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HORMONES AND SIGNALING

Amino acid control of the human glyceraldehyde 3-phosphate dehydrogenase gene transcription in hepatocyte

¹EA 3234 and I.F.R. 23, Faculté de Médecine-Pharmacie, 76183 Rouen; ²Institut National de la Santé et de la Recherche Médicale Unité 519 and I.F.R. 23, Faculté de Médecine-Pharmacie, 76183 Rouen, France; and ³Department of Legal Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan 755-8505

Submitted 6 February 2003 ; accepted in final form 25 June 2003

Glutamine (Gln) is the most potent of the amino acids (AAs) that regulate liver anabolism, and its effect is similar to that of insulin in peripheral tissues. However, the influence of AAs on regulation of metabolic enzyme-encoding genes is not known at the molecular level in liver. We now report that Gln and some essential AAs activate the human GAPDH gene that codes for GAPDH, a central enzyme of glycolysis and a target for insulin regulation. In HepG2 cells, Gln upregulated the GAPDH mRNA level, and this effect was additive to that of insulin. Transient transfection of GAPDH promoter/cat constructs demonstrated that a gene-specific and insulin-independent transcriptional step is involved in the Gln responsiveness of GAPDH. Transfected HepG2 cells challenged with various AAs, Gln metabolites or inhibitors of Gln metabolism showed that the Gln-induced effect is similar to that of some essential AAs and that Gln metabolism is a necessary step for GAPDH activation. Deletion mutants and site-directed mutagenesis of the GAPDH promoter indicated that the Gln responsiveness is mediated by a sequence that is distinct from insulin-responsive elements and from positively acting elements previously described in this promoter. This motif located at -126/-118 clearly differs from AA-responsive elements recently identified in other genes. Electromobility shift assay and supershifts showed that the transcription factors bound to the Gln-responsive element in the GAPDH promoter are C/EBP and -. This finding is consistent with the role of C/EBP family members in controlling the hepatic expression of genes involved in nutrient metabolism.

amino acid-responsive element; glutamine; insulin; transcription factor

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