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ResearchIn-Press PreviewHepatologyMetabolism Open Access | 10.1172/JCI163508

Asparagine protects pericentral hepatocytes during acute liver injury

Yu Sun,1 Hadrien Demagny,1 Adrien Faure,1 Francesca Pontanari,1 Antoine Jalil,1 Nadia Bresciani,1 Ece Yildiz,1 Melanie Korbelius,1 Alessia Perino,1 and Kristina Schoonjans1

1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

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1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

2Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Austria

Find articles by Schoonjans, K. in: JCI | PubMed | Google Scholar

Published January 31, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI163508.
Copyright © 2023, Sun et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 31, 2023 - Version history
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Abstract

The non-essential 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 two models of acute liver injury: carbon tetrachloride (CCl4) and acetaminophen (APAP). We found that mice with hepatocyte-specific Asns deletion (Asnshep-/-) were more prone to pericentral liver damage than their control (Asnshep+/+) littermates after toxin exposure. This phenotype could be reverted by intravenous administration of asparagine. Unexpectedly, the stress-induced upregulation of ASNS involved an ATF4-independent, non-canonical 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 intravenous delivery of asparagine can dampen hepatotoxin-induced pericentral hepatocellular death.

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