Asparagine protects pericentral hepatocytes during acute liver injury
Yu Sun, … , Alessia Perino, Kristina Schoonjans
Yu Sun, … , Alessia Perino, Kristina Schoonjans
Published January 31, 2023
Citation Information: J Clin Invest. 2023;133(7):e163508. https://doi.org/10.1172/JCI163508.
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Research Article Hepatology Metabolism

Asparagine protects pericentral hepatocytes during acute liver injury

Abstract

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.

Authors

Yu Sun, Hadrien Demagny, Adrien Faure, Francesca Pontanari, Antoine Jalil, Nadia Bresciani, Ece Yildiz, Melanie Korbelius, Alessia Perino, Kristina Schoonjans

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Figure 7

Asparagine treatment rescues Asns depletion-induced cell death and liver damage.

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Asparagine treatment rescues Asns depletion-induced cell death and liver...
(A) Asparagine (Asn) over aspartate (Asp) ratio and glutamate (Glu) over glutamine (Gln) ratio in livers of untreated Asnshep+/+ and Asnshep–/– mice. n = 6 animals for each group. (B) Workflow of asparagine delivery upon CCl4 treatment. Mice were i.p. injected with CCl4 followed by 2 i.v. injections of 240 mg/kg asparagine (Asn) or PBS 1 hour and 8 hours later. (C) Serum ALT activity of Asnshep+/+ and Asnshep–/– mice subjected to the treatment described in (B). n = 6 (CCl4 of Asnshep+/+ and Asnshep–/–) and n = 7 (CCl4 + Asn of Asnshep+/+ and Asnshep–/–). (D) Representative images of TUNEL assay and immunohistochemistry analysis of p-H2A.X in livers from (C). Scale bar: 100 μm. Quantification results are indicated on the right. (E–F) Serum ALT activity and quantification results of TUNEL staining in livers from CCl4-treated Asnshep+/+ and Asnshep–/– mice, followed by i.v. injection of glutamate (Glu) or valine (Val). n = 6 (Asnshep+/+ CCl4, CCl4 + Glu and CCl4 + Val); n = 7 (CCl4 of Asnshep–/–); and n = 5 (Asnshep–/– CCl4 + Glu and CCl4 + Val). (G) Representative images and quantification results of TUNEL assay in livers from APAP-treated Asnshep+/+ and Asnshep–/– mice, followed by asparagine (Asn) i.v. injection. n = 6 animals for each group. Error bars denote SEM. Statistical analysis was performed by unpaired t test (A) and 2-way ANOVA followed by Bonferroni’s posthoc test (C–G). *P < 0.05; **P < 0.01.