The role of SLC37A2, a glucose 6 phosphate transporter, in inflammation and metabolic diseases

SLC37A2（一种葡萄糖 6 磷酸转运蛋白）在炎症和代谢疾病中的作用

• 批准号: 9234061
• 负责人: Xuewei Zhu
• 金额: $ 37.04万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234061
• 关键词: Acute; Adipose tissue; Affect; Agonist; Antiatherogenic; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Attenuated; Bone Marrow; C57BL/6 Mouse; Cardiovascular Diseases; Cause of Death; Chronic; Data; Development; Diet; Disease; Endoplasmic Reticulum; Energy-Generating Resources; Family; Family member; Fatty Acids; Gene Expression; Glucose; Glucose Transporter; Glucose-6-Phosphate; Glycolysis; Goals; Hematopoietic; High Fat Diet; Homeostasis; Hyperglycemia; Hyperinsulinism; Impairment; Inflammation; Inflammatory; Inorganic Phosphate Transporter; Insulin; Insulin Resistance; Interleukin-4; Knockout Mice; Lead; Lesion; Link; Lipids; Macrophage Activation; Measures; Mediating; Membrane; Metabolic; Metabolic Diseases; Molecular; Mus; Myelogenous; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peripheral; Phenotype; Plasma; Play; Reporting; Research Personnel; Role; Testing; Tissues; Toll-like receptors; Transplantation; atherogenesis; attenuation; blood glucose regulation; cytokine; design; fatty acid metabolism; fatty acid oxidation; glucose metabolism; immune function; inorganic phosphate; insulin signaling; interest; macrophage; male; metabolic phenotype; multidisciplinary; neutrophil; novel; novel therapeutics; overexpression; oxidation; public health relevance; response; solute; sugar; uptake

 DESCRIPTION (provided by applicant): Obesity is one of the most prevalent diseases globally, leading to insulin resistance and atherosclerosis, which are driven by obesity-associated chronic inflammation. A hallmark of obesity-associated inflammation is a switch from alternative-activated (M2) to classically-activated pro-inflammatory (M1) macrophage in adipose tissue with enhanced local and systemic inflammation and impaired immune function. Of interest, M1 macrophages require glucose as an energy source, while alternative activated (M2) macrophages switch to fatty acid oxidation for energy needs. Despite the critical role of glucose metabolism during macrophage activation, molecular mechanisms linking altered glucose metabolism to macrophage polarization are not well understood. Solute carrier (SLC) 37A2 has been reported anchored in the endoplasmic reticulum (ER) membrane and is a phosphate-linked glucose-6-phosphate (G6P) transporter. SLC37A2 is highly expressed in macrophages and neutrophils relative to other SLC37 family members. Our preliminary data suggest that macrophage SLC37A2 is acutely downregulated during classical activation and upregulated during alternative activation. Suppression of SLC37A2 is sufficient to promote M1 and attenuate M2 polarization of mouse macrophages. Conversely, constitutive overexpression of SLC37A2 blunts M1 polarization in response to Toll like receptor (TLR) agonists. This proposal aims to explore a novel SLC37A2-mediated metabolic reprogramming pathway, which plays a critical role in regulating macrophage glucose flux, utilization and fatty acid oxidation. We will test a novel hypothesis that SLC37A2 promotes macrophage M1 to M2 phenotypic switch by regulating intracellular glucose utilization and homeostasis, protecting against insulin resistance and atherosclerosis. The proposed studies will demonstrate whether SLC37A2 regulates macrophage glucose metabolism and reprograms macrophage M1/M2 polarization. This project, led by a New Investigator with an expert multidisciplinary team, will provide novel information regarding the role of glucose metabolism in macrophage phenotypic switching, and has the potential to lead to novel therapeutic strategies for chronic inflammatory diseases driven by M1-skewed proinflammatory macrophages.

 描述（由适用提供）：肥胖是全球最普遍的疾病之一，导致胰岛素抵抗和动脉粥样硬化，这是由肥胖相关的慢性感染驱动的。肥胖相关感染的标志是从替代激活（M2）转变为脂肪组织中经典激活的促疾病（M1）巨噬细胞，具有增强的局部和全身感染以及免疫功能受损的功能。感兴趣的是，M1巨噬细胞需要葡萄糖作为能源，而替代激活（M2）巨噬细胞转向脂肪酸氧化满足能量需求。尽管葡萄糖代谢在巨噬细胞激活中的重要作用至关重要，但尚不清楚将改变的葡萄糖代谢与巨噬细胞极化联系起来的分子机制。据报道，溶质载体（SLC）37A2锚定在内质网（ER）膜中，是磷酸盐连接的6-磷酸葡萄糖（G6P）转运蛋白。相对于其他SLC37家庭成员，SLC37A2在巨噬细胞和中性粒细胞中高度表达。我们的初步数据表明，巨噬细胞SLC37A2在经典激活过程中急性下调，并在替代激活过程中进行了更新。 SLC37A2的抑制足以促进M1并减轻小鼠巨噬细胞的M2极化。相反，SLC37A2的本构过表达响应Toll像受体（TLR）激动剂的TOLL钝化M1极化。该建议旨在探索一种新型的SLC37A2介导的代谢重编程途径，该途径在控制巨噬细胞葡萄糖通量，利用率和脂肪酸氧化中起着至关重要的作用。我们将通过控制细胞内葡萄糖利用率和稳态促进，可促进SLC37A2的新假设，即SLC37A2促进巨噬细胞M1至M2表型开关 和动脉粥样硬化。拟议的研究将证明SLC37A2是否调节巨噬细胞葡萄糖代谢并重新编程巨噬细胞M1/M2极化。该项目由由专家多学科团队的新研究人员领导，将提供有关葡萄糖代谢在巨噬细胞表型转换中的作用的新信息，并有可能导致新的治疗策略，以实现由M1链球运动促性促炎性巨噬细胞驱动的慢性炎症性疾病。