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

 描述（由申请人提供）：肥胖是全球最流行的疾病之一，导致胰岛素抵抗和动脉粥样硬化，这是由肥胖相关的慢性炎症驱动的。肥胖相关炎症的标志是脂肪组织中从替代活化（M2）到经典活化的促炎（M1）巨噬细胞的转变，局部和全身炎症增强，免疫功能受损。有趣的是，M1巨噬细胞需要葡萄糖作为能量来源，而替代活化（M2）巨噬细胞则转换为脂肪酸氧化以满足能量需求。尽管葡萄糖代谢在巨噬细胞活化过程中起着关键作用，但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尚未得到很好的理解。据报道，溶质载体（SLC）37 A2锚定在内质网（ER）膜上，是一种磷酸连接的葡萄糖-6-磷酸（G6 P）转运蛋白。相对于其他SLC 37家族成员，SLC 37 A2在巨噬细胞和嗜中性粒细胞中高度表达。我们的初步数据表明，巨噬细胞SLC 37 A2在经典激活过程中急剧下调，在替代激活过程中上调。SLC 37 A2的抑制足以促进小鼠巨噬细胞的M1极化并减弱M2极化。相反，SLC 37 A2的组成型过表达减弱了响应于Toll样受体（TLR）激动剂的M1极化。本研究旨在探索一种新的SLC 37 A2介导的代谢重编程途径，该途径在调节巨噬细胞葡萄糖通量、利用和脂肪酸氧化中起关键作用。我们将测试一个新的假设，即SLC 37 A2通过调节细胞内葡萄糖利用和稳态，促进巨噬细胞M1到M2表型转换，防止胰岛素抵抗 和动脉粥样硬化。拟议的研究将证明SLC 37 A2是否调节巨噬细胞葡萄糖代谢和重编程巨噬细胞M1/M2极化。该项目由一位新研究者和一个多学科专家团队领导，将提供有关葡萄糖代谢在巨噬细胞表型转换中作用的新信息，并有可能为M1-偏斜促炎巨噬细胞驱动的慢性炎症性疾病提供新的治疗策略。

 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.