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（由申请人提供）：代谢综合征是一组代谢异常，包括肥胖、胰岛素抵抗和动脉粥样硬化，慢性炎症是其潜在的致病机制。肥胖症中的炎症反应可通过改变的营养代谢（例如过量的脂质和修饰的脂蛋白颗粒）激活。本文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活化蛋白激酶（AMPK）是一种进化上保守的细胞能量传感器，调节脂质、胆固醇和葡萄糖代谢途径。AMPK信号传导和表达在巨噬细胞和脂肪组织中通过炎性刺激和在营养丰富的条件下（例如暴露于脂多糖（LPS）、游离脂肪酸（FFA）、氧化低密度脂蛋白（oxLDL）颗粒）和在饮食诱导的肥胖中下调。此外，巨噬细胞AMPK信号传导的激活显著抑制LPS、FFA和oxLDL诱导的炎症，以及巨噬细胞趋化性和粘附，这是动脉粥样硬化发展中的重要过程。这种作用主要通过巨噬细胞中的11 AMPK同种型发挥。因此，总体假设是巨噬细胞AMPK是将细胞营养代谢与炎症反应联系起来的关键信号分子，并且激活巨噬细胞AMPK通过抑制巨噬细胞炎症来保护免受动脉粥样硬化和胰岛素抵抗。新近产生了巨噬细胞特异性过表达显性负性（功能丧失）或组成性活性（功能获得）11 AMPK（分别为DN-11和CA-11）的小鼠，并将用于特异性确定巨噬细胞AMPK在拮抗肥胖诱导的炎症、动脉粥样硬化和胰岛素抵抗中的作用。具体目标1将使用巨噬细胞特异性CA-11或DN-11小鼠与LDL受体（LDLR）敲除小鼠杂交来确定巨噬细胞AMPK对动脉粥样硬化的保护作用。将在这些小鼠中测定动脉粥样硬化的发展以及巨噬细胞在早期和更晚期疾病阶段向动脉粥样硬化病变中的浸润。具体目标2将使用巨噬细胞特异性CA-11或DN-11小鼠确定巨噬细胞AMPK对肥胖诱导的炎症和胰岛素抵抗的保护作用。将在这些小鼠中测定食物或高脂肪饮食的胰岛素敏感性和脂肪组织炎症。这些研究的完成将为肥胖及其相关代谢综合征的研究提供新的视角。也就是说，AMPK作为细胞营养代谢和炎症之间的信号联系;激活巨噬细胞AMPK显著抑制肥胖中的巨噬细胞炎症，其对动脉粥样硬化和胰岛素抵抗都具有保护作用; AMPK降低动脉粥样硬化和胰岛素抵抗的治疗作用可能是通过减少肥胖诱导的炎症。