Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02115, USA.
Cell Rep. 2021 Nov 23;37(8):110037. doi: 10.1016/j.celrep.2021.110037.
Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of primary islets from human donors and identified de novo glutathione synthesis as a prominent glucose-driven pro-survival pathway. We find that pyruvate carboxylase is required for glutathione synthesis in islets and promotes their antioxidant capacity to counter inflammation and nitrosative stress. Loss- and gain-of-function studies indicate that pyruvate carboxylase is necessary and sufficient to mediate the metabolic input from glucose into glutathione synthesis and the oxidative stress response. Altered redox metabolism and cellular capacity to replenish glutathione pools are relevant in multiple pathologies beyond obesity and diabetes. Our findings reveal a direct interplay between glucose metabolism and glutathione biosynthesis via pyruvate carboxylase. This metabolic axis may also have implications in other settings where sustaining glutathione is essential.
葡萄糖代谢调节胰岛β细胞对致糖尿病应激的反应，包括炎症。在这里，我们通过分析来自人类供体的原代胰岛的代谢物谱，探究了葡萄糖在炎症中发挥保护作用的代谢机制，确定从头合成谷胱甘肽是一种突出的葡萄糖驱动的促生存途径。我们发现，丙酮酸羧化酶是胰岛中谷胱甘肽合成所必需的，可增强其抗氧化能力以抵抗炎症和硝化应激。缺失和功能获得研究表明，丙酮酸羧化酶对于将葡萄糖代谢输入到谷胱甘肽合成和氧化应激反应中是必需且充分的。在肥胖和糖尿病以外的多种病理情况下，氧化还原代谢和细胞补充谷胱甘肽池的能力的改变是相关的。我们的发现揭示了葡萄糖代谢和通过丙酮酸羧化酶合成谷胱甘肽之间的直接相互作用。这个代谢轴在其他需要维持谷胱甘肽的环境中也可能具有重要意义。
