CEACAM1: A link between metabolic and cardiovascular diseases

CEACAM1：代谢与心血管疾病之间的联系

• 批准号: 8237746
• 负责人: Sonia M. Najjar
• 金额: $ 38.78万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237746
• 关键词: Ablation; Address; Adipose tissue; Animal Model; Apolipoprotein E; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Blood; Blood Vessels; Cardiovascular Diseases; Cattle; Cause of Death; Cell physiology; Cells; Central obesity; Cholesterol; Clinical Research; Data; Development; Diet; Disease; Dyslipidemias; Endothelial Cells; Exhibits; Experimental Models; Eye; Fatty Acids; Functional disorder; Genes; Hepatic; Hepatocyte; Hyperinsulinism; Hyperlipidemia; Incidence; Indium; Individual; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Knockout Mice; LDL Cholesterol Lipoproteins; Link; Lipids; Liver; Low Density Lipoprotein Receptor; Mediating; Membrane; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Plasma; Play; Predisposition; Production; Regulation; Reporting; Role; Serum; Signal Transduction; Site; Skeletal Muscle; Testing; Therapeutic; Toxic effect; Triglycerides; United States; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasodilation; Very low density lipoprotein; Work; atherogenesis; base; carcinoembryonic antigen-related cell adhesion molecules; cell type; feeding; gain of function; high risk; human NOS3 protein; in vivo; innovation; insulin sensitivity; insulin signaling; lipid biosynthesis; loss of function; mouse model; prevent; response

DESCRIPTION (provided by applicant): Individuals with metabolic diseases are at a higher risk of developing atherosclerosis, a leading cause of death in the United States and worldwide. Earlier studies have linked dyslipidemia to the initiation and progression of atherosclerosis. However, recent clinical studies raised concerns about the efficacy of lowering plasma cholesterol levels in the progression of atherosclerosis. Although insulin resistance is associated with increased incidence of cardiovascular disease, whether it leads to atherosclerosis independently of its accompanying dyslipidemia remains unclear, largely because of the lack of a suitable animal model to address this question. The CarcinoEmbryonic Antigen-related Cell Adhesion Molecule-1 (CEACAM1) regulates insulin sensitivity by promoting insulin clearance in liver. Accordingly, global null deletion of Ceacam1 gene impairs hepatic insulin clearance and causes hyperinsulinemia, which in turn, results in systemic insulin resistance. Preliminary data show: (i) that global Cc1-/- null mice develop early atherosclerotic lesions and vascular dysfunction even under normal feeding conditions, and (ii) that this occurs in the absence of hyperlipidemia, despite VLDL/LDL cholesterol levels that are usually associated with atherosclerosis regression, not development. This unique animal model of atherogenesis with isolated insulin resistance in the absence of hyperlipidemia demonstrates that systemic insulin resistance resulting from hyperinsulinemia leads to vascular dysfunction and atherosclerosis in the absence of hyperlipidemia. Because phosphorylation of CEACAM1 by both insulin and VEGF receptors regulates Akt1 activation of endothelial Nitric Oxide Synthase (eNOS), an essential step in mediating endothelial function, it is reasonable to propose that CEACAM1 is the shared downstream element in VEGF and insulin signaling in endothelial cells, whose inactivation impinges upon both pathways and causes endothelial dysfunction in insulin resistance. To test this hypothesis, the regulatory effect of CEACAM1 on insulin action along the liver/endothelial cell axis will be investigated. Aim 1 examines whether hyperinsulinemia caused by impaired hepatic insulin clearance, alters insulin action in the endothelial cell, and in this cell-nonautonomous fashion, initiates atheroma development. Aim 2 examines whether altered signaling through CEACAM1-dependent pathways disrupts the endothelial cell's response to insulin and VEGF, and in this cell-autonomous fashion, drives endothelial dysfunction and initiates atherosclerosis. To investigate the specific role of hepatic and endothelial cell CEACAM1 in the pathogenesis of atherosclerosis and vascular dysfunction, a newly generated set of unique animal models of loss-of-function and gain-of-function will be used. Answering these questions will delineate new CEACAM1-dependent mechanisms underlying atherosclerosis along the liver/endothelial cell axis, and pinpoint sites of pharmacologic intervention. PUBLIC HEALTH RELEVANCE: Individuals with metabolic syndrome are at a higher risk of developing atherosclerosis, a leading cause of death in the United States. A strategy based on lowering blood cholesterol has been shown to be of limited value in stopping progression of atherosclerosis in patients with metabolic syndrome. Building on the pioneering work on the role of CEACAM1 in the regulation of insulin metabolism in liver, new compelling evidence is now presented to link its regulatory role of systemic insulin resistance to the pathogenesis of atherosclerosis. This proposal seeks to explore this mechanistic link with an eye on developing a more effective therapeutic strategy against the disease.

描述（由申请人提供）：具有代谢疾病的人患动脉粥样硬化的风险更高，这是美国和全球的主要死亡原因。早期的研究将血脂异常与动脉粥样硬化的起始和进展联系起来。但是，最近的临床研究引起了人们对降低血浆胆固醇水平在动脉粥样硬化进展中的疗效的担忧。尽管胰岛素抵抗与心血管疾病的发病率增加有关，但它是否导致动脉粥样硬化独立于其伴随的血脂异常尚不清楚，这主要是因为缺乏适当的动物模型来解决这个问题。癌胚抗原相关的细胞粘附分子1（CEACAM1）通过促进肝脏中的胰岛素清除来调节胰岛素敏感性。因此，CEACAM1基因的全球无效缺失会损害肝胰岛素清除率并导致高胰岛素血症，从而导致全身性胰岛素抵抗。初步数据表明：（i）全球CC1 - / - 无效小鼠即使在正常喂养条件下也会发展早期的动脉粥样硬化病变和血管功能障碍，并且（ii）尽管没有VLDL/LDL胆固醇水平，但通常与动脉粥样硬化的回归相关，而不是发育。在没有高脂血症的情况下，这种具有分离的胰岛素耐药性动脉粥样硬化的动物模型表明，高胰岛素血症导致的全身性胰岛素抵抗会导致血管功能障碍和动脉粥样硬化在没有高脂血症的情况下。因为胰岛素和VEGF受体对CeCAM1的磷酸化调节AKT1激活内皮氮氧化物合酶（ENOS）（ENOS）是介导内皮功能的重要步骤，是合理地提出，CEACAM1是CEACAM1在蔬菜和胰岛素中的下游元素，其在内利层中的下降元素，其源自胰岛素的下降元素，其源自胰岛素的含量和胰岛素的渗透率是源源不断的，该元素是源自胰岛素的启用元素。胰岛素抵抗的内皮功能障碍。为了检验该假设，将研究CEACAM1对沿肝脏/内皮细胞轴胰岛素作用的调节作用。 AIM 1检查了肝胰岛素清除受损，改变内皮细胞中的胰岛素作用以及这种细胞非纳科疗法引起的高胰岛素血症是否引起了动脉瘤发展。 AIM 2检查了通过CEACAM1依赖性途径改变信号是否会破坏内皮细胞对胰岛素和VEGF的反应，并且以这种细胞自主的方式驱动内皮功能障碍并引发动脉粥样硬化。为了研究肝细胞和内皮细胞CEACAM1在动脉粥样硬化和血管功能障碍的发病机理中的特定作用，将使用新生成的一组新的功能丧失和功能障碍的独特动物模型。回答这些问题将描述沿着肝脏/内皮细胞轴的动脉粥样硬化的新的CEACAM1依赖机制，并确定药理学干预的位点。 公共卫生相关性：代谢综合征的患者患动脉粥样硬化的风险更高，这是美国的主要死亡原因。已经证明，基于降低血液胆固醇的策略在停止代谢综合征患者的动脉粥样硬化进展方面具有有限的价值。基于CEACAM1在调节胰岛素代谢在肝脏中的作用的开创性工作，现在提出了新的引人注目的证据，以将其全身性胰岛素抵抗的调节作用与动脉粥样硬化的发病机理联系起来。该提案旨在探索这种机械联系，以关注针对该疾病的更有效的治疗策略。