Macrophage AMPK, Inflammation, and Atherosclerosis

巨噬细胞 AMPK、炎症和动脉粥样硬化

• 批准号: 8470984
• 负责人: Bingzhong Xue
• 金额: $ 21.23万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470984
• 关键词: 5' -AMP-activated protein kinase; Address; Adhesions; Adipocytes; Adipose tissue; Affect; Animal Model; Area; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Cells; Chemotaxis; Cholesterol Homeostasis; Chronic; Coculture Techniques; Collection; Data; Development; Diet; Disease; Dominant-Negative Mutation; Event; Exposure to; Fatty acid glycerol esters; Goals; Homeostasis; Hormonal; Hypothalamic structure; ITGAM gene; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Lesion; Link; Lipids; Lipopolysaccharides; Lipoproteins; Low Density Lipoprotein Receptor; Macrophage Activation; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Nutritional; Obesity; Pathway interactions; Prevention; Process; Protein Isoforms; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Stimulus; System; Testing; Therapeutic Effect; Transgenic Mice; advanced disease; cell type; feeding; gain of function; glucose metabolism; glucose uptake; improved; insulin sensitivity; lipid metabolism; loss of function; macrophage; monocyte; mouse model; novel; nutrient metabolism; oxidized low density lipoprotein; particle; prevent; programs; promoter; protective effect; research study; sensor; therapeutic target

DESCRIPTION (provided by applicant): The metabolic syndrome is a collection of metabolic abnormalities, including obesity, insulin resistance and atherosclerosis, with chronic inflammation as a causative underlying mechanism. Inflammatory responses in obesity can be activated by altered nutrient metabolism (e.g. excess lipids and modified lipoprotein particles). The studies proposed here aim to determine cellular mechanisms linking nutrient metabolism to inflammation, atherosclerosis and insulin resistance. AMP-activated protein kinase (AMPK) is an evolutionally conserved cellular energy sensor that regulates metabolic pathways in lipid, cholesterol and glucose metabolism. AMPK signaling and expression are down-regulated in macrophages and adipose tissue by inflammatory stimuli and in nutrient-rich conditions, such as exposure to lipopolysaccharide (LPS), free fatty acids (FFAs), oxidized low- density lipoprotein (oxLDL) particles, and in diet-induced obesity. In addition, activation of macrophage AMPK signaling significantly suppresses LPS-, FFAs- and oxLDL-induced inflammation, as well as macrophage chemotaxis and adhesion, important processes in the development of atherosclerosis. This effect is exerted primarily through the 11AMPK isoform in macrophages. Therefore, the overall hypothesis is that macrophage AMPK is a key signaling molecule linking cellular nutrient metabolism to inflammatory responses, and activating macrophage AMPK protects against both atherosclerosis and insulin resistance through suppression of macrophage inflammation. Mice with macrophage-specific over-expression of dominant negative (loss-of- function) or constitutively active (gain-of-function) 11AMPK (DN-11 and CA-11, respectively) have been newly generated and will be used to determine specifically the role of macrophage AMPK in antagonizing obesity- induced inflammation, atherosclerosis and insulin resistance. Specific aim 1 will determine the protective effects of macrophage AMPK against atherosclerosis using macrophage-specific CA-11 or DN-11 mice crossed with LDL receptor (LDLR) knockout mice. The development of atherosclerosis and the infiltration of macrophages into atherosclerotic lesions at both early and more advanced disease stages will be determined in these mice on an atherogenic diet. Specific aim 2 will determine the protective effects of macrophage AMPK against obesity-induced inflammation and insulin resistance using macrophage-specific CA-11 or DN-11 mice. The insulin sensitivity and adipose tissue inflammation will be determined in these mice on either chow or high fat diet. Completing these studies will provide novel perspectives in the studying of obesity and associated metabolic syndrome. That is, AMPK serves as a signaling link between cellular nutrient metabolism and inflammation; activating macrophage AMPK significantly suppresses macrophage inflammation in obesity, which have protective effects on both atherosclerosis and insulin resistance; and the therapeutic effects of AMPK to reduce atherosclerosis and insulin resistance may be through reduction of obesity-induced inflammation.

描述(申请人提供)：代谢综合征是代谢异常的集合，包括肥胖、胰岛素抵抗和动脉粥样硬化，慢性炎症是潜在的致病机制。肥胖症中的炎症反应可以通过改变营养代谢(如过量的脂类和修饰的脂蛋白颗粒)来激活。这里提出的研究旨在确定将营养代谢与炎症、动脉粥样硬化和胰岛素抵抗联系起来的细胞机制。AMP激活的蛋白激酶(AMPK)是一种进化保守的细胞能量感受器，调节脂肪、胆固醇和葡萄糖代谢的代谢途径。在巨噬细胞和脂肪组织中，AMPK信号和表达受到炎性刺激和营养丰富的条件下的下调，例如暴露在脂多糖(LPS)、游离脂肪酸(FFAs)、氧化型低密度脂蛋白(OxLDL)颗粒中，以及饮食诱导的肥胖。此外，巨噬细胞AMPK信号的激活显著抑制了内毒素、游离脂肪酸和氧化低密度脂蛋白诱导的炎症，以及巨噬细胞的趋化和黏附，这是动脉粥样硬化发展过程中的重要过程。这种作用主要通过巨噬细胞中的11AMPK亚型发挥作用。因此，总体假设是巨噬细胞AMPK是连接细胞营养代谢和炎症反应的关键信号分子，激活巨噬细胞AMPK通过抑制巨噬细胞炎症来保护动脉粥样硬化和胰岛素抵抗。巨噬细胞特异性过表达显性阴性(功能丧失)或结构性活性(功能增强)11AMPK(分别为DN-11和CA-11)的小鼠已经被新产生，并将被用于特异性地确定巨噬细胞AMPK在对抗肥胖诱导的炎症、动脉粥样硬化和胰岛素抵抗中的作用。具体目标1将通过巨噬细胞特异性CA-11或DN-11小鼠与低密度脂蛋白受体(LDLR)基因敲除小鼠杂交，确定巨噬细胞AMPK对动脉粥样硬化的保护作用。在这些接受致动脉粥样硬化饮食的小鼠中，将确定动脉粥样硬化的发展和巨噬细胞在早期和晚期疾病阶段对动脉粥样硬化病变的渗透。特定目的2将通过巨噬细胞特异性CA-11或DN-11小鼠来确定巨噬细胞AMPK对肥胖诱导的炎症和胰岛素抵抗的保护作用。这些小鼠的胰岛素敏感性和脂肪组织炎症将在饮食或高脂肪饮食中进行测定。完成这些研究将为肥胖和相关代谢综合征的研究提供新的视角。也就是说，AMPK是细胞营养代谢和炎症之间的信号纽带；激活巨噬细胞AMPK显著抑制肥胖大鼠的巨噬细胞炎症，对动脉粥样硬化和胰岛素抵抗具有保护作用；AMPK减轻动脉粥样硬化和胰岛素抵抗的治疗作用可能是通过减轻肥胖引起的炎症反应而实现的。