid levels, allowing us to study how changes in bile acid levels and composition alter lipid absorption in vivo. While much has been studied in recent years about bile acid signaling, the role of bile acids as detergents that facilitate the absorption of different dietary lipid species has been less well studied. To determine how bile acids alter the absorption of different lipids, we have developed and validated a novel AAV- CRISPR strategy to disrupt specific bile acid metabolism genes exclusively in the liver of adult mice. We have also established a non-invasive and quantitative mass spectrometry approach to measure the absorption of different dietary fatty acids in the intestine. Using these tools, we show that specific modulations in the total amount and/or composition of bile acids have profound effects on fatty acid absorption and atherosclerosis progression. Furthermore, we show that specific changes in bile acids can further accelerate and exacerbate atherosclerosis. We have designed two specific aims to test the hypothesis that defined changes in bile acids, mediated by specific disruption of enzymes of the bile acid synthesis pathway are protective against atherosclerosis. Completion of these studies will further our understanding of the role of bile acids as detergents and implicate bile acid metabolism as an important contributor in the pathogenesis atherosclerosis and CVD.

摘要 心血管疾病（CVD）是美国的主要死亡原因。动脉粥样硬化是 心血管疾病和许多不良事件的基础。膳食脂质摄入量增加是导致 CVD疾病负担。血脂升高，特别是LDL胆固醇的升高， 动脉粥样硬化是心血管疾病的主要原因。新出现的证据表明，其他脂质，如甘油三酯 (TAG)，在CVD的发展中发挥作用，独立于LDL胆固醇。迄今为止，降脂治疗 主要集中在降低低密度脂蛋白胆固醇，但不良事件继续上升。在这个应用程序中，我们把 提出了调节胆汁酸（人体的天然清洁剂）可以起到保护作用的框架和假设 对抗动脉粥样硬化的发生。膳食脂质如TAG和胆固醇酯（CE）是不溶性的， 需要洗涤剂（胆汁酸）来吸收。胆汁酸是由肝脏中的胆固醇合成的。有 许多不同的胆汁酸，它们的化学结构不同，这导致作为洗涤剂的不同性质 也可以作为信号分子。因此，肝脏是协调调节胆汁酸的中心枢纽， 以及许多营养物质的代谢，包括脂质。我们提出了一个核心假设 脂质的吸收是由胆汁酸的类型和数量来调节的， 一顿饭我们假设胆汁酸是驱动肠-肝通讯轴调节肝细胞凋亡的关键管道。 脂质吸收我们选择性地靶向胆汁酸合成途径中的酶， 胆汁酸水平的变化，使我们能够研究胆汁酸水平和组成的变化如何改变脂质 体内吸收虽然近年来已经对胆汁酸信号传导进行了大量研究，但胆汁酸的作用 作为促进不同膳食脂质物质吸收的清洁剂，研究得较少。到 确定胆汁酸如何改变不同脂质的吸收，我们已经开发并验证了一种新的AAV- CRISPR策略专门破坏成年小鼠肝脏中的特定胆汁酸代谢基因。我们有 还建立了一种非侵入性和定量质谱法来测量吸收 不同的膳食脂肪酸在肠道。使用这些工具，我们表明，在总的特定调制 胆汁酸的量和/或组成对脂肪酸吸收和动脉粥样硬化具有深远的影响 进展此外，我们表明，胆汁酸的具体变化可以进一步加速和加剧 动脉粥样硬化我们设计了两个特定的目标来检验定义胆汁酸变化的假设， 通过特异性破坏胆汁酸合成途径的酶介导的， 动脉粥样硬化这些研究的完成将进一步加深我们对胆汁酸作为洗涤剂的作用的理解 提示胆汁酸代谢在动脉粥样硬化和心血管疾病的发病机制中起重要作用。