巨噬细胞 AMPK、炎症和动脉粥样硬化-猫眼课题宝

巨噬细胞 AMPK、炎症和动脉粥样硬化

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

项目状态：

已结题

起止时间：

2011-12-01 至 2016-11-30

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

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中文摘要

翻译

描述（由申请人提供）：amp活化蛋白激酶（AMPK）是一种进化保守的细胞能量传感器，调节脂质，胆固醇和葡萄糖代谢的代谢途径。我们已经报道了巨噬细胞AMPK在体外对脂质诱导的炎症和胰岛素抵抗有保护作用。此外，用5-氨基咪唑-4-carboxamide-1-2-4-核糖呋喃苷（AICAR）激活ApoE-/-小鼠AMPK可减轻动脉粥样硬化负担。然而，AMPK的多效性使得我们很难明确确定巨噬细胞AMPK在炎症相关代谢紊乱（包括动脉粥样硬化和胰岛素抵抗）发病机制中的作用。本课题将利用巨噬细胞特异性过表达显性阴性或组成性活性11AMPK （DN11和CA11）的转基因小鼠，以及巨噬细胞特异性11MAPK敲除（MAKO）小鼠，研究巨噬细胞AMPK在这些代谢紊乱中的作用。我们发现CA11小鼠巨噬细胞显著降低脂质和胆固醇诱导的内质网应激、炎症和凋亡，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外排来调节巨噬细胞脂质和胆固醇的稳态，从而防止脂质和胆固醇诱导的内质网应激、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。特异性目的1将利用CA11、DN11和MAKO小鼠巨噬细胞，确定巨噬细胞AMPK预防脂质和胆固醇诱导的内质网应激、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的稳态，2)这些途径在AMPK抑制脂质和胆固醇诱导的内质网应激、炎症和凋亡中是否必要。特异性目的2将通过CA11、DN11和MAKO小鼠与低密度脂蛋白受体敲除小鼠杂交，确定巨噬细胞AMPK对动脉粥样硬化的保护作用。我们将确定：1)血浆脂蛋白表型，2)体内巨噬细胞逆向胆固醇转运，3)动脉粥样硬化程度，4)巨噬细胞数量，脂质含量，内质网应激，动脉粥样硬化病变中的炎症和凋亡，以及5)巨噬细胞积聚，内质网应激，炎症和凋亡发展的动力学在动脉粥样硬化病变的早期和晚期。特异性目的3将确定巨噬细胞AMPK对CA11、DN11和MAKO小鼠胰岛素抵抗的保护作用。观察高脂饮食小鼠的胰岛素敏感性、脂肪组织巨噬细胞浸润、内质网应激和炎症反应。完成这些研究将大大提高我们对巨噬细胞AMPK在预防炎症相关代谢紊乱（包括动脉粥样硬化和胰岛素抵抗）中的作用的认识。

英文摘要

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.

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