Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice.
Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice.
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DOI：
10.1016/j.cmet.2017.05.006
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发表时间：
2017-06-06
期刊：
影响因子：
29
通讯作者：
Gromada J
中科院分区：
文献类型：
--
作者：
Kim J;Okamoto H;Huang Z;Anguiano G;Chen S;Liu Q;Cavino K;Xin Y;Na E;Hamid R;Lee J;Zambrowicz B;Unger R;Murphy AJ;Xu Y;Yancopoulos GD;Li WH;Gromada J
胰高血糖素通过刺激肝脏糖异生来支持葡萄糖稳态，部分是通过促进氨基酸的摄取和转化为糖异生前体。遗传干扰或药物抑制胰高血糖素信号导致血浆氨基酸升高和代偿性胰高血糖素高分泌，包括胰腺α细胞团的扩大。最近的研究表明，高胺酸血症通过mtor依赖途径触发胰腺α细胞增殖。我们通过证明胰高血糖素通路阻断选择性地增加高增殖α细胞亚群中钠偶联中性氨基酸转运体Slc38a5的表达，并且Slc38a5控制胰腺对胰高血糖素通路阻断的反应，证实并扩展了这些发现；最值得注意的是，缺乏Slc38a5的小鼠表现出胰高血糖素通路阻断诱导的高氨基酸酸血症的α细胞增生明显减少。这些结果表明，Slc38a5是小鼠肝脏胰高血糖素受体信号传导与氨基酸依赖性胰腺α细胞质量调节之间反馈回路的关键组成部分。胰高血糖素受体抑制降低肝脏对氨基酸的摄取和分解代谢。Kim等人表明，Slc38a5是氨基酸传感机制的关键组成部分，将循环氨基酸与控制胰腺α细胞功能和质量联系起来。
Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids and compensatory glucagon hypersecretion involving expansion of pancreatic α cell mass. Recent findings indicate that hyperaminoacidemia triggers pancreatic α cell proliferation via an mTOR-dependent pathway. We confirm and extend these findings by demonstrating that glucagon pathway blockade selectively increases expression of the sodium-coupled neutral amino acid transporter Slc38a5 in a subset of highly proliferative α cells and that Slc38a5 controls the pancreatic response to glucagon pathway blockade; most notably, mice deficient in Slc38a5 exhibit markedly decreased α cell hyperplasia to glucagon pathway blockade-induced hyperaminoacidemia. These results show that Slc38a5 is a key component of the feedback circuit between glucagon receptor signaling in the liver and amino-acid-dependent regulation of pancreatic α cell mass in mice. Glucagon receptor inhibition reduces hepatic uptake and catabolism of amino acids. Kim et al. show that Slc38a5 is a key component of the amino acid sensing machinery linking circulating amino acids to control of pancreatic α cell function and mass.
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DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.6
作者：
KELLEY, DS;SHULL, JD;POTTER, VR
通讯作者：
POTTER, VR
影响因子：
5.5
作者：
Baird, FE;Beattie, KJ;Taylor, PM
通讯作者：
Taylor, PM
影响因子：
11.4
作者：
Chaudhry, FA;Krizaj, D;Edwards, RH
通讯作者：
Edwards, RH
影响因子：
15.9
作者：
BODEN, G;MASTER, RW;OWEN, OE
通讯作者：
OWEN, OE