ArticleAmerican journal of physiology. Endocrinology and metabolism2015
GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment.
Article in American journal of physiology. Endocrinology and metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 51 citations in OpenAlex.
- The hallmarks of protein and amino acid restriction in aging and longevity.Cell press blue · 2026Article
- Amino acid insufficiency impairs hepatic vitamin A mobilization in mice.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Manipulating dietary protein and amino acids in the common marmoset Callithrix jacchus impacts circulating metabolites and FGF21 levels.Scientific reports · 2025Article
- Calaspargase pegol and pegaspargase cause similar hepatosteatosis in mice.Haematologica · 2025Article
- The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21.Science advances · 2025Article
- Autophagy-related 7 (ATG7) regulates food intake and liver health during asparaginase exposure.The Journal of biological chemistry · 2025Article
- Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation.Cancers · 2024Review
- GCN2 is required to maintain core body temperature in mice during acute cold.American journal of physiology. Endocrinology and metabolism · 2023Article
- A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis.Science translational medicine · 2023Article
- Growth-Promoting Effects of Zhenqi Granules on Finishing Pigs.Animals : an open access journal from MDPI · 2022Article
- Sensing of the non-essential amino acid tyrosine governs the response to protein restriction in Drosophila.Nature metabolism · 2022Article
- Activation and execution of the hepatic integrated stress response by dietary essential amino acid deprivation is amino acid specific.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation.Redox biology · 2022Article
- Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice.Acta pharmaceutica Sinica. B · 2021Article
- Protein Appetite at the Interface between Nutrient Sensing and Physiological Homeostasis.Nutrients · 2021Review
- HepaticNutrients · 2021Article
- Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution.Nature communications · 2020Article
- Altered nutrient status reprograms host inflammation and metabolic health via gut microbiota.The Journal of nutritional biochemistry · 2020Review
- FGF21 and the Physiological Regulation of Macronutrient Preference.Endocrinology · 2020Review
- Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges.International journal of molecular sciences · 2019Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
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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