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）：代谢综合征是代谢异常的集合，包括肥胖、胰岛素抵抗和动脉粥样硬化，其中慢性炎症是潜在的致病机制。肥胖症的炎症反应可以通过改变营养代谢（例如过量的脂质和修饰的脂蛋白颗粒）来激活。这里提出的研究旨在确定营养代谢与炎症、动脉粥样硬化和胰岛素抵抗之间联系的细胞机制。 AMP 激活蛋白激酶 (AMPK) 是一种进化保守的细胞能量传感器，可调节脂质、胆固醇和葡萄糖代谢的代谢途径。巨噬细胞和脂肪组织中的 AMPK 信号传导和表达在炎症刺激和营养丰富的条件下下调，例如暴露于脂多糖 (LPS)、游离脂肪酸 (FFA)、氧化低密度脂蛋白 (oxLDL) 颗粒和在饮食引起的肥胖中。此外，巨噬细胞 AMPK 信号传导的激活可显着抑制 LPS、FFAs 和 oxLDL 诱导的炎症，以及巨噬细胞趋化和粘附，这是动脉粥样硬化发展中的重要过程。这种作用主要是通过巨噬细胞中的 11AMPK 亚型发挥的。因此，总体假设是巨噬细胞 AMPK 是连接细胞营养代谢与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预防动脉粥样硬化和胰岛素抵抗。巨噬细胞特异性过度表达显性失活（功能丧失）或组成型活性（功能获得）11AMPK（分别为 DN-11 和 CA-11）的小鼠是新生成的，将用于确定特别是巨噬细胞 AMPK 在对抗肥胖引起的炎症、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，确定巨噬细胞 AMPK 对动脉粥样硬化的保护作用。将在这些致动脉粥样硬化饮食的小鼠中确定动脉粥样硬化的发展以及早期和更晚期疾病阶段巨噬细胞向动脉粥样硬化病变的浸润。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 对肥胖引起的炎症和胰岛素抵抗的保护作用。将在这些小鼠的食物或高脂肪饮食中测定胰岛素敏感性和脂肪组织炎症。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 充当细胞营养代谢和炎症之间的信号传导纽带；激活巨噬细胞AMPK可显着抑制肥胖中的巨噬细胞炎症，对动脉粥样硬化和胰岛素抵抗均具有保护作用； AMPK 减少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引起的炎症来实现的。