Project 3: Lipolysis regulation and diabetes-impaired regression

项目 3：脂肪分解调节和糖尿病受损回归

• 批准号: 10642753
• 负责人: Ira J Goldberg
• 金额: $ 49.64万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642753
• 关键词: ANGPTL4 gene; Adipose tissue; Affect; Angiopoietins; Animal Model; Animals; Antisense Oligonucleotides; Aorta; Apolipoproteins; Arterial Fatty Streak; Arteries; Atherosclerosis; Biology; Blood Vessels; Bone Marrow Transplantation; Cardiovascular Diseases; Cells; Characteristics; Cholesterol; Data; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Diet; Dyslipidemias; Eicosapentaenoic Acid; Endothelial Cells; Fasting; Fatty acid glycerol esters; Fibrates; Foam Cells; Gene Expression; Generations; Genes; Glucose; Heterozygote; High Density Lipoproteins; High Fat Diet; Human; Hyperglycemia; Hyperlipidemia; Hypertriglyceridemia; Impairment; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Investigation; Knock-out; Knockout Mice; Knowledge; Laboratories; Lesion; Leukocytes; Lipids; Lipolysis; Lipoproteins; Loss of Heterozygosity; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Macrophage; Meta-Analysis; Methods; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Omega-3 Fatty Acids; Pathogenesis; Patients; Plasma; Process; Proteins; Regulation; Role; Smooth Muscle Myocytes; Sodium; Sorting; Source; Streptozocin; Subgroup; Sucrose; Testing; Toxic effect; Triglyceride Metabolism; Triglycerides; Vascular Diseases; atherogenesis; cardiovascular disorder risk; feeding; genome wide association study; human data; hypercholesterolemia; inhibitor; insulin sensitivity; interest; islet; laser capture microdissection; lipoprotein lipase; lipoprotein lipase inhibitor; magnetic beads; monocyte; novel; particle; prevent; programs; repaired; single-cell RNA sequencing; symporter; transcriptomics; type I and type II diabetes

Diabetes is associated with greater cardiovascular disease (CVD), likely due at least in part to increased circulating levels of atherogenic lipoproteins. The most common dyslipidemia in patients with diabetes, especially Type 2 diabetes, is hypertriglyceridemia (hyperTG). Moreover, recent human data also implicate genes associated with hyperTG such as lipoprotein lipase (LPL), apolipoprotein C3 (APOC3), and angiopoietin-like protein (ANGPTL)3 with CVD. Despite more than 4 decades of investigation, a mechanistic understanding of the relationship of hyperTG and CVD has not been clearly defined. Project 3 of this Program Project proposes to develop and use new animal models to assess how hyperTG and diabetes interact to alter vascular pathobiology. Our studies will focus on changes in arterial LPL using models that increase and decrease lipolysis within and likely along the arterial wall. Monocyte/macrophages are the only white blood cells that highly express LPL and they are the primary source of vascular LPL. Using single cell RNA sequencing, we have found that arterial macrophages have a cluster of high LPL expressing cells and our studies will uncover how LPL itself and LPL in the presence of hyperTG and diabetes alter cells in this and the other clusters. This Project has two specific aims. Aim 1 will determine how hyperTG and local lipolysis affect vascular disease. To do this, we will transplant bone marrow from mice that have an inducible deletion of either LPL (to reduce lipolysis) or ANGPTL4 (to increased LPL activity) into animals that have either normal or increased circulating levels of triglyceride (TGs) due to induced global deletion of LPL. Both atherogenesis and regression will be studied using a novel method we developed to delete and then replenish LDL receptors. In addition, we will test whether changing the composition of circulating TGs by feeding mice an omega 3 fatty acid-rich diet, recently shown to reduce CVD risk, will modify the vascular effects of altering macrophage LPL expression or levels of remnant lipoprotein particles. Aim 2 will test how changes in hyperglycemia/insulin actions and altered lipolysis products affect atherosclerosis regression, endothelial cell lipid accumulation and gene expression. We will create models with insulin deficiency and defective insulin sensitivity due to high fat diets. We were the first to show that defective regression is a robust vascular disease manifestation of diabetes. These studies will involve extensive interactions with the other projects of this Program and use of Cores B and C.

糖尿病与更严重的心血管疾病 (CVD) 相关，可能至少部分是由于 致动脉粥样硬化脂蛋白的循环水平。糖尿病患者最常见的血脂异常， 尤其是2型糖尿病，就是高甘油三酯血症（hyperTG）。此外，最近的人类数据也暗示 与 hyperTG 相关的基因，例如脂蛋白脂肪酶 (LPL)、载脂蛋白 C3 (APOC3) 和 血管生成素样蛋白 (ANGPTL)3 与 CVD。尽管经过了 4 多年的研究，机械论 对hyperTG和CVD关系的理解尚未明确。本计划项目3 项目建议开发和使用新的动物模型来评估 hyperTG 和糖尿病如何相互作用以改变 血管病理学。我们的研究将重点关注动脉 LPL 的变化，使用模型增加和 减少动脉壁内和可能沿动脉壁的脂肪分解。单核细胞/巨噬细胞是唯一的白细胞 高表达LPL的细胞是血管LPL的主要来源。使用单细胞 RNA 测序，我们发现动脉巨噬细胞有一群高LPL表达细胞，我们的 研究将揭示 LPL 本身以及在 hyperTG 和糖尿病存在下 LPL 如何改变细胞 其他集群。该项目有两个具体目标。目标 1 将确定 hyperTG 和局部脂肪分解如何影响 血管疾病。为此，我们将从具有诱导性缺失的小鼠身上移植骨髓 将 LPL（减少脂肪分解）或 ANGPTL4（增加 LPL 活性）注入具有正常或 由于 LPL 的诱导整体缺失，甘油三酯 (TG) 的循环水平增加。动脉粥样硬化和 我们将使用我们开发的删除然后补充 LDL 受体的新方法来研究回归。在 此外，我们将测试是否通过给小鼠喂食 omega 3 脂肪来改变循环 TG 的组成 最近被证明可以降低 CVD 风险的富含酸性饮食将改变巨噬细胞 LPL 的血管效应 残余脂蛋白颗粒的表达或水平。目标 2 将测试高血糖/胰岛素的变化 作用和改变的脂解产物影响动脉粥样硬化的消退、内皮细胞脂质的积累和 基因表达。我们将创建因高脂肪而导致胰岛素缺乏和胰岛素敏感性缺陷的模型 饮食。我们是第一个证明缺陷性回归是血管疾病的一种强有力的表现 糖尿病。这些研究将涉及与本计划的其他项目的广泛互动以及使用 核心 B 和 C。