Hepatic Steatosis and Severe Coagulopathy Precede Premature Death in GCN2 Null Mice Treated with Asparaginase

Abstract

The anti‐leukemic agent Asparaginase (ASNase) triggers the amino acid stress response (AAR) in liver by activating the eukaryotic initiation factor 2 (eIF2) kinase GCN2. We hypothesize that liver dysfunction and metabolic complications associated with ASNase are related to deficiencies in the GCN2‐directed AAR. To address this hypothesis, wildtype (WT) and GCN2 null mice were injected once‐daily for 14 d with 0 or 3 IU/g BW of E. Coli ASNase. WT mice administered ASNase for 14 d demonstrated no change in BW or liver size and appeared healthy. In contrast, GCN2 nulls suffered ~20% decreased bodyweight, hepatic steatosis, internal bleeding, and 100% mortality by d 12. Phosphorylation of eIF2 and expression of AAR targets ATF4, ATF5, 4E‐BP1 and CHOP were increased in the liver of WT but not GCN2 null mice treated with ASNase. Furthermore, WT mice treated with ASNase demonstrated a 17‐fold increase in FGF‐21 in liver as compared to WT mice treated with excipient; in contrast, GCN2 nulls treated with ASNase showed a 80% reduction in FGF‐21 as compared to excipient‐treated controls. FGF‐21 is critically important for inducing hepatic fat oxidation, ketogenesis and gluconeogenesis. Thus, the ability of liver metabolism to adapt to ASNase depends in part on the ability of the GCN2‐directed AAR pathway to activate FGF‐21.