title: Obesity challenges the hepatoprotective function of the integrated stress response to asparaginase exposure in mice.
abstract: 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, aloneversusalongside 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 ofGcn2intensified hepatic PERK activation to asparaginase, yet surprisingly, mRNA levels of key ISR gene targets such asAtf5andTrib3failed 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 ofAtf4expression, whereas hydrogen sulfide production is promoted via GCN2-ATF4 pathway.
authors.affiliation: From the Department of Nutritional Sciences, and.
authors.forename: Inna A
authors.initials: IA
authors.lastname: Nikonorova
authors.affiliation: the Endocrinology and Animal Biosciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901.
authors.forename: Rana J T
authors.initials: RJT
authors.lastname: Al-Baghdadi
authors.affiliation: From the Department of Nutritional Sciences, and.
authors.forename: Emily T
authors.initials: ET
authors.lastname: Mirek
authors.affiliation: From the Department of Nutritional Sciences, and.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Nutritional Sciences, and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Goudie
authors.affiliation: From the Department of Nutritional Sciences, and.
authors.forename: Berish B
authors.initials: BB
authors.lastname: Wetstein
authors.affiliation: From the Department of Nutritional Sciences, and.|the Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, New Brunswick, New Jersey 08901.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Dixon
authors.affiliation: the Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hine
authors.affiliation: the Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115.
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
authors.affiliation: the Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, and.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
authors.affiliation: the Department of Biochemistry and Molecular Biology, Indiana University, School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Ronald C
authors.identifier: 0000-0002-2087-5504
authors.initials: RC
authors.lastname: Wek
authors.affiliation: From the Department of Nutritional Sciences, and tracy.anthony@rutgers.edu.|the Endocrinology and Animal Biosciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901.|the Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, New Brunswick, New Jersey 08901.
authors.forename: Tracy G
authors.identifier: 0000-0002-8586-5884
authors.initials: TG
authors.lastname: Anthony
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics; D051696:Activating Transcription Factors / Q000378:metabolism; D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism; D001215:Asparaginase / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D005978:Glutathione / Q000737:chemistry; D006862:Hydrogen Sulfide / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D009765:Obesity / Q000378:metabolism*; D010544:Peroxidases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D000084622:Sestrins
chemical_list: D051701:Activating Transcription Factor 4; D051696:Activating Transcription Factors; D053299:Apolipoprotein B-100; D001215:Asparaginase; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D005978:Glutathione; D006862:Hydrogen Sulfide; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010544:Peroxidases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C471855:Atf5 protein, mouse; C474830:TRB3 protein, mouse; C529380:Sesn2 protein, mouse; D000084622:Sestrins; C070634:Eif2ak4 protein, mouse
keywords: PKR-like endoplasmic reticulum kinase (PERK); activating transcription factor 4 (ATF4); eukaryotic initiation factor 2 (eIF2); general control nonderepressible 2 (GCN2); hydrogen sulfide; integrated stress response; liver; mammalian target of rapamycin (mTOR); obesity; sestrin2