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

Gabriel J. Wilson, Brittany A. Lennox, Pengxiang She, Emily T. Mirek, Rana J T Al Baghdadi, Michael E. Fusakio, Joseph L. Dixon, Gregory C. Henderson, Ronald Wek, Tracy G. Anthony

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The antileu-kemic 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 aspara-ginase 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.

Original languageEnglish
Pages (from-to)E283-E293
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume308
Issue number4
DOIs
StatePublished - 2015

Fingerprint

Asparaginase
Triglycerides
Homeostasis
Liver
Amino Acids
Lipid Metabolism
Messenger RNA
Liver Diseases
Eukaryotic Initiation Factor-2
Lipids
Gene Expression
White Adipose Tissue
Antithrombin III
fibroblast growth factor 21
Hemostasis
Lipid Peroxidation
Phosphotransferases
Eating
Antioxidants
Phosphates

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

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment. / 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.; Wek, Ronald; Anthony, Tracy G.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 308, No. 4, 2015, p. E283-E293.

Research output: Contribution to journalArticle

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. ; Wek, Ronald ; Anthony, Tracy G. / GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment. In: American Journal of Physiology - Endocrinology and Metabolism. 2015 ; Vol. 308, No. 4. pp. E283-E293.
@article{b912e6782926484e9a04ba21593adf90,
title = "GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment",
abstract = "The antileu-kemic 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 aspara-ginase 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",
author = "Wilson, {Gabriel J.} and Lennox, {Brittany A.} and Pengxiang She and Mirek, {Emily T.} and {Al Baghdadi}, {Rana J T} and Fusakio, {Michael E.} and Dixon, {Joseph L.} and Henderson, {Gregory C.} and Ronald Wek and Anthony, {Tracy G.}",
year = "2015",
doi = "10.1152/ajpendo.00361.2014",
language = "English",
volume = "308",
pages = "E283--E293",
journal = "American Journal of Physiology",
issn = "0193-1857",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment

AU - Wilson, Gabriel J.

AU - Lennox, Brittany A.

AU - She, Pengxiang

AU - Mirek, Emily T.

AU - Al Baghdadi, Rana J T

AU - Fusakio, Michael E.

AU - Dixon, Joseph L.

AU - Henderson, Gregory C.

AU - Wek, Ronald

AU - Anthony, Tracy G.

PY - 2015

Y1 - 2015

N2 - The antileu-kemic 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 aspara-ginase 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.

AB - The antileu-kemic 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 aspara-ginase 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.

KW - Adipose

KW - Amino acid response

KW - Antithrombin III

KW - Apolipoprotein B-100

KW - Eukaryotic initiation factor 2

KW - Fibroblast growth factor 21

KW - General control nonderepressible 2

KW - Liver

KW - Mice

KW - Oxidative stress

KW - Steatosis

UR - http://www.scopus.com/inward/record.url?scp=84922918736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922918736&partnerID=8YFLogxK

U2 - 10.1152/ajpendo.00361.2014

DO - 10.1152/ajpendo.00361.2014

M3 - Article

C2 - 25491724

AN - SCOPUS:84922918736

VL - 308

SP - E283-E293

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0193-1857

IS - 4

ER -