title: Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation.
abstract: Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation factor 2), global protein synthesis reduction and increased ATF4 (activating transcription factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5' regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent transcriptional activation of this gene. These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Pharmacy and the Institute of Biomedicine of the University of Barcelona (IBUB), Av. Joan XXIII s/n, E-08028 Barcelona, Spain.
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: De Sousa-Coelho
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Marrero
authors.forename: Diego
authors.initials: D
authors.lastname: Haro
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000172:deficiency*; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D024202:Electrophoretic Mobility Shift Assay; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D020218:Response Elements; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C497109:ATF4 protein, human; D000596:Amino Acids; D007976:Leupeptins; D061988:Proteasome Inhibitors; C414620:fibroblast growth factor 21; D051701:Activating Transcription Factor 4; D005346:Fibroblast Growth Factors; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde