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.