Cited by 246Fibroblast Growth Factor ResearchEndoplasmic Reticulum Stress and DiseaseDietary Effects on Health

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Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation

De Sousa-Coelho, Ana Luísa, Marrero, Pedro F., Haro, Diego·2012·Biochemical Journal

DOI 10.1042/bj20111748

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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.

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Authors: De Sousa-Coelho, A. L., Marrero, P. F., & Haro, D.
Affiliations: 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
Institut de Biomedicina de la Universitat de Barcelona (ES)
ORCID: Marrero, Pedro F.
Haro, Diego
Venue: Biochemical Journal
Publisher: Portland Press Ltd.
Published: 2012-03-14
Volume: 443
Issue: 1
Pages: 165-171
ISSN: 0264-6021 (ISSN-L)
1470-8728
DOI: 10.1042/bj20111748
OpenAlex: W2108364290
Cited by: 246
References: 43
Citations by year: 2026: 7 · 2025: 11 · 2024: 21 · 2023: 12 · 2022: 28 · 2021: 20 · 2020: 17 · 2019: 15 · 2018: 23 · 2017: 19 · 2016: 23 · 2015: 19 · 2014: 16 · 2013: 10 · 2012: 5
FWCI: 6.41
Type: journal article
Language: en
Open access: closed
Locations: Biochemical Journal (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
Keywords: FGF21, ATF4, amino acid starvation, nutrient deprivation, GCN2, eIF2α phosphorylation, transcriptional activation, 5' regulatory region, hepatic gene expression, fasting adaptation, HepG2 cells, mouse liver
MeSH terms: Amino Acids, Animals, Base Sequence, Fibroblast Growth Factors, Gene Expression Regulation, Humans, Leupeptins, Liver, Male, Mice, Inbred C57BL, Protein Binding, Transcription, Genetic, Transcriptional Activation, Conserved Sequence, Response Elements, Electrophoretic Mobility Shift Assay, Proteasome Endopeptidase Complex, Mice, Activating Transcription Factor 4, Hep G2 Cells, Proteasome Inhibitors

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Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation

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