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Loss of Activating Transcription Factor 4 (ATF4) Alters the Homeostatic Amino Acid Response (AAR) in the Liver of Mice Treated with Asparaginase
Author(s) -
AlBaghdadi Rana,
Mirek Emily,
PhillipsonWeiner Lindsey,
Belden William,
Wek Ronald,
Anthony Tracy
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.973.3
Subject(s) - atf4 , inflammation , endocrinology , medicine , integrated stress response , unfolded protein response , biology , immunology , apoptosis , biochemistry , messenger rna , gene , translation (biology)
L‐asparaginase (ASNase) is widely used to treat leukemia in children but it causes metabolic complications and liver toxicity. ASNase activates the amino acid response (AAR), increasing gene‐specific translation of the transcription factor ATF4 to regain homeostasis via altered gene expression. We hypothesized that ATF4 deficiency would compromise the hepatic AAR to ASNase and augment hepatotoxicity. Intact ( Atf4 wt ), heterozygous ( Atf4 het ) and homozygous null ( Atf4 null ) mice were administered ASNase (3 IU/g BW i.p.) or saline once daily for 8d. Blood and tissues were collected 8h after final injection. Atf4 null mice treated with ASNase lost body weight and experienced premature mortality while all other strains appeared healthy. ASNase did not alter liver mass but promoted lipid accumulation in all genetic strains of mice to a similar degree. Phosphorylation of eIF2 was increased in the liver of all mice treated with ASNase and in saline‐injected Atf4 null mice. Examination of the hepatic AAR showed many genes including Asns , Atf5 , Chop , Fgf21 , 4ebp1 and Gadd34 required ATF4 for full induction. Furthermore, inflammatory stress was evident in the liver of Atf4 null but not Atf4 het or Atf4 wt mice treated with ASNase, similar to that previously reported in Gcn2 null mice (AJP 305:E1124, 2013). These results suggest that ATF4 mediates GCN2‐driven hepatic adaptive responses to ASNase and prevents liver inflammation but not lipid accumulation. HD070487 (TGA); GM49164 (RCW)