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

Am J Physiol Endocrinol Metab. 2015 Feb 15;308(4):E283-93. doi: 10.1152/ajpendo.00361.2014. Epub 2014 Dec 9.


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.

Keywords: adipose; amino acid response; antithrombin III; apolipoprotein B-100; eukaryotic initiation factor 2; fibroblast growth factor 21; general control nonderepressible 2; liver; mice; oxidative stress; steatosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / pathology
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Asparaginase / administration & dosage
  • Asparaginase / adverse effects*
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology
  • Escherichia coli Proteins / administration & dosage
  • Escherichia coli Proteins / adverse effects
  • Female
  • Fibroblast Growth Factors / agonists*
  • Fibroblast Growth Factors / blood
  • Gene Expression Regulation / drug effects
  • Homeostasis / drug effects
  • Injections, Intraperitoneal
  • Lipid Peroxidation / drug effects
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Triglycerides / metabolism*


  • Antineoplastic Agents
  • Biomarkers
  • Escherichia coli Proteins
  • RNA, Messenger
  • Triglycerides
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Eif2ak4 protein, mouse
  • Protein Serine-Threonine Kinases
  • Asparaginase