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.
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The Fgf21 promoter has multiple ATF4 binding sites, and GCN2-mediated activation of ATF4 leads to induction of hepatic and circulating FGF21.
“The Fgf21 promoter has multiple ATF4 binding sites, and GCN2-mediated activation of ATF4 leads to the induction of hepatic and circulating levels of FGF21 (24, 68, 72).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [24]
FGF21 is also increased by the restriction of individual amino acids.
“with FGF21 also being increased by the restriction of individual amino acids”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [153]
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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)
- 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
- 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 › 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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