Cited by 52Fibroblast Growth Factor ResearchDrug-Induced Hepatotoxicity and ProtectionCancer, Lipids, and Metabolism

GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment

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Wilson, Gabriel J., Lennox, Brittany A., She, Pengxiang, Mirek, Emily T., Al Baghdadi, Rana J. T., Fusakio, Michael E., Dixon, Joseph L., Henderson, Gregory C. +2 more·2015·American Journal of Physiology-Endocrinology and Metabolism

Abstract

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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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
Published
2015-02-15
Volume
308
Issue
4
Pages
E283-E293
ISSN
  • 0193-1849 (ISSN-L)
  • 1522-1555
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
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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