Deleterious mutation V369M in the mouse GCGR gene causes abnormal plasma amino acid levels indicative of a possible liver-α-cell axis.
Deleterious mutation V369M in the mouse GCGR gene causes abnormal plasma amino acid levels indicative of a possible liver-α-cell axis.
复制标题
小鼠GCGR基因中的有害突变V369M导致血浆氨基酸水平异常，表明可能存在肝-α细胞轴
DOI：
10.1042/bsr20210758
复制
发表时间：
2021-06-25
影响因子：
4
通讯作者：
Wang MW
中科院分区：
文献类型：
--
作者：
Liu Q;Lin G;Chen Y;Feng W;Xu Y;Lyu J;Yang D;Wang MW
胰高血糖素在葡萄糖稳态和氨基酸代谢中起重要作用。它调节血浆氨基酸水平，进而调节胰腺α细胞的胰高血糖素分泌，从而建立最近描述的肝α细胞轴。我们以前报道过，携带纯合V369 M置换（相当于人胰高血糖素受体GCGR中天然存在的突变V368 M）的基因敲入小鼠导致低血糖，并改善葡萄糖耐量。它们还表现出高胰高血糖素血症、胰腺增大和α细胞增生。在此，我们研究了V369 M/V368 M突变对胰高血糖素介导的氨基酸代谢的影响。研究发现，GcgrV 369 M +/+小鼠的血浆氨基酸水平总体上升高，但在高脂饲料（HFD）喂养的动物中观察到生酮/生糖氨基酸显著蓄积，导致α细胞增殖和高胰高血糖素血症特征性的有害代谢后果。
Glucagon plays an important role in glucose homeostasis and amino acid metabolism. It regulates plasma amino acid levels which in turn modulate glucagon secretion from the pancreatic α-cell, thereby establishing a liver–α-cell axis described recently. We reported previously that the knock-in mice bearing homozygous V369M substitution (equivalent to a naturally occurring mutation V368M in the human glucagon receptor, GCGR) led to hypoglycemia with improved glucose tolerance. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia. Here, we investigated the effect of V369M/V368M mutation on glucagon-mediated amino acid metabolism. It was found that GcgrV369M+/+ mice displayed increased plasma amino acid levels in general, but significant accumulation of the ketogenic/glucogenic amino acids was observed in animals fed with a high-fat diet (HFD), resulting in deleterious metabolic consequence characteristic of α-cell proliferation and hyperglucagonemia.