Mechanisms of glycine-based therapy for atherosclerosis

甘氨酸治疗动脉粥样硬化的机制

• 批准号: 10649691
• 负责人: Oren Shalom Rom
• 金额: $ 24.9万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649691
• 关键词: Acute myocardial infarction; Amino Acids; Anabolism; Antiatherogenic; Antioxidants; Apolipoprotein E; Atherosclerosis; Automobile Driving; Bile fluid; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Cholesterol; Cholesterol Homeostasis; Crossbreeding; Development; Development Plans; Drug Kinetics; Dyslipidemias; Excretory function; Fatty Liver; Genes; Glucose; Glutathione; Glycine; Goals; Hepatic; Human; Hyperglycemia; Impairment; Intestines; Link; Lipid Peroxidation; Lipids; Macrophage; Mediating; Metabolism; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Phenotype; Property; Reporting; Research; Research Personnel; Risk Factors; Role; Sampling; Training; Variant; amino acid metabolism; atherogenesis; atheroprotective; cardiometabolism; cardiovascular disorder risk; career development; deprivation; genome wide association study; hypercholesterolemia; metabolomics; non-alcoholic fatty liver disease; novel; transcriptomics; western diet

Cardiovascular disease (CVD) arising from atherosclerosis remains a leading cause of death. Current lipid- lowering therapies cannot completely eliminate CVD risk, likely due to lack of influence on other major risk factors beyond dyslipidemia. Dysregulated metabolism of amino acids (AA) was reported in cardiometabolic diseases with lower circulating glycine as a common denominator in acute myocardial infarction, type 2 diabetes (T2D), obesity and nonalcoholic fatty liver disease (NAFLD). While potential mechanisms by which glycine protects from T2D and NAFLD have been identified, the role of glycine in cholesterol metabolism and atherosclerosis is unknown. We recently reported glycine as the most potent AA in lowering lipid accumulation in macrophages. In our preliminary studies here, suppression of key pathways driving glycine biosynthesis was evident in atherogenic conditions in humans and mice. Glycine deprivation using our newly developed AA- modified Western diets (WD) enhanced hypercholesterolemia and atherosclerosis in apoE-/- mice. In contrast, glycine treatment was protective of those phenotypes, while lowering hyperglycemia and hepatic steatosis, which are other major CVD risk factors. This was associated with lower lipid peroxidation and induction of pathways driving glutathione biosynthesis and transport of cholesterol into bile. Furthermore, we identified a glycine-based compound (DT-109) with dual cholesterol- and glucose-lowering properties in mice. Our findings led us to hypothesize that glycine-based treatments are atheroprotective by inducing glutathione-mediated antioxidant defense and hepatic-intestinal cholesterol excretion. The long-term objectives of this study are to ascertain impaired glycine metabolism in atherogenesis, establish antiatherogenic glycine-based therapy able to reduce other CVD risk factors and uncover the underlying mechanisms. Aim 1 will assess impaired synthesis and increased utilization of glycine in atherogenesis. We will use transcriptomics and metabolomics in apoE-/-, our new AGXT1-/- mice and human fatty liver samples. The link between variants in genes driving glycine metabolism and atherosclerotic disease will be determined by human GWAS. Aim 2 will determine the effects of lower and higher glycine availability on atherosclerosis development. We will use apoE-/- mice fed WD with or without glycine or treated with DT-109. AGXT1-/- mice crossbred with apoE-/- mice will be used to determine the role endogenous glycine. Aim 3 will establish DT-109 as a glycine-based therapy for atherosclerosis, its pharmacokinetics and the underlying mechanisms. Atherosclerotic apoE-/- mice will be used to assess glycine incorporation to glutathione by metabolomics and fluxomics and hepatic-intestinal cholesterol excretion. We will study the ability of DT-109, compared to glycine, to regress established atherosclerosis in apoE-/- mice. Completing these studies will set the basis for novel glycine-based treatments for atherosclerosis, while the outlined career development plan, including hands-on training, coursework and seminars, will allow me to develop my long-term goal of becoming an independent investigator in cardiometabolic research.

由动脉粥样硬化引起的心血管疾病（CVD）仍然是死亡的主要原因。当前脂质- 降低治疗不能完全消除CVD风险，可能是由于对其他主要风险缺乏影响 血脂异常以外的因素。据报道，心脏代谢性疾病中的氨基酸（AA）代谢失调， 2型急性心肌梗死中循环甘氨酸水平降低的疾病 糖尿病（T2 D）、肥胖和非酒精性脂肪肝（NAFLD）。虽然潜在的机制， 已经鉴定了甘氨酸保护免受T2 D和NAFLD的作用，甘氨酸在胆固醇代谢和 动脉粥样硬化是未知的。我们最近报道甘氨酸作为最有效的AA在降低脂质积累 在巨噬细胞中。在我们这里的初步研究中，抑制驱动甘氨酸生物合成的关键途径， 在人类和小鼠的致动脉粥样硬化条件下是明显的。使用我们新开发的AA- 改良西方饮食（WD）增强apoE-/-小鼠的高胆固醇血症和动脉粥样硬化。与此相反， 甘氨酸治疗对这些表型具有保护作用，同时降低高血糖症和肝脂肪变性， 这是其他主要的CVD风险因素。这与较低的脂质过氧化和诱导 驱动谷胱甘肽生物合成和胆固醇转运到胆汁中的途径。此外，我们还发现了一个 甘氨酸化合物（DT-109）在小鼠中具有双重降低胆固醇和葡萄糖的特性。我们的研究结果 使我们假设基于甘氨酸的治疗通过诱导谷胱甘肽介导的 抗氧化防御和肝-肠胆固醇排泄。本研究的长期目标是 确定动脉粥样硬化形成中受损的甘氨酸代谢，建立基于甘氨酸的抗动脉粥样硬化治疗， 以减少其他CVD风险因素并揭示潜在机制。目标1将评估受损 合成和增加甘氨酸在动脉粥样硬化形成中的利用。我们将使用转录组学和代谢组学 在apoE-/-，我们新的AGXT 1-/-小鼠和人类脂肪肝样本中。基因驱动变异之间的联系 甘氨酸代谢和动脉粥样硬化疾病将通过人GWAS确定。目标2将决定 较低和较高的甘氨酸可用性对动脉粥样硬化发展的影响。我们将使用apoE-/-小鼠， WD与或不与甘氨酸或用DT-109处理。将使用与apoE-/-小鼠杂交的AGXT 1-/-小鼠， 确定内源性甘氨酸的作用。目标3将DT-109作为一种基于甘氨酸的治疗方法， 动脉粥样硬化，其药代动力学和潜在机制。将使用动脉粥样硬化apoE-/-小鼠 通过代谢组学和通量组学评估甘氨酸与谷胱甘肽的结合以及肝-肠胆固醇 排泄我们将研究DT-109与甘氨酸相比，在大鼠中消退已建立的动脉粥样硬化的能力。 apoE-/-小鼠。完成这些研究将为基于甘氨酸的动脉粥样硬化新疗法奠定基础， 虽然概述的职业发展计划，包括实践培训，课程和研讨会，将允许 我的长期目标是成为心脏代谢研究的独立研究者。