A novel amino acid signaling process governs glucose-6-phosphatase transcription
Sara Fukushima,
Hiroki Nishi,
Mikako Kumano,
Daisuke Yamanaka,
Naoyuki Kataoka,
Fumihiko Hakuno,
Shin-Ichiro Takahashi
Affiliations
Sara Fukushima
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
Hiroki Nishi
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
Mikako Kumano
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
Daisuke Yamanaka
Department of Veterinary Medical Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
Naoyuki Kataoka
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
Fumihiko Hakuno
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; Corresponding author
Shin-Ichiro Takahashi
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; Corresponding author
Summary: 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.
