Macrophage AMPK, Inflammation, and Atherosclerosis

巨噬细胞 AMPK、炎症和动脉粥样硬化

基本信息

批准号：
8586350
负责人：
Bingzhong Xue
金额：
$ 36.26万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8586350
关键词：
5&apos -AMP-activated protein kinase Acute Address Adipocytes Adipose tissue Antigen Presentation Apolipoprotein E Apoptosis Arterial Fatty Streak Atherogenic Diet Atherosclerosis Body Weight Cardiac Death Cells Cholesterol Cholesterol Homeostasis Chronic Coculture Techniques Development Diet Disease Dominant-Negative Mutation Endoplasmic Reticulum Euglycemic Clamping Event Exhibits Fatty acid glycerol esters Gene Expression Genes Glucose Glucose Clamp Goals Immune In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Kinetics Knock-out Knockout Mice Knowledge Lead Lesion Link Lipids Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Metabolic Metabolic Diseases Metabolic Pathway Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathology Pathway interactions Phagocytosis Phenotype Plasma Prevention Reporting Role Saturated Fatty Acids Signal Pathway Signal Transduction Signaling Molecule Staging System Testing Therapeutic Tissues Toxic effect Transgenic Mice Up-Regulation cytokine endoplasmic reticulum stress fatty acid oxidation feeding glucose metabolism glucose tolerance glucose uptake improved in vivo insulin sensitivity insulin signaling insulin tolerance lipid metabolism macrophage migration mouse model novel nutrient metabolism oxidation oxidized low density lipoprotein particle prevent protective effect reverse cholesterol transport sensor

项目摘要

DESCRIPTION (provided by applicant): AMP-activated protein kinase (AMPK) is an evolutionally conserved cellular energy sensor that regulates metabolic pathways in lipid, cholesterol and glucose metabolism. We have reported that macrophage AMPK protects against lipid-induced inflammation and insulin resistance in vitro. In addition, activating AMPK by 5- aminoimidazole-4-carboxamide-1-2-4-ribofuranoside (AICAR) in ApoE-/- mice alleviates atherosclerosis burden. However, the pleiotropic functions of AMPK make it difficult to determine specifically the role of macrophage AMPK in the pathogenesis of inflammation-associated metabolic disorders, including atherosclerosis and insulin resistance. In this proposal, transgenic mice with macrophage-specific over- expression of dominant negative or constitutively active 11AMPK (DN11 and CA11, respectively), and macrophage-specific 11MAPK knockout (MAKO) mice will be used to study the role of macrophage AMPK in these metabolic disorders. We find that macrophages from CA11 mice have significantly lower lipid- and cholesterol-induced ER stress, inflammation and apoptosis, which is associated with up-regulation of genes involved in fatty acid oxidation and cholesterol efflux. We hypothesize that macrophage AMPK regulates macrophage lipid and cholesterol homeostasis by promoting fatty oxidation and cholesterol efflux, thereby preventing lipid- and cholesterol-induced ER stress, inflammation and apoptosis. This may contribute to macrophage AMPK's protective effects against atherosclerosis and insulin resistance. Specific aim 1 will determine mechanisms by which macrophage AMPK prevents lipid- and cholesterol-induced ER stress, inflammation and apoptosis using macrophages from CA11, DN11 and MAKO mice. We will determine: 1) whether AMPK regulates macrophage lipid and cholesterol homeostasis by promoting cholesterol efflux and fatty acid oxidation, and 2) whether these pathways are necessary in mediating AMPK's suppression of lipid- and cholesterol-induced ER stress, inflammation and apoptosis. Specific aim 2 will determine the protective effects of macrophage AMPK against atherosclerosis using CA11, DN11 and MAKO mice crossed with low density lipoprotein receptor knockout mice. We will determine: 1) plasma lipoprotein phenotype, 2) in vivo reverse cholesterol transport from macrophages, 3) atherosclerosis extent, 4) macrophage number, lipid content, ER stress, inflammation and apoptosis in atherosclerotic lesions, and 5) kinetics of macrophage accumulation, ER stress, inflammation and apoptosis development in early and late atherosclerotic lesions in these mice fed an atherogenic diet. Specific aim 3 will determine the protective effects of macrophage AMPK against insulin resistance using CA11, DN11 and MAKO mice. The insulin sensitivity and adipose tissue macrophage infiltration, ER stress and inflammation will be determined in these mice on a high fat diet. Completing these studies will greatly improve our knowledge on the role of macrophage AMPK in the protection against inflammation-associated metabolic disorders, including atherosclerosis and insulin resistance.

描述（由申请人提供）：AMP激活的蛋白激酶（AMPK）是一种进化保守的细胞能传感器，可调节脂质，胆固醇和葡萄糖代谢中的代谢途径。我们报告说，巨噬细胞AMPK可以防止体外脂质诱导的炎症和胰岛素抵抗。此外，通过5-氨基咪唑-4-羧酰胺-1-2-4-核呋喃糖苷（AICAR）激活AMPK（APOE-/ - 小鼠）减轻了动脉粥样硬化负担。然而，AMPK的多效功能使得很难具体确定巨噬细胞AMPK在炎症相关代谢性疾病的发病机理中的作用，包括动脉粥样硬化和胰岛素抵抗。在该提案中，具有巨噬细胞特异性的过度表达的转基因小鼠的主动或组成型活性11AMPK（分别为DN11和CA11）和巨噬细胞特异性的11mapk敲除（Mako）小鼠将使用这些小鼠研究这些巨噬细胞AMPK在这些中的作用代谢障碍。我们发现，来自CA11小鼠的巨噬细胞的脂质和胆固醇诱导的ER应激，炎症和凋亡显着降低，这与参与脂肪酸氧化和胆固醇外排的基因上调有关。我们假设巨噬细胞AMPK通过促进脂肪氧化和胆固醇排出来调节巨噬细胞脂质和胆固醇稳态，从而防止脂质和胆固醇诱导的ER应激，炎症和凋亡。这可能有助于巨噬细胞AMPK对动脉粥样硬化和胰岛素抵抗的保护作用。具体目标1将确定巨噬细胞AMPK通过CA11，DN11和Mako小鼠的巨噬细胞AMPK防止脂质和胆固醇诱导的ER应力，炎症和凋亡的机制。我们将确定：1）AMPK是否通过促进胆固醇外排和脂肪酸氧化来调节巨噬细胞脂质和胆固醇稳态，以及2）2）2）在介导AMPK抑制脂肪剂和胆固醇诱导的ER应激，炎症和凋亡时，这些途径是否是必需的。特定的目标2将使用CA11，DN11和Mako小鼠与低密度脂蛋白受体敲除小鼠交叉的巨噬细胞AMPK对动脉粥样硬化的保护作用。我们将确定：1）血浆脂蛋白表型，2）在体内反向胆固醇从巨噬细胞转运，3）动脉粥样硬化程度，4）巨噬细胞数量，巨噬细胞数量，脂质含量，ER应激，炎症，炎症，动脉粥样硬化病变以及5）巨噬细胞堆积的动力学动力学。这些小鼠的早期和晚期动脉粥样硬化病变中的ER胁迫，炎症和凋亡发展。特定的目标3将使用CA11，DN11和Mako小鼠确定巨噬细胞AMPK对胰岛素抵抗的保护作用。胰岛素敏感性和脂肪组织巨噬细胞浸润，ER应激和炎症将在这些小鼠的高脂肪饮食中确定。完成这些研究将大大提高我们对巨噬细胞AMPK在防止与炎症相关的代谢性疾病（包括动脉粥样硬化和胰岛素抵抗）的作用的知识。