Metabolic Reprogramming by Hexosamine Biosynthetic and Golgi N-Glycan Branching Pathways.
Metabolic Reprogramming by Hexosamine Biosynthetic and Golgi N-Glycan Branching Pathways.
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DOI：
10.1038/srep23043
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发表时间：
2016-03-14
影响因子：
4.6
通讯作者：
Dennis JW
中科院分区：
文献类型：
--
作者：
Ryczko MC;Pawling J;Chen R;Abdel Rahman AM;Yau K;Copeland JK;Zhang C;Surendra A;Guttman DS;Figeys D;Dennis JW
尿苷二磷酸-N-乙酰葡糖胺（UDP-GlcNAc）的从头生物合成需要葡萄糖、谷氨酰胺、乙酰辅酶A和尿苷，然而，从糖缀合物周转和膳食来源中回收的GlcNAc也对细胞内库做出显著贡献。在此，我们询问饮食GlcNAc是否通过增加UDP-GlcNAc进而增加高尔基体N-聚糖分支来调节C57 BL/6小鼠的营养转运和中间代谢。添加到饮用水中的GlcNAc显示出幼年小鼠生长的剂量依赖性增加，而成熟成年小鼠的脂肪和体重增加，但不影响卡路里摄入、活动、能量消耗或微生物组。口服GlcNAc增加肝UDP-GlcNAc和肝糖蛋白上的N-聚糖分支。GlcNAc治疗改变了葡萄糖稳态、肝糖原、脂质代谢和对禁食的反应。在培养的细胞中，GlcNAc增强葡萄糖、谷氨酰胺和脂肪酸的摄取，并增强脂质合成，而抑制高尔基体N-聚糖分支阻断GlcNAc依赖的脂质积累。N-聚糖分支途径的N-乙酰葡糖胺转移酶（Mgat 1，2，4，5）显示对UDP-GlcNAc的多步超敏感性，以及分支依赖性补偿。事实上，口服GlcNAc挽救了瘦Mgat 5 −/−小鼠和培养的Mgat 5 −/−肝细胞中的脂肪积累，与N-聚糖分支补偿一致。我们的研究结果表明，GlcNAc通过UDP-GlcNAc向N-聚糖分支途径的供应来增强营养摄取和脂质储存，从而重新编程细胞代谢。
De novo uridine-diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis requires glucose, glutamine, acetyl-CoA and uridine, however GlcNAc salvaged from glycoconjugate turnover and dietary sources also makes a significant contribution to the intracellular pool. Herein we ask whether dietary GlcNAc regulates nutrient transport and intermediate metabolism in C57BL/6 mice by increasing UDP-GlcNAc and in turn Golgi N-glycan branching. GlcNAc added to the drinking water showed a dose-dependent increase in growth of young mice, while in mature adult mice fat and body-weight increased without affecting calorie-intake, activity, energy expenditure, or the microbiome. Oral GlcNAc increased hepatic UDP-GlcNAc and N-glycan branching on hepatic glycoproteins. Glucose homeostasis, hepatic glycogen, lipid metabolism and response to fasting were altered with GlcNAc treatment. In cultured cells GlcNAc enhanced uptake of glucose, glutamine and fatty-acids, and enhanced lipid synthesis, while inhibition of Golgi N-glycan branching blocked GlcNAc-dependent lipid accumulation. The N-acetylglucosaminyltransferase enzymes of the N-glycan branching pathway (Mgat1,2,4,5) display multistep ultrasensitivity to UDP-GlcNAc, as well as branching-dependent compensation. Indeed, oral GlcNAc rescued fat accumulation in lean Mgat5−/− mice and in cultured Mgat5−/− hepatocytes, consistent with N-glycan branching compensation. Our results suggest GlcNAc reprograms cellular metabolism by enhancing nutrient uptake and lipid storage through the UDP-GlcNAc supply to N-glycan branching pathway.