Abstract
Asparaginase is an amino acid-depleting agent used to treat blood cancers. Metabolic complications due to asparaginase affect liver function in humans. To examine how the liver response to asparaginase changes during maturity to adulthood, here we treated juvenile (2-week), young adult (8-week), and mature adult (16-week) mice with drug or excipient for 1 week and conducted RNA-Seq and functional analyses. Asparaginase reduced body growth and liver mass in juveniles but not in the adult animals. Unbiased exploration of the effect of asparaginase on the liver transcriptome revealed that the integrated stress response (ISR) was the only molecular signature shared across the ages, corroborating similar eukaryotic initiation factor 2 phosphorylation responses to asparaginase at all ages. Juvenile livers exhibited steatosis and iron accumulation following asparaginase exposure along with a hepatic gene signature indicating that asparaginase uniquely affects lipid, cholesterol, and iron metabolism in juvenile mice. In contrast, asparaginase-treated adult mice displayed greater variability in liver function, which correlated with an acute-phase inflammatory response gene signature. Asparaginase-exposed adults also had a serine/glycine/one-carbon metabolism gene signature in liver that corresponded with reduced circulating glycine and serine levels. These results establish the ISR as a conserved response to asparaginase-mediated amino acid deprivation and provide new insights into the relationship between the liver transcriptome and hepatic function upon asparaginase exposure.
Highlights
Asparaginase is an amino acid– depleting agent used to treat blood cancers
Unbiased exploration of the effect of asparaginase on the liver transcriptome revealed that the integrated stress response (ISR) was the only molecular signature shared across the ages, corroborating similar eukaryotic initiation factor 2 phosphorylation responses to asparaginase at all ages
Our previous efforts to understand the molecular events induced by asparaginase in livers of cancerfree mice [2, 3] show that in nongrowing adults, asparaginase triggers phosphorylation of eukaryotic translation initiation factor 22 by the eIF2 kinases general control nonderepressible 2 (GCN2) and protein kinase R–like endoplasmic reticulum kinase (PERK) (2, 4 – 6)
Summary
Asparaginase is an amino acid– depleting agent used to treat blood cancers. Metabolic complications due to asparaginase affect liver function in humans. Asparaginaseexposed adults had a serine/glycine/one-carbon metabolism gene signature in liver that corresponded with reduced circulating glycine and serine levels These results establish the ISR as a conserved response to asparaginase-mediated amino acid deprivation and provide new insights into the relationship between the liver transcriptome and hepatic function upon asparaginase exposure. Age-specific differences in the liver transcriptome included inhibition of lipid and cholesterol biosynthesis and iron bioavailability in juveniles, whereas adult livers displayed increased serine/glycine/one-carbon metabolism and inflammation These results provide insight into the relationship between age and the resources available to support recovery from amino acid depletion by asparaginase
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