Asparagine protects pericentral hepatocytes during acute liver injury

The nonessential amino acid asparagine can only be synthesized de novo by the enzymatic activity of asparagine synthetase (ASNS). While ASNS and asparagine have been implicated in the response to numerous metabolic stressors in cultured cells, the in vivo relevance of this enzyme in stress-related p...

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Published in:The Journal of clinical investigation 2023-04, Vol.133 (7), p.1-13
Main Authors: Sun, Yu, Demagny, Hadrien, Faure, Adrien, Pontanari, Francesca, Jalil, Antoine, Bresciani, Nadia, Yildiz, Ece, Korbelius, Melanie, Perino, Alessia, Schoonjans, Kristina
Format: Article
Language:English
Subjects:
Acetaminophen
Amino Acids
Animals
Apoptosis
Asparagine
Aspartate-ammonia ligase
Biomedical research
Carbon tetrachloride
Care and treatment
Cytochrome
Detoxification
Drug overdose
Enzymatic activity
Enzymes
Health aspects
Hepatocytes
Hepatology
Hepatotoxicity
Ligases
Liver
Liver diseases
Metabolism
Metabolites
Mice
Patient outcomes
Phenotypes
Proteins
Veins & arteries
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Summary:The nonessential amino acid asparagine can only be synthesized de novo by the enzymatic activity of asparagine synthetase (ASNS). While ASNS and asparagine have been implicated in the response to numerous metabolic stressors in cultured cells, the in vivo relevance of this enzyme in stress-related pathways remains unexplored. Here, we found ASNS to be expressed in pericentral hepatocytes, a population of hepatic cells specialized in xenobiotic detoxification. ASNS expression was strongly enhanced in 2 models of acute liver injury: carbon tetrachloride (CCl4) and acetaminophen. We found that mice with hepatocyte-specific Asns deletion were more prone to pericentral liver damage than their control littermates after toxin exposure. This phenotype could be reverted by i.v. administration of asparagine. Unexpectedly, the stress-induced upregulation of ASNS involved an ATF4-independent, noncanonical pathway mediated by the nuclear receptor, liver receptor homolog 1 (LRH-1; NR5A2). Altogether, our data indicate that the induction of the asparagine-producing enzyme ASNS acts as an adaptive mechanism to constrain the necrotic wave that follows toxin administration and provide proof of concept that i.v. delivery of asparagine can dampen hepatotoxin-induced pericentral hepatocellular death.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI163508