ABCG1 Function in Diabetes

ABCG1 在糖尿病中的功能

基本信息

批准号：
7473369
负责人：
Catherine C Hedrick
金额：
$ 49.67万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7473369
关键词：
ATP-Binding Cassette Transporters Adhesions Arachidonate 15-Lipoxygenase Arterial Fatty Streak Atherosclerosis Blood Glucose Boxing Breeding Cardiovascular Diseases Cell Adhesion Molecules Cells Cholesterol Cholesterol Esters Cholesterol Homeostasis Chronic Condition Data Development Diabetes Mellitus Diabetic mouse Diet Eicosanoids Elevation Endothelial Cells Endothelium Epidemiology Event Excision Face Fatty Acids Flow Cytometry Follow-Up Studies Gene Activation Genetic Transcription Glucose High Density Lipoproteins Homeostasis Hyperglycemia Hyperlipidemia In Vitro Inflammatory Insulin-Dependent Diabetes Mellitus Intercellular adhesion molecule 1 Intervention Knockout Mice Leukocytes Link Lipids Lipoproteins Low Density Lipoprotein Receptor Low-Density Lipoproteins Lymphocyte Measurement Measures Mediating Mus Non-Insulin-Dependent Diabetes Mellitus Patients Phenotype Phosphorylation Plant Roots Plasma Polymerase Chain Reaction Prevention Production Proteins Public Health Regulation Reporting Response Elements Role Study Subject Surface System Techniques Testing Time Transcription Repressor/Corepressor Transgenic Mice blood glucose regulation cardiovascular risk factor chemokine cholesterol transporters cytokine diabetes mellitus therapy diabetic feeding gene therapy helix-loop-helix protein E47 in vivo innovation macrophage monocyte mortality mouse Numb protein mouse model novel oxidized low density lipoprotein prevent promoter protein expression reverse cholesterol transport uptake

项目摘要

DESCRIPTION (provided by applicant): EC are constantly exposed to high levels of lipoprotein lipids, yet do not become lipid-laden. We have recently discovered that EC have a dramatic ability to efflux cholesterol, most likely to preserve endothelial integrity. Aortic EC express ABCG1 and ABCA1, two key cholesterol transporters. ABCG1 is a primary regulator of cholesterol efflux to HDL in reverse cholesterol transport. We have found a 70% reduction in ABCG1 expression in diabetic mouse aortic EC, causing a significant reduction in cholesterol efflux, and leading to increased EC cholesteryl ester content. In the current application, we hypothesize that chronic hyperglycemia in diabetes decreases EC ABCG1 function, thereby disturbing cholesterol homeostasis in the EC, and triggering endothelial activation. Endothelial activation and monocyte:endothelial interactions in the vessel wall are key initiating events in atherosclerotic plaque formation. We hypothesize that initiation of atherosclerosis is increased in the setting of Type 2 diabetes due to endothelial activation caused by a reduction in endothelial ABCG1 activity. Specific Aim 1 will test the hypothesis that ABCG1 expression regulates activation of EC by maintaining endothelial cholesterol homeostasis. We will utilize approaches in vitro to directly test the role of ABCG1 on endothelial activation. Intracellular cholesteryl ester accumulation, cholesterol efflux, chemokine production, and monocyte:endothelial interactions will be measured. Specific Aim 2 will test the hypothesis that endothelial ABCG1 expression regulates atherosclerotic plaque initiation in diabetic mouse models in vivo. Low density lipoprotein receptor (LDLR)-deficient mice are atherosclerosis-susceptible mice that develop diabetes when fed a diabetogenic diet. We will perform atherosclerosis studies using a conditional knockout mouse in which ABCG1 is deleted from endothelial cells to test that endothelial ABCG1 expression is a critical determinant of atherosclerosis initiation. Specific Aim 3 will test the hypothesis that glucose regulates ABCG1 promoter activity through action of the transcriptional repressor Id3. Our preliminary data indicate that the transcription factor E47 activates the ABCG1 promoter, and the repressor Id3, inhibits this activation. We will also examine regulation of ABCG1 protein by fatty acids. If we find that ABCG1 is an important regulator of atherosclerosis in diabetes, therapies to upregulate ABCG1 expression in diabetic patients could prove beneficial for prevention of atherosclerosis. PUBLIC HEALTH RELEVANCE: Endothelial cells have a surprising capacity to effectively efflux cholesterol to maintain normal endothelial homeostasis. Cholesterol efflux is regulated by ABC transporters, including ABCA1 and ABCG1. We hypothesize that ABCG1 function is necessary for normal endothelial function; in the absence of ABCG1, endothelial cells become activated and pro-inflammatory, contributing to a pro-atherogenic phenotype. We will explore this hypothesis using endothelial-specific ABCG1-deficient mice in atherosclerosis studies in vivo.

描述（由申请人提供）：EC 不断暴露于高水平的脂蛋白脂质，但不会变得充满脂质。我们最近发现 EC 具有显着的流出胆固醇的能力，最有可能保持内皮完整性。主动脉 EC 表达 ABCG1 和 ABCA1，这是两种关键的胆固醇转运蛋白。 ABCG1 是胆固醇逆向转运中胆固醇流出至 HDL 的主要调节因子。我们发现糖尿病小鼠主动脉 EC 中 ABCG1 的表达减少了 70%，导致胆固醇流出显着减少，并导致 EC 胆固醇酯含量增加。在当前的应用中，我们假设糖尿病中的慢性高血糖会降低 EC ABCG1 功能，从而扰乱 EC 中的胆固醇稳态，并触发内皮激活。血管壁中的内皮活化和单核细胞：内皮相互作用是动脉粥样硬化斑块形成的关键起始事件。我们假设，由于内皮 ABCG1 活性降低导致内皮激活，2 型糖尿病患者动脉粥样硬化的发生会增加。具体目标 1 将检验 ABCG1 表达通过维持内皮胆固醇稳态来调节 EC 激活的假设。我们将利用体外方法直接测试 ABCG1 对内皮激活的作用。将测量细胞内胆固醇酯积累、胆固醇流出、趋化因子产生和单核细胞：内皮相互作用。具体目标 2 将验证糖尿病小鼠模型体内内皮 ABCG1 表达调节动脉粥样硬化斑块起始的假设。低密度脂蛋白受体（LDLR）缺陷小鼠是动脉粥样硬化易感小鼠，在喂食致糖尿病饮食时会患上糖尿病。我们将使用条件敲除小鼠（其中内皮细胞中删除了 ABCG1）进行动脉粥样硬化研究，以测试内皮 ABCG1 表达是动脉粥样硬化起始的关键决定因素。具体目标 3 将检验葡萄糖通过转录阻遏物 Id3 的作用调节 ABCG1 启动子活性的假设。我们的初步数据表明转录因子 E47 激活 ABCG1 启动子，而阻遏物 Id3 抑制这种激活。我们还将研究脂肪酸对 ABCG1 蛋白的调节。如果我们发现 ABCG1 是糖尿病动脉粥样硬化的重要调节因子，那么上调糖尿病患者中 ABCG1 表达的治疗可能有利于预防动脉粥样硬化。公共卫生相关性：内皮细胞具有惊人的能力，可以有效地排出胆固醇以维持正常的内皮稳态。胆固醇流出受 ABC 转运蛋白调节，包括 ABCA1 和 ABCG1。我们假设 ABCG1 功能对于正常的内皮功能是必需的；在缺乏 ABCG1 的情况下，内皮细胞会被激活并促炎，从而导致促动脉粥样硬化表型。我们将使用内皮特异性 ABCG1 缺陷小鼠在体内动脉粥样硬化研究中探索这一假设。