A novel amino acid signaling process governs glucose-6-phosphatase transcription.
A novel amino acid signaling process governs glucose-6-phosphatase transcription.
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DOI：
10.1016/j.isci.2021.102778
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发表时间：
2021-07-23
期刊：
影响因子：
5.8
通讯作者：
Takahashi SI
中科院分区：
文献类型：
--
作者：
Fukushima S;Nishi H;Kumano M;Yamanaka D;Kataoka N;Hakuno F;Takahashi SI
新出现的证据表明，氨基酸作为代谢调节信号。在这里，我们发现，葡萄糖-6-磷酸酶（G6 β）mRNA水平在培养的肝细胞模型中下调的氨基酸耗尽的培养基。然而，用氨基酸刺激增加了G6 β mRNA水平，表明G6 β mRNA水平以可逆的方式直接受氨基酸控制。启动子分析表明，这些氨基酸介导的G6 β mRNA水平的变化可归因于转录调控，独立于经典的激素信号通路。代谢组学分析表明，氨基酸饥饿诱导尿素循环的缺陷，减少鸟氨酸，一个主要的中间体，和补充的鸟氨酸在氨基酸耗尽的培养基中完全救出G6 β mRNA转录，类似于氨基酸刺激的效果。该途径也独立于已建立的哺乳动物雷帕霉素复合物1靶途径。总的来说，我们提出了一个假设的概念“代谢调节氨基酸信号”，可能是由鸟氨酸介导的。氨基酸独立于激素调节肝细胞中的G6 β转录尿素循环活性变化反映细胞外氨基酸浓度鸟氨酸以与蛋白原氨基酸相同的方式调节G6 β mRNA水平氨基酸/鸟氨酸信号独立于典型mTORC 1途径自然科学;生物科学;生物化学;分子生物学;基因调节的分子机制;细胞生物学;代谢组学
Emerging evidence has shown that amino acids act as metabolic regulatory signals. Here, we showed that glucose-6-phosphatase (G6Pase) mRNA levels in cultured hepatocyte models were downregulated in an amino-acid-depleted medium. Inversely, stimulation with amino acids increased G6Pase mRNA levels, demonstrating that G6Pase mRNA level is directly controlled by amino acids in a reversible manner. Promoter assay revealed that these amino-acid-mediated changes in G6Pase mRNA levels were attributable to transcriptional regulation, independent of canonical hormone signaling pathways. Metabolomic analysis revealed that amino acid starvation induces a defect in the urea cycle, decreasing ornithine, a major intermediate, and supplementation of ornithine in an amino-acid-depleted medium fully rescued G6Pase mRNA transcription, similar to the effects of amino acid stimulation. This pathway was also independent of established mammalian target of rapamycin complex 1 pathway. Collectively, we present a hypothetical concept of “metabolic regulatory amino acid signal,” possibly mediated by ornithine. Amino acids regulate G6Pase transcription in hepatocytes independently of hormones Urea cycle activity changes reflecting the extracellular amino acid concentration Ornithine regulates G6Pase mRNA level in the same manner as proteinogenic amino acids Amino acids/ornithine signals are independent of canonical mTORC1 pathway Natural sciences; Biological sciences; Biochemistry; Molecular biology; Molecular mechanism of gene regulation; Cell biology; Metabolomics
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影响因子：
4.6
作者：
Nishi H;Yamanaka D;Kamei H;Goda Y;Kumano M;Toyoshima Y;Takenaka A;Masuda M;Nakabayashi Y;Shioya R;Kataoka N;Hakuno F;Takahashi SI
通讯作者：
Takahashi SI
调节健康和疾病中肝葡萄糖代谢。
DOI：
10.1038/nrendo.2017.80
发表时间：
2017-10
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
Petersen MC;Vatner DF;Shulman GI
通讯作者：
Shulman GI
影响因子：
5.8
作者：
ALBAROTH, J;MULLER, OA;VONWERDER, K
通讯作者：
VONWERDER, K
影响因子：
--
作者：
Kokubo, Takeshi;Maeda, Shyuichi;Kirisako, Takayoshi
通讯作者：
Kirisako, Takayoshi
DOI：
10.1038/nrm3522
发表时间：
2013-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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