Myeloid-specific Triacylglycerol Storage in Inflammation and Metabolic Disease

炎症和代谢疾病中的骨髓特异性三酰甘油储存

• 批准号: 8616374
• 负责人: SUNEIL Krishna KOLIWAD
• 金额: $ 7.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616374
• 关键词: Accounting; Acyl Coenzyme A; Address; Adipocytes; Adipose tissue; Apoptosis; Bone Marrow; Cells; Cessation of life; Chronic; Complex; Consumption; Data; Dendritic Cells; Development; Diabetes Mellitus; Diet; Dietary Fats; Enzymes; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Genetic; Hematopoietic; Hepatocyte; Immunologics; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Resistance; K-Series Research Career Programs; Link; Lipids; Lipolysis; Liver; Liver diseases; Metabolic; Metabolic Diseases; Monounsaturated Fatty Acids; Mus; Myelogenous; Myeloid Cell Activation; Myeloid Cells; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Oleic Acids; Palmitates; Palmitic Acids; Parents; Pathway interactions; Process; Resistance; Role; Saturated Fatty Acids; Scientist; Sentinel; Steatohepatitis; Sterility; Stress; Testing; Tissues; Toxic effect; Transgenic Organisms; Transplantation; Triglycerides; Work; cell type; design; diacylglycerol O-acyltransferase; experience; liver inflammation; macrophage; mouse model; prevent; progenitor; response; stem; tool

DESCRIPTION (provided by applicant): Macrophages and dendritic cells (myeloid cells; MCs) function as immunologic sentinels, patrolling tissues to recognize and eliminate foreign invaders. Unfortunately, these cells can also respond to chronic diet-induced obesity (DIO) with inflammatory activation, accumulating in insulin-responsive tissues in a "sterile" inflammatory cascade implicated in the development of diabetes type 2. Emerging data support the concept that this response is instigated by lipids released from, for example, fat or liver cells, that are taken up by resident MCs, modulating their function to incite an inflammatory sequence in the tissue. My NIDDK-sponsored Clinician-Scientist Career Development Award (K08) explores the important biomedical question of how MCs contend with pro-inflammatory lipids, in particular saturated fatty acids (FAs). I have hypothesized that MCs can reduce toxicity from a rising tide of intracellular FAs by storing them as triacylglycerol (TG), preventing their flux into damaging cellular compartments and pathways. I have used genetics to manipulate TG storage capacity in murine MCs in order to modulate FA-induced inflammation in tissues and ameliorate metabolic diseases. I showed that MCs with increased expression of acyl CoA: diacylglycerol acyltransferase 1 (DGAT1), an enzyme involved in TG synthesis (aP2-Dgat1), have increased TG storage capacity and resistance to FA-induced inflammation (4). Remarkably, mice transplanted with aP2-Dgat1 bone marrow have less diet-induced inflammation and MC infiltration in fat tissue, and are protected from diet-induced insulin resistance (4). This proposl seeks to extend the impact of my current K08 on delineating the role of MCs in the progression of DIO to diabetes, and does so in two ways: A. Until now, our work has focused on DGAT1. However, DGAT1 is one of two known mammalian DGAT enzymes (DGAT2 is the other), and their combined action accounts for essentially all the TG formed in most cell types. Therefore, determining the degree to which TG storage per se limits the toxic effects of saturated FAs in MCs requires tools that target both DGAT enzymes, allowing the study of MCs in which TG storage capacity has been abolished altogether. We propose to transplant genetically modified hematopoietic progenitors that cannot store TG into irradiated mice, producing mice with MCs lacking TG storage capacity altogether. We will test the response of these mice to a chronically high-fat diet. B. Until now, we have focused on processes governing inflammation and insulin resistance in white adipose tissue. However, MCs coexist with parenchymal cells in several other tissues important to the development of diabetes, and we would like to explore how MC TG storage modulates inflammation in each of these contexts. We propose here to do so in the liver, by determining the role of MC-specific TG storage in the progression of fatty liver disease to liver inflammation and insulin resistance.

描述(申请人提供)：巨噬细胞和树突状细胞(髓系细胞；MC)作为免疫哨兵，巡逻组织以识别和消除外来入侵者。不幸的是，这些细胞也可以对慢性饮食诱导的肥胖(DIO)做出炎症激活的反应，在胰岛素反应组织中积聚，这与2型糖尿病的发展有关。新的数据支持这样的概念，即这种反应是由脂肪或肝细胞释放的脂类激发的，例如，脂肪或肝细胞 被常驻的MC吸收，调节它们的功能，在组织中激发炎症序列。我的NIDDK赞助的临床医生-科学家职业发展奖(K08)探索了MC如何与促炎脂质，特别是饱和脂肪酸(FA)作斗争的重要生物医学问题。我曾假设，MC可以通过将细胞内不断上升的脂肪酸储存为三酰甘油(TG)来减少它们的毒性，防止它们的流量进入破坏细胞隔间和途径。我曾使用遗传学来控制小鼠巨噬细胞中甘油三酯的储存能力，以调节FA诱导的组织炎症，并改善代谢性疾病。I表明，参与甘油三酯合成的酶(aP2-Dgat1)酰基辅酶A：二酰甘油酰基转移酶1(DGAT1)表达增加的MC具有更高的甘油三酯储存能力和对FA诱导的炎症的抵抗力(4)。值得注意的是，移植了aP2-Dgat1骨髓的小鼠减少了饮食诱导的炎症和脂肪组织中MC的渗透，并保护了饮食诱导的胰岛素抵抗(4)。这项提议试图扩大我目前的K08在描述MC在DIO向糖尿病的进展中的作用方面的影响，并通过两种方式做到这一点：a.到目前为止，我们的工作重点是DGAT1。然而，DGAT1是已知的两种哺乳动物DGAT酶之一(DGAT2是另一种)，它们的联合作用基本上解释了大多数细胞类型中形成的所有TG。因此，要确定甘油三酯储存本身在多大程度上限制了饱和脂肪酸对MC的毒性影响，需要针对两种DGAT酶的工具，从而允许对TG储存能力已完全取消的MC进行研究。我们建议将不能储存甘油三酯的转基因造血祖细胞移植到受照射的小鼠体内，使小鼠的MC完全缺乏甘油三酯储存能力。我们将测试这些小鼠对长期高脂肪饮食的反应。B.到目前为止，我们一直专注于白色脂肪组织中炎症和胰岛素抵抗的调控过程。然而，MC与实质细胞共存于其他几个对糖尿病发展至关重要的组织中，我们想要探索MC TG存储如何在这些背景下调节炎症。我们建议在肝脏中这样做，通过确定MC特异性甘油三酯存储在脂肪肝疾病发展到肝脏炎症和胰岛素抵抗中的作用。