Project 3: Lipolysis regulation and diabetes-impaired regression

糖尿病与更严重的心血管疾病(CVD)有关，这可能至少部分是由于 循环中致动脉粥样硬化的脂蛋白水平。糖尿病患者最常见的血脂异常， 尤其是2型糖尿病，是高甘油三酯血症。此外，最近的人类数据也表明 与高甘油三酯相关的基因，如脂蛋白脂酶(LPL)、载脂蛋白C3(APOC3)和 血管生成素样蛋白(ANGPTL)3与心血管疾病尽管进行了40多年的调查，一个机械主义者 高甘油三酯与心血管疾病的关系目前还没有明确的认识。本计划的项目3 该项目建议开发和使用新的动物模型来评估高甘油三酯和糖尿病是如何相互作用改变的 血管病理生物学。我们的研究将集中在动脉LPL的变化上，使用增加和 减少动脉壁内和可能沿动脉壁的脂解。单核/巨噬细胞是唯一的白血球 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簇高表达LPL的细胞，我们的 研究将揭示LPL本身以及LPL在高甘油三酯和糖尿病存在时是如何改变这两种细胞的 其他星系团。该项目有两个具体目标。目标1将确定高甘油三酯和局部脂肪分解如何影响 血管疾病。为了做到这一点，我们将移植小鼠的骨髓，这些小鼠的骨髓中有可诱导的缺失 LPL(减少脂解)或ANGPTL4(增加LPL活性) 由于诱导LPL的整体缺失，循环中的甘油三酯(TGS)水平增加。动脉粥样硬化和动脉粥样硬化 回归将使用我们开发的一种新方法来研究，该方法删除并补充低密度脂蛋白受体。在……里面 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TGS的组成 最近被证明可以降低心血管疾病风险的富酸饮食将改变巨噬细胞脂蛋白脂蛋白的血管效应 残留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 作用和脂解产物改变影响动脉粥样硬化消退、内皮细胞脂质积聚和 基因表达。我们将建立胰岛素缺乏和高脂肪引起的胰岛素敏感性缺陷的模型 节食。我们首次证明缺陷回归是一种强健的血管疾病表现。 糖尿病。这些研究将涉及与本计划其他项目的广泛互动，并使用 核心B和C。

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.