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.

抽象的 心血管疾病（CVD）是美国的首要死因。动脉粥样硬化是一个标志 CVD 的发生，也是许多不良事件的根源。饮食中脂质摄入量的增加是导致肥胖的主要原因 CVD疾病负担。血浆脂质升高，特别是以低密度脂蛋白胆固醇的形式，加速 动脉粥样硬化，CVD的主要原因。新的证据表明其他脂质，例如甘油三酯 (TAG) 在 CVD 的发展中发挥作用，与 LDL 胆固醇无关。迄今为止，降脂疗法 主要集中在降低低密度脂蛋白胆固醇上，但不良事件仍在增加。在这个应用程序中，我们放置 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， 需要清洁剂（胆汁酸）来吸收。胆汁酸是由肝脏中的胆固醇合成的。有 许多不同的胆汁酸的化学结构不同，导致其作为洗涤剂的特性不同 也可作为信号分子。因此，肝脏是协调调节胆汁酸的中枢， 进而延伸到许多营养物质的代谢，包括脂质。我们提出了一个中心假设 脂质吸收受分泌到肠道的胆汁酸的类型和量调节 一顿饭。我们假设胆汁酸是驱动肠-肝通讯轴调节的关键管道 脂质吸收。我们选择性地靶向胆汁酸合成途径中的酶，以引发特定的 胆汁酸水平的变化，使我们能够研究胆汁酸水平和成分的变化如何改变脂质 体内吸收。尽管近年来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吸收的清洁剂，目前尚未得到充分研究。到 为了确定胆汁酸如何改变不同脂质的吸收，我们开发并验证了一种新型 AAV- CRISPR 策略仅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定量质谱方法来测量吸收 肠道内的膳食脂肪酸不同。使用这些工具，我们表明了总体中的特定调制 胆汁酸的数量和/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，我们发现胆汁酸的特定变化可以进一步加速和加剧 动脉粥样硬化。我们设计了两个具体目标来检验定义胆汁酸变化的假设， 由胆汁酸合成途径的酶的特定破坏介导，可预防 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作用的理解 并表明胆汁酸代谢是动脉粥样硬化和心血管疾病发病机制的重要贡献者。