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）：患有代谢性疾病的个体患动脉粥样硬化的风险较高，动脉粥样硬化是美国和全世界死亡的主要原因。早期研究已将血脂异常与动脉粥样硬化的发生和进展联系起来。然而，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功效的担忧。尽管胰岛素抵抗与心血管疾病发病率增加有关，但它是否会独立于伴随的血脂异常而导致动脉粥样硬化，这主要是因为缺乏合适的动物模型来解决这个问题。癌胚抗原相关细胞粘附分子-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 基因的整体缺失会损害肝脏胰岛素清除率并导致高胰岛素血症，进而导致全身胰岛素抵抗。初步数据显示：(i) 即使在正常喂养条件下，全局 Cc1-/- 缺失小鼠也会出现早期动脉粥样硬化病变和血管功能障碍，以及 (ii) 这种情况发生在没有高脂血症的情况下，尽管 VLDL/LDL 胆固醇水平通常为与动脉粥样硬化的消退有关，而不是发展。这种在不存在高脂血症的情况下具有孤立的胰岛素抵抗的动脉粥样硬化形成的独特动物模型表明，在不存在高脂血症的情况下，由高胰岛素血症引起的全身胰岛素抵抗会导致血管功能障碍和动脉粥样硬化。由于胰岛素和 VEGF 受体对 CEACAM1 的磷酸化可调节内皮一氧化氮合酶 (eNOS) 的 Akt1 激活，这是介导内皮功能的重要步骤，因此有理由认为 CEACAM1 是内皮细胞中 VEGF 和胰岛素信号转导中共享的下游元件，其失活会影响这两种途径并导致胰岛素抵抗中的内皮功能障碍。为了检验这一假设，我们将研究 CEACAM1 对沿着肝脏/内皮细胞轴的胰岛素作用的调节作用。目标 1 检查肝脏胰岛素清除受损引起的高胰岛素血症是否会改变内皮细胞中的胰岛素作用，并以这种细胞非自主方式引发动脉粥样硬化形成。目标 2 检查通过 CEACAM1 依赖性途径改变的信号传导是否会破坏内皮细胞对胰岛素和 VEGF 的反应，并以这种细胞自主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发病机制中的具体作用，将使用一套新生成的独特的功能丧失和功能获得动物模型。回答这些问题将描述沿肝/内皮细胞轴发生动脉粥样硬化的新的 CEACAM1 依赖性机制，并查明药物干预的位点。 公共卫生相关性：患有代谢综合征的个体患动脉粥样硬化的风险较高，动脉粥样硬化是美国的一个主要原因。事实证明，基于降低血液胆固醇的策略对于阻止代谢综合征患者动脉粥样硬化的进展价值有限。基于 CEACAM1 在肝脏胰岛素代谢调节中的作用的开创性工作，现在提出了新的令人信服的证据，将其全身胰岛素抵抗的调节作用与动脉粥样硬化的发病机制联系起来。该提案旨在探索这种机制联系，着眼于开发针对该疾病的更有效的治疗策略。