GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment
Open accessAbstract
The antileukemic agent asparaginase triggers the amino acid response (AAR) in the liver by activating the eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2). To explore the mechanism by which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent liver dysfunction during continued asparaginase treatment, wild-type and Gcn2 null mice were injected once daily with asparaginase or phosphate buffered saline for up to 14 days. Asparaginase induced mRNA expression of multiple AAR genes and greatly increased circulating concentrations of the metabolic hormone fibroblast growth factor 21 (FGF21) independent of food intake. Loss of Gcn2 precluded mRNA expression and circulating levels of FGF21 and blocked mRNA expression of multiple genes regulating lipid synthesis and metabolism including Fas, Ppara, Pparg, Acadm, and Scd1 in both liver and white adipose tissue. Furthermore, rates of triglyceride export and protein expression of apolipoproteinB-100 were significantly reduced in the livers of Gcn2 null mice treated with asparaginase, providing a mechanistic basis for the increase in hepatic lipid content. Loss of AAR-regulated antioxidant defenses in Gcn2 null livers was signified by reduced Gpx1 gene expression alongside increased lipid peroxidation. Substantial reductions in antithrombin III hepatic expression and activity in the blood of asparaginase-treated Gcn2 null mice indicated liver dysfunction. These results suggest that the ability of the liver to adapt to prolonged asparaginase treatment is influenced by GCN2-directed regulation of FGF21 and oxidative defenses, which, when lost, corresponds with maladaptive effects on lipid metabolism and hemostasis.
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Low-protein diets, amino acid starvation, and the amino acid-depleting drug asparaginase induce plasma FGF21 levels.
“Low-protein diets (73, 85), amino acid starvation (25, 121), and the amino acid–depleting drug asparaginase (138) also induce plasma FGF21 levels.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [138]
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 [156]
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Self-citationThe clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21
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Self-citationHomeostatic responses to amino acid insufficiency
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Restriction of essential amino acids dictates the systemic response to dietary protein dilutionPreprint
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Amino acid insufficiency impairs hepatic vitamin A mobilization in mice
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Self-citation
- Authors
- Wilson, G. J., Lennox, B. A., She, P., Mirek, E. T., Al Baghdadi, R. J. T., Fusakio, M. E., Dixon, J. L., Henderson, G. C., Wek, R. C., & Anthony, T. G.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Endocrinology and Animal Biosciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, New Jersey;
- Indiana University School of Medicine (US)
- Corresponding author
- Anthony, Tracy G.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2015-02-15
- Volume
- 308
- Issue
- 4
- Pages
- E283-E293
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC4329494
- OpenAlex
- W2096510691
- Cited by
- 52
- References
- 54
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 8 · 2018: 5 · 2017: 6 · 2016: 7 · 2015: 2
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Child Health and Human Development (NICHD) (HD070487)
- HHS | NIH | National Institute of General Medical Sciences (NIGMS) (GM49164)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- GCN2, L-asparaginase, amino acid response, FGF21, hepatic lipid accumulation, eIF2 kinase, lipid export, apolipoprotein B-100, lipid peroxidation, antioxidant defense, antithrombin III, liver dysfunction, white adipose tissue, lipid metabolism
- MeSH terms
- Animals, Antineoplastic Agents, Asparaginase, Female, Fibroblast Growth Factors, Gene Expression Regulation, Homeostasis, Injections, Intraperitoneal, Liver, Male, Mice, Inbred C57BL, RNA, Messenger, Triglycerides, Lipid Peroxidation, Biomarkers, Protein Serine-Threonine Kinases, Mice, Knockout, Escherichia coli Proteins, Adipose Tissue, White, Chemical and Drug Induced Liver Injury
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