Role of extracellular vesicles in the regulation of immunometabolism in obesity

细胞外囊泡在肥胖免疫代谢调节中的作用

• 批准号: 10641864
• 负责人: Takahisa Nakamura
• 金额: $ 57.16万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641864
• 关键词: Adolescent obesity; Attention; Biogenesis; Biological Assay; Body Fluids; Cardiovascular Diseases; Cells; Characteristics; Complex; Computing Methodologies; Coupled; Data; Development; Distant; Exposure to; Extracellular Space; FRAP1 gene; Fatty Liver; Genes; Genetic Variation; Gluconeogenesis; Hepatic; Hepatocyte; Human; Human Genetics; Hyperinsulinism; Inflammation; Inflammatory; Insulin; Insulin Resistance; Macrophage; Macrophage Activation; Mediating; Mediator; Metabolic; Metabolic syndrome; MicroRNAs; Molecular; Monitor; Mus; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Prevalence; Protein Deficiency; RNA; RNA Interference; RNA-Binding Proteins; Regulation; Research; Resistance; Role; Sampling; Serum; System; Testing; bariatric surgery; cell type; exosome; extracellular; extracellular vesicles; immune activation; improved; in vivo; insulin sensitivity; lipid biosynthesis; metabolic phenotype; microvesicles; monocyte; mouse model; nonalcoholic steatohepatitis; novel; obese patients; pandemic disease; pathogen; role model; sensor; therapeutic target; trait

Project Summary The worldwide prevalence of obesity has reached pandemic proportions. Obesity has strong inflammatory underpinnings, which are associated with the development of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). However, the mechanisms by which obesity provokes aberrant inflammation are not clearly defined. In this study, we aim to demonstrate that in obesity, the mTOR pathway enhances the biogenesis and secretion of pro-inflammatory extracellular vesicles (EVs) carrying a distinct set of extracellular RNAs (exRNAs) from hepatocytes and that these hepatocyte-derived EVs (H-EVs) cause the aberrant inflammation. EVs, including exosomes (30–150 nm) and microvesicles (100–1000 nm), are released from many cell types into the extracellular space and are distributed in body fluids. These EVs are taken up by neighboring or distant cells and subsequently modulate functions of recipient cells. Using novel computational methods9, we identified strong associations between human genetic variations of genes regulating EV biogenesis and metabolic syndrome, particularly T2D. Our analyses of EVs from adolescent obese patients undergoing bariatric surgery have shown that serum EV concentration is inversely correlated to metabolic improvements in insulin sensitivity and inflammation post-surgery, with unique EVs’ exRNA profiles. Further, our newly established mouse model that permits monitoring of specific cell type-derived EVs in vivo indicates that in obesity, H-EVs behave like a pathogen recognized by macrophages and induce inflammation. Mechanistically, we found that in hepatocytes, the insulin-mTOR pathway enhances secretion of EVs and that insulin- stimulated EVs are more pro-inflammatory in activating macrophages. We have also discovered that a component of the RNA silencing machinery is a mediator of the pro-inflammatory EVs and is required for the EV-induced macrophage activation. These preliminary data suggest unique and pivotal roles for H-EVs, leading us to hypothesize that during the development of hyperinsulinemia, hepatocytes secrete pathologic EVs carrying unique exRNAs which are sensed by recipient macrophages, promoting aberrant inflammation. Studies in this proposal will: (1) define the molecular pathway that confers the proinflammatory trait to the H- EVs, (2) determine the role of RNA silencing machinery in macrophages as a mediator of pro-inflammatory EVs, and (3) evaluate the role of EVs in immunometabolism in human obese patients. By utilizing our novel mouse models coupled with access to human samples, our systematical approaches will demonstrate novel mechanisms concerning how the pathogenicity of H-EVs is involved in the development of inflammation in hyperinsulinemia and obesity.

项目摘要 肥胖症的全球流行率已经达到了大流行的比例。肥胖具有强烈的炎症性 基础，与2型糖尿病（T2D）和非酒精性的发展有关 脂肪性肝炎（NASH）。但是，肥胖引起异常炎症的机制不是 明确定义。在这项研究中，我们旨在证明在肥胖症中，mTOR途径增强了 促炎细胞外蔬菜（EV）的生物发生和分泌，携带一组独特的集合 细胞外RNA（EXRNA）来自肝细胞，这些肝细胞衍生的EV（H-EV）导致 异常炎症。 电动汽车，包括外泌体（30-150 nm）和微泡（100-1000 nm），从许多细胞类型中释放 进入细胞外空间，分布在体液中。这些电动汽车由邻近或 远处细胞，随后调节受体细胞的功能。使用新颖的计算方法9，我们 确定了调节EV生物发生的基因的人类遗传变异与 代谢综合征，特别是T2D。我们对正在进行的青少年肥胖患者的电动汽车的分析 减肥手术表明，血清EV浓度与代谢改善成反比 在胰岛素敏感性和手术后感染中，具有独特的电动汽车特征。此外，我们的新近 已建立的鼠标模型允许监视体内特定细胞类型衍生的EV，这表明在 肥胖，H-EV的行为就像是巨噬细胞识别并诱导注射的病原体。机械上， 我们发现，在肝细胞中，胰岛素-MTOR途径增强了电动汽车的分泌，并且胰岛素 - 刺激的电动汽车在激活巨噬细胞方面更具促炎性。我们还发现 RNA沉默机制的组成部分是促炎性电动汽车的中介者，是必需的 EV诱导的巨噬细胞激活。这些初步数据表明H-evs的独特和关键作用， 导致我们假设在高胰岛素血症的发展过程中，肝细胞分泌 携带受体巨噬细胞感知的独特exrnas的病理EVS，促进 异常炎症。 该提案中的研究将：（1）定义将促炎特征赋予H-的分子途径 EV，（2）确定RNA沉默机制在巨噬细胞中的作用，作为促炎的介体 EV和（3）评估EV在人肥胖患者中免疫代谢中的作用。 通过使用我们的新型鼠标模型，加上访问人类样品的方法，我们的系统方法 将展示有关H-EV的致病性如何参与的新型机制 高胰岛素血症和肥胖症中炎症的发展。

项目成果

A Label-Free Electrical Impedance Spectroscopy for Detection of Clusters of Extracellular Vesicles Based on Their Unique Dielectric Properties.

• DOI: 10.3390/bios12020104
• 发表时间: 2022-02-09
• 期刊: Biosensors
• 作者: Zhang Y;Murakami K;Borra VJ;Ozen MO;Demirci U;Nakamura T;Esfandiari L
• 通讯作者: Esfandiari L

Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation.

• DOI: 10.1016/j.stemcr.2020.12.008
• 发表时间: 2021-02-09
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Hayashi H;Osaka S;Sakabe K;Fukami A;Kishimoto E;Aihara E;Sabu Y;Mizutani A;Kusuhara H;Naritaka N;Zhang W;Huppert SS;Sakabe M;Nakamura T;Hu YC;Mayhew C;Setchell K;Takebe T;Asai A
• 通讯作者: Asai A

Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor.

• DOI: 10.3389/fmed.2022.1060244
• 发表时间: 2022
• 期刊: Frontiers in medicine
• 影响因子: 3.9