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Cited by 98Amino Acid Enzymes and MetabolismMetabolism and Genetic DisordersLiver Disease and Transplantation

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

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Qvartskhava, Natalia, Lang, Philipp A., Görg, Boris, Pozdeev, Vitaly I., Ortiz, Marina Pascual, Lang, Karl S., Bidmon, Hans J., Lang, Elisabeth +5 more·2015·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1423968112PMC PMC4418919
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Abstract

Significance: Ammonia metabolism in the liver is critical to prevent serious clinical conditions, such as hepatic encephalopathy. It was hypothesized that the Gln synthetase (GS) can metabolize ammonia with high affinity in the perivenous region of the liver. However, the in vivo relevance of this metabolic pathway remains unclear in view of other intra- and extrahepatic ammonia metabolizing pathways. Here, we show by creating a conditional GS KO mouse that specific deletion of the GS in the liver results in increased ammonia levels in the blood, induction of oxidative stress in brain tissue, and behavior abnormalities. In conclusion, GS in the liver is a key player in the maintenance of ammonia homeostasis.

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  • EC-derived RSPO3 regulates only the most pericentral WNThigh hepatocytes that have a key role in the liver's glutamine synthesis and ammonia detoxification.

    “By contrast, EC-derived RSPO3 regulates only the most pericentral WNThigh hepatocytes that have a key role in the liver’s glutamine synthesis and ammonia detoxification44.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [44]

    The Discussion (page not provided) identifies a small population of perivenous hepatocytes whose glutamine synthetase is pivotal for ammonia detoxification, and notes that its expression depends on Wnt-mediated β-catenin activation. The paper does not establish that endothelial-cell-derived RSPO3 regulates only those hepatocytes, or identify them as WNT-high. (LLM, conf=0.88)

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References 61 · Cited by 98

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Authors
Qvartskhava, N., Lang, P. A., Görg, B., Pozdeev, V. I., Ortiz, M. P., Lang, K. S., Bidmon, H. J., Lang, E., Leibrock, C. B., Herebian, D., Bode, J. G., Lang, F., & Häussinger, D.
Affiliations
  • Department of Gastroenterology, Hepatology, and Infectious Diseases,
  • University of Duisburg-Essen (DE)
  • Cécile and Oskar Vogt Institute for Brain Research, and
  • University of Tübingen (DE)
  • Heinrich Heine University Düsseldorf (DE)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-04-13
Volume
112
Issue
17
Pages
5521-5526
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1423968112
PMC
PMC4418919
OpenAlex
W2091311110
Cited by
98
References
61
Citations by year
2026: 11 · 2025: 7 · 2024: 14 · 2023: 13 · 2022: 11 · 2021: 7 · 2020: 6 · 2019: 10 · 2018: 3 · 2017: 9 · 2016: 5 · 2015: 2
FWCI
3.16
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 183 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (SFB575, SFB974)
  • Heinrich-Heine-Universität Düsseldorf (VIVID)
  • Alexander von Humboldt-Stiftung (SKP2010)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
Keywords
hyperammonemia, glutamine synthetase, liver-specific knockout mice, tyrosine nitration, fear memory, locomotion, lifespan
MeSH terms
Animals, Behavior, Animal, Brain, Disease Models, Animal, Glutamate-Ammonia Ligase, Liver, Locomotion, Memory, Mice, Knockout, Oxidative Stress, Gene Targeting, Hyperammonemia, Mice

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