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.
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Research Article|
March 14 2012
Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation
Ana Luísa De Sousa-Coelho;
Ana Luísa De Sousa-Coelho
1Department 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
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Pedro F. Marrero;
Pedro F. Marrero
1Department 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
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Diego Haro
Diego Haro
1
1Department 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
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 03 2011
Revision Received:
January 10 2012
Accepted:
January 11 2012
Accepted Manuscript online:
January 11 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (1): 165–171.
Article history
Received:
October 03 2011
Revision Received:
January 10 2012
Accepted:
January 11 2012
Accepted Manuscript online:
January 11 2012
Citation
Ana Luísa De Sousa-Coelho, Pedro F. Marrero, Diego Haro; Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J 1 April 2012; 443 (1): 165–171. doi: https://doi.org/10.1042/BJ20111748
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