CEACAM1: A link between metabolic and cardiovascular diseases

描述（由申请人提供）：患有代谢性疾病的个体发展为动脉粥样硬化的风险较高，动脉粥样硬化是美国和世界范围内死亡的主要原因。早期的研究已经将血脂异常与动脉粥样硬化的发生和发展联系起来。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关注。虽然胰岛素抵抗与心血管疾病的发病率增加有关，但它是否独立于伴随的血脂异常导致动脉粥样硬化仍不清楚，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）通过促进肝脏胰岛素清除调节胰岛素敏感性。因此，Ceacam1基因的全局零缺失会损害肝脏胰岛素清除，导致高胰岛素血症，进而导致全身性胰岛素抵抗。初步数据显示：(i)即使在正常喂养条件下，全球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；（ii）尽管VLDL/LDL胆固醇水平通常与动脉粥样硬化消退而非发展相关，但这种情况发生在没有高脂血症的情况下。这种独特的无高脂血症情况下伴有孤立胰岛素抵抗的动脉粥样硬化动物模型表明，在无高脂血症情况下，由高胰岛素血症引起的全身胰岛素抵抗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的磷酸化调节了内皮一氧化氮合酶（eNOS）的Akt1激活，这是介导内皮功能的重要步骤，因此我们有理由认为CEACAM1是内皮细胞中VEGF和胰岛素信号传导的共同下游元件，其失活影响了这两个途径，并导致胰岛素抵抗中的内皮功能障碍。为了验证这一假设，我们将研究CEACAM1在肝/内皮细胞轴上对胰岛素作用的调节作用。目的1研究由肝脏胰岛素清除受损引起的高胰岛素血症是否改变了内皮细胞中的胰岛素作用，并以这种细胞非自主的方式引发了动脉粥样硬化的发展。目的2研究通过ceacam1依赖通路改变的信号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，我们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。回答这些问题将揭示新的ceacam1依赖的肝/内皮细胞轴动脉粥样硬化机制，并确定药物干预的位置。

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.