Fukushima Sara, Nishi Hiroki, Kumano Mikako, Yamanaka Daisuke, Kataoka Naoyuki, Hakuno Fumihiko, Takahashi Shin-Ichiro
Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Department of Veterinary Medical Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
iScience. 2021 Jun 24;24(7):102778. doi: 10.1016/j.isci.2021.102778. eCollection 2021 Jul 23.
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.
新出现的证据表明，氨基酸作为代谢调节信号。在此，我们表明，在培养的肝细胞模型中，葡萄糖-6-磷酸酶（G6Pase）mRNA水平在氨基酸缺乏的培养基中下调。相反，用氨基酸刺激可增加G6Pase mRNA水平，表明G6Pase mRNA水平以可逆方式直接受氨基酸控制。启动子分析显示，这些氨基酸介导的G6Pase mRNA水平变化归因于转录调控，独立于经典激素信号通路。代谢组学分析表明，氨基酸饥饿会导致尿素循环缺陷，减少主要中间体鸟氨酸，并且在氨基酸缺乏的培养基中补充鸟氨酸可完全挽救G6Pase mRNA转录，类似于氨基酸刺激的效果。该途径也独立于已确定的哺乳动物雷帕霉素靶蛋白复合物1途径。总的来说，我们提出了一个“代谢调节氨基酸信号”的假设概念，可能由鸟氨酸介导。
