Targeting hepatic glutaminase activity to ameliorate hyperglycemia.
Targeting hepatic glutaminase activity to ameliorate hyperglycemia.
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DOI：
10.1038/nm.4514
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发表时间：
2018-05
期刊：
影响因子：
82.9
通讯作者：
Birnbaum MJ
中科院分区：
文献类型：
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作者：
Miller RA;Shi Y;Lu W;Pirman DA;Jatkar A;Blatnik M;Wu H;Cárdenas C;Wan M;Foskett JK;Park JO;Zhang Y;Holland WL;Rabinowitz JD;Birnbaum MJ
胰高血糖素水平在体内平衡、禁食条件下增加，通过加速糖原分解（也称为糖原分解）促进葡萄糖从肝脏释放。胰高血糖素还增强促血管生成通量，包括来自氨基酸的肝脏消耗的增加。在2型糖尿病中，胰高血糖素信号转导失调导致在这种情况下发生的肝葡萄糖输出升高和空腹高血糖症。然而，胰高血糖素刺激胰岛异生的机制仍不完全清楚。与胰高血糖素主要作用于细胞质和细胞核靶点的普遍看法相反，我们发现胰高血糖素依赖性刺激来自谷氨酰胺的线粒体回补通量，其增加了这种氨基酸对线粒体异生过程中产生的葡萄糖碳的贡献。这种葡萄糖生成的增强依赖于蛋白激酶A（PKA），并与胰高血糖素刺激的内质网钙释放、线粒体α-酮戊二酸脱氢酶激活和β-氨基丁酸分解增加有关。肝谷氨酰胺酶2（GLS 2）（催化谷氨酰胺代谢第一步的酶）水平降低的小鼠体内胰高血糖素刺激的谷氨酰胺-葡萄糖转化率较低，GLS 2敲除导致空腹血浆胰高血糖素和谷氨酰胺水平较高，胰岛素抵抗条件下空腹血糖水平较低。全基因组关联研究（GWAS）发现，人类GLS 2区域的遗传变异与较高的空腹血糖相关;在此，我们在体外冻存的人原代肝细胞中发现，GLS 2中的这些天然功能获得性错义突变导致较高的β-氨基糖苷酶分解和葡萄糖生成。这些数据强调了谷氨酰胺的促新生作用的重要性，特别是在胰高血糖素信号传导增加的病理状态下，同时表明了治疗高血糖症的可能的新治疗途径。
Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids. In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition. Yet, the mechanism by which glucagon stimulates gluconeogenesis remains incompletely understood. Contrary to the prevailing belief that glucagon acts primarily on cytoplasmic and nuclear targets, we find glucagon-dependent stimulation of mitochondrial anaplerotic flux from glutamine that increases the contribution of this amino acid to the carbons of glucose generated during gluconeogenesis. This enhanced glucose production is dependent on protein kinase A (PKA) and is associated with glucagon-stimulated calcium release from the endoplasmic reticulum, activation of mitochondrial α-ketoglutarate dehydrogenase, and increased glutaminolysis. Mice with reduced levels of hepatic glutaminase 2 (GLS2), the enzyme that catalyzes the first step in glutamine metabolism, show lower glucagon-stimulated glutamine-to-glucose fluxin vivo, and GLS2 knockout results in higher fasting plasma glucagon and glutamine levels with lower fasting blood glucose levels in insulin-resistant conditions. As found in genome-wide association studies (GWAS), human genetic variation in the region ofGLS2is associated with higher fasting plasma glucose,; here we show in human cryopreserved primary hepatocytesin vitrothat these natural gain-of-function missense mutations inGLS2result in higher glutaminolysis and glucose production. These data emphasize the importance of gluconeogenesis from glutamine, particularly in pathological states of increased glucagon signaling, while suggesting a possible new therapeutic avenue to treat hyperglycemia.
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