摘要：SummaryEmerging 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.Graphical abstractDisplay OmittedHighlights•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 pathwayNatural sciences; Biological sciences; Biochemistry; Molecular biology; Molecular mechanism of gene regulation; Cell biology; Metabolomics
