Effect of Dietary Fatty Acids on Adipose Tissue Inflammation

膳食脂肪酸对脂肪组织炎症的影响

基本信息

批准号：
8903548
负责人：
ALAN CHAIT
金额：
$ 43.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903548
关键词：
Address Adipocytes Adipose tissue Adverse effects Affect Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Apolipoproteins Atherosclerosis Back Biology Blood Vessels Body Weight decreased Bone Marrow Cardiovascular Diseases Cell membrane Cells Chemotactic Factors Cholesterol Conjugated Linoleic Acids Cyclodextrins Data Diet Dietary Fatty Acid Excision Exposure to Fatty Acids Funding Generations Genes Grant Health High Density Lipoproteins Human In Vitro Inflammation Inflammatory Inflammatory Response Insulin Resistance Isomerism Laurates Lead Link Lipids Mediating Metabolic Metabolic syndrome Mitochondria Myristates NADPH Oxidase Nutritional Obesity Oxidative Stress Palmitates Pathway interactions Prevention Process Production Protein translocation Proteins Reactive Oxygen Species Role Saturated Fatty Acids Signal Transduction Supplementation Testing Transgenic Mice Transplantation Triglycerides adipocyte differentiation base cardiovascular disorder risk cholesterol transporters dietary excess disorder control fatty acid oxidation in vivo macrophage monocyte mouse model novel overexpression prevent

项目摘要

DESCRIPTION (provided by applicant): Adipose tissue inflammation is associated with insulin resistance and an increased risk of cardiovascular disease. Excess dietary saturated fatty acids (SFA) such as palmitate stimulate the production of reactive oxygen species (ROS) by a NOX4-dependent mitochondria-independent pathway, and increase the generation of monocyte chemotactic factors and inflammatory signals in adipocytes. Conversely, an isomer of conjugated linoleic acid (CLA) that is used as a weight loss supplement, decreases triglyceride accumulation and stimulates ROS production by mitochondria rather than NOX4. This too leads to adipocyte chemotactic factor generation and inflammation. On the basis of our preliminary data, we hypothesize that SFA such as palmitate stimulate adipose tissue inflammation by NOX4-dependent generation of ROS by adipocytes. This process involves transfer of key cellular proteins such as NOX4 to the plasma membrane, and can be blocked by removing cholesterol from plasma membranes by exposure to HDL. Conversely, we hypothesize that CLA stimulates adipose tissue inflammation by a distinct pathway that involves generation of ROS by mitochondria, is associated with reduced triglyceride accumulation in adipocytes, is not associated with translocation of proteins to the cell membrane, and is not blocked by HDL. To determine whether NOX expression by adipocytes is required for SFA-induced adipose tissue inflammation, we will specifically delete NOX4 in adipocytes. We also will determine mechanisms by which HDL and its major apolipoprotein, apoA-I, exert anti-inflammatory effects on adipocytes and adipose tissue in vitro and in vivo. Our in vivo studies will focus on the role o the cholesterol transporter, ABCG1, which we have shown in preliminary data to be a likely candidate for the removal of cholesterol from plasma membranes. Since ABCG1 is likely to be produced by adipose tissue macrophages rather than adipocytes, we will transplant either wild type or ABCG1-deficient bone marrow into apoA-I transgenic mice, in which SFA-mediated adipose tissue inflammation is blunted. We will identify differences in how adipocytes metabolize CLA versus palmitate, and determine why CLA leads to triglyceride reduction and fatty acid utilization by mitochondria rather than storage of triglycerides as occurs with other SFA. We also will investigate how this metabolic switch is linked to the generation of mitochondrial ROS, chemotactic factors and inflammatory molecules. Findings from this grant have important implications for preventing diet-induced adipose tissue inflammation and the accompanying insulin resistance and cardiovascular disease risk.

描述（由申请人提供）：脂肪组织炎症与胰岛素抵抗和心血管疾病风险增加有关。过量的膳食饱和脂肪酸（SFA）如棕榈酸通过NOX4依赖性线粒体独立途径刺激活性氧（ROS）的产生，并增加脂肪细胞中单核细胞趋化因子和炎症信号的产生。相反，共轭亚油酸 (CLA) 的异构体用作减肥补充剂，可减少甘油三酯的积累并刺激线粒体而不是 NOX4 产生 ROS。这也导致脂肪细胞趋化因子的产生和炎症。根据我们的初步数据，我们假设棕榈酸等 SFA 通过脂肪细胞依赖 NOX4 产生 ROS 来刺激脂肪组织炎症。该过程涉及关键细胞蛋白（例如 NOX4）转移到质膜，并且可以通过暴露于 HDL 从质膜去除胆固醇来阻断。相反，我们假设 CLA 通过一种独特的途径刺激脂肪组织炎症，该途径涉及线粒体产生 ROS，与脂肪细胞中甘油三酯积累减少有关，与蛋白质易位到细胞膜无关，并且不被 HDL 阻断。为了确定脂肪细胞表达 NOX 是否是 SFA 诱导的脂肪组织炎症所必需的，我们将特异性删除脂肪细胞中的 NOX4。我们还将确定 HDL 及其主要载脂蛋白 apoA-I 在体外和体内对脂肪细胞和脂肪组织发挥抗炎作用的机制。我们的体内研究将重点关注胆固醇转运蛋白 ABCG1 的作用，我们在初步数据中表明它可能是从质膜上去除胆固醇的候选蛋白。由于 ABCG1 可能是由脂肪组织巨噬细胞而不是脂肪细胞产生，因此我们将野生型或 ABCG1 缺陷型骨髓移植到 apoA-I 转基因小鼠中，在这种小鼠中，SFA 介导的脂肪组织炎症被减弱。我们将确定脂肪细胞代谢 CLA 与棕榈酸酯的差异，并确定为什么 CLA 会导致甘油三酯减少和线粒体利用脂肪酸，而不是像其他 SFA 那样储存甘油三酯。我们还将研究这种代谢开关如何与线粒体 ROS、趋化因子和炎症分子的产生相关。这项资助的研究结果对于预防饮食引起的脂肪组织炎症以及随之而来的胰岛素抵抗和心血管疾病风险具有重要意义。