N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway
N-Glycan Remodeling on Glucagon Receptor Is an Effector of Nutrient Sensing by the Hexosamine Biosynthesis Pathway
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DOI：
10.1074/jbc.m114.563734
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发表时间：
2014-06-06
影响因子：
4.8
通讯作者：
Dennis, James W.
中科院分区：
文献类型：
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作者：
Johswich, Anita;Longuet, Christine;Dennis, James W.
哺乳动物体内的葡萄糖稳态依赖于胰岛素和胰高血糖素的相反作用。由Mgat 1、Mgat 2、Mgat 4a/B/c和Mgat 5编码的高尔基体N-乙酰葡糖氨基转移酶修饰受体和溶质转运蛋白上的N-聚糖，可能使活性适应代谢环境。在此，我们报告了Mgat 5（-/-）小鼠显示出对外源性胰高血糖素的血糖反应降低，以及胰岛素敏感性增加。Mgat 5（-/-）培养的肝细胞中胰高血糖素受体信号传导和胰高血糖素生成受损。在HEK 293细胞中，异位表达的胰高血糖素受体的信号传导通过Mgat 5表达和GlcNAc补充至UDP-GlcNAc而增加，UDP-GlcNAc是Mgat分支酶共享的供体底物。原代肝细胞中胰高血糖素受体的迁移率通过半乳糖凝集素-9结合而降低，并且相互作用的强度取决于Mgat 5和UDP-GlcNAc水平。最后，口服GlcNAc补充剂挽救了Mgat 5（-/-）肝细胞和小鼠中的胰高血糖素反应，以及肝脏中的糖酵解代谢物和UDP-GlcNAc水平。我们的研究结果表明，己糖胺生物合成途径和GlcNAc补救有助于通过胰高血糖素受体上的N-聚糖分支的葡萄糖稳态。
Glucose homeostasis in mammals is dependent on the opposing actions of insulin and glucagon. The Golgi N-acetylglucos-aminyltransferases encoded by Mgat1, Mgat2, Mgat4a/b/c, and Mgat5 modify the N-glycans on receptors and solute transporter, possibly adapting activities in response to the metabolic environment. Herein we report that Mgat5(-/-) mice display diminished glycemic response to exogenous glucagon, together with increased insulin sensitivity. Glucagon receptor signaling and gluconeogenesis in Mgat5(-/-) cultured hepatocytes was impaired. In HEK293 cells, signaling by ectopically expressed glucagon receptor was increased by Mgat5 expression and GlcNAc supplementation to UDP-GlcNAc, the donor substrate shared by Mgat branching enzymes. The mobility of glucagon receptor in primary hepatocytes was reduced by galectin-9 binding, and the strength of the interaction was dependent on Mgat5 and UDP-GlcNAc levels. Finally, oral GlcNAc supplementation rescued the glucagon response in Mgat5(-/-) hepatocytes and mice, as well as glycolytic metabolites and UDP-GlcNAc levels in liver. Our results reveal that the hexosamine biosynthesis pathway and GlcNAc salvage contribute to glucose homeostasis through N-glycan branching on glucagon receptor.