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: 8428612
• 负责人: SUNEIL Krishna KOLIWAD
• 金额: $ 7.84万
• 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/8428612
• 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; Modeling; 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; public health relevance; 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（由申请人提供）：巨噬细胞和树突状细胞（髓样细胞; MC）作为免疫哨兵，巡逻组织以识别和清除外来入侵者。不幸的是，这些细胞也可以响应慢性饮食诱导的肥胖症（DIO）与炎症激活，积累在胰岛素反应组织中的“无菌”炎症级联涉及2型糖尿病的发展。新出现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质引起的， 由常驻MC摄取，调节其功能以刺激组织中的炎症序列。我的NIDDK赞助的临床科学家职业发展奖（K08）探讨了重要的生物医学问题，即MC如何与促炎脂质，特别是饱和脂肪酸（FA）相抗衡。我假设MC可以通过将细胞内脂肪酸储存为三酰甘油（TG）来降低细胞内脂肪酸上升的毒性，防止它们流入破坏性的细胞区室和途径。我已经使用遗传学来操纵小鼠MC中的TG储存能力，以调节组织中FA诱导的炎症并改善代谢疾病。我发现，酰基CoA：二酰基甘油酰基转移酶1（DGAT 1）（一种参与TG合成的酶（aP2-Dgat 1））表达增加的MC具有增加的TG储存能力和对FA诱导的炎症的抗性（4）。值得注意的是，移植了aP2-Dgat 1骨髓的小鼠在脂肪组织中具有较少的饮食诱导的炎症和MC浸润，并且受到保护免于饮食诱导的胰岛素抵抗（4）。这个提议试图扩大我目前的K08对描述MC在DIO发展为糖尿病中的作用的影响，并以两种方式实现：到目前为止，我们的工作主要集中在DGAT1上。然而，DGAT 1是两种已知的哺乳动物DGAT酶之一（DGAT 2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，确定TG储存本身限制MC中饱和FA的毒性作用的程度需要靶向两种DGAT酶的工具，从而允许研究其中TG储存能力已经完全消除的MC。我们建议将不能储存TG的遗传修饰的造血祖细胞移植到受辐射的小鼠中，产生完全缺乏TG储存能力的MC小鼠。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，我们一直专注于控制白色脂肪组织中炎症和胰岛素抵抗的过程。然而，MC与实质细胞共存于其他几种对糖尿病发展很重要的组织中，我们想探讨MC TG储存如何在这些情况下调节炎症。我们建议在肝脏中这样做，通过确定MC特异性TG储存在脂肪肝疾病进展为肝脏炎症和胰岛素抵抗中的作用。