Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice.
Obesity increases risk for liver toxicity by the anti-leukemic agent asparaginase, but the mechanism is unknown. Asparaginase activates the integrated stress response (ISR) via sensing amino acid depletion by the eukaryotic initiation factor 2 (eIF2) kinase GCN2. The goal of this work was to discern the impact of obesity, alone versus alongside genetic disruption of the ISR, on mechanisms of liver protection during chronic asparaginase exposure in mice. Following diet-induced obesity, biochemical analysis of livers revealed that asparaginase provoked hepatic steatosis that coincided with activation of another eIF2 kinase PKR-like endoplasmic reticulum kinase (PERK), a major ISR transducer to ER stress. Genetic loss of Gcn2 intensified hepatic PERK activation to asparaginase, yet surprisingly, mRNA levels of key ISR gene targets such as Atf5 and Trib3 failed to increase. Instead, mechanistic target of rapamycin complex 1 (mTORC1) signal transduction was unleashed, and this coincided with liver dysfunction reflected by a failure to maintain hydrogen sulfide production or apolipoprotein B100 (ApoB100) expression. In contrast, obese mice lacking hepatic activating transcription factor 4 (Atf4) showed an exaggerated ISR and greater loss of endogenous hydrogen sulfide but normal inhibition of mTORC1 and maintenance of ApoB100 during asparaginase exposure. In both genetic mouse models, expression and phosphorylation of Sestrin2, an ATF4 gene target, was increased by asparaginase, suggesting mTORC1 inhibition during asparaginase exposure is not driven via eIF2-ATF4-Sestrin2. In conclusion, obesity promotes a maladaptive ISR during asparaginase exposure. GCN2 functions to repress mTORC1 activity and maintain ApoB100 protein levels independently of Atf4 expression, whereas hydrogen sulfide production is promoted via GCN2-ATF4 pathway.
['Nikonorova|Inna A|IA|', 'Al-Baghdadi|Rana J T|RJT|', 'Mirek|Emily T|ET|', 'Wang|Yongping|Y|', 'Goudie|Michael P|MP|', 'Wetstein|Berish B|BB|', 'Dixon|Joseph L|JL|', 'Hine|Christopher|C|', 'Mitchell|James R|JR|', 'Adams|Christopher M|CM|', 'Wek|Ronald C|RC|0000-0002-2087-5504', 'Anthony|Tracy G|TG|0000-0002-8586-5884']
D051701:Activating Transcription Factor 4 D051696:Activating Transcription Factors D000818:Animals D053299:Apolipoprotein B-100 D001215:Asparaginase D018797:Cell Cycle Proteins D004195:Disease Models, Animal D015852:Eukaryotic Initiation Factor-2 D005234:Fatty Liver D017353:Gene Deletion D005978:Glutathione D006862:Hydrogen Sulfide D008099:Liver D000076222:Mechanistic Target of Rapamycin Complex 1 D051379:Mice D008810:Mice, Inbred C57BL D008820:Mice, Obese D008822:Mice, Transgenic D046912:Multiprotein Complexes D009687:Nuclear Proteins D009765:Obesity D010544:Peroxidases D017346:Protein Serine-Threonine Kinases D058570:TOR Serine-Threonine Kinases D019892:eIF-2 Kinase
obesity integrated stress response liver eukaryotic initiation factor 2 (eIF2) PKR-like endoplasmic reticulum kinase (PERK) hydrogen sulfide activating transcription factor 4 (ATF4) sestrin2 general control nonderepressible 2 (GCN2) mammalian target of rapamycin (mTOR)