Activation and execution of the hepatic integrated stress response by dietary essential amino acid deprivation is amino acid specific.
Activation and execution of the hepatic integrated stress response by dietary essential amino acid deprivation is amino acid specific.
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通过膳食必需氨基酸剥夺激活和执行肝脏综合应激反应是氨基酸特异性的。
DOI：
10.1096/fj.202200204rr
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发表时间：
2022-07
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膳食中必需氨基酸（EAA）的去除触发肝脏的综合应激反应（ISR）。在此，我们探讨了激活ISR并根据缺失的EAA执行转录和翻译变化的机制。对野生型小鼠和缺乏一般对照非去阻遏蛋白2（Gcn 2）的小鼠饲喂氨基酸完全饲料或不含亮氨酸或含硫氨基酸（蛋氨酸和半胱氨酸）的饲料。在喂食缺乏亮氨酸的饲料的前6小时内，血清和肝脏亮氨酸浓度显著降低，对应于Atf4 mRNA翻译和选定ISR靶基因（Fgf21，Slc7a5，Slc7a11）诱导的适度GCN 2依赖性增加。与此相反，饮食中去除含硫氨基酸降低血清蛋氨酸，但不是细胞内蛋氨酸，但肝Atf4，Fgf21，Slc7a5，Slc7a11的mRNA丰度大幅增加，无论GCN 2的状态。肝脏tRNA充电水平与细胞内EAA浓度或GCN 2状态无关，并且与喂食完全饮食的小鼠相似。此外，Gcn 2的丢失增加了肝脏中核糖体碰撞的发生，并使雷帕霉素复合物1信号转导的机制靶点去抑制，但这些变化并不影响ISR的执行。我们的结论是，ISR的激活是由细胞内EAA浓度，但ISR的执行是不是。此外，缺乏含硫氨基酸的饮食不需要GCN 2来使ISR执行转录组的改变。
Dietary removal of an essential amino acid (EAA) triggers the integrated stress response (ISR) in liver. Herein, we explored the mechanisms that activate the ISR and execute changes in transcription and translation according to the missing EAA. Wild‐type mice and mice lacking general control nonderepressible 2 (Gcn2) were fed an amino acid complete diet or a diet devoid of either leucine or sulfur amino acids (methionine and cysteine). Serum and liver leucine concentrations were significantly reduced within the first 6 h of feeding a diet lacking leucine, corresponding with modest, GCN2‐dependent increases in Atf4 mRNA translation and induction of selected ISR target genes (Fgf21, Slc7a5, Slc7a11). In contrast, dietary removal of the sulfur amino acids lowered serum methionine, but not intracellular methionine, and yet hepatic mRNA abundance of Atf4, Fgf21, Slc7a5, Slc7a11 substantially increased regardless of GCN2 status. Liver tRNA charging levels did not correlate with intracellular EAA concentrations or GCN2 status and remained similar to mice fed a complete diet. Furthermore, loss of Gcn2 increased the occurrence of ribosome collisions in liver and derepressed mechanistic target of rapamycin complex 1 signal transduction, but these changes did not influence execution of the ISR. We conclude that ISR activation is directed by intracellular EAA concentrations, but ISR execution is not. Furthermore, a diet devoid of sulfur amino acids does not require GCN2 for the ISR to execute changes to the transcriptome.