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Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5521-6. doi: 10.1073/pnas.1423968112. Epub 2015 Apr 13.

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase.

Author information

1
Department of Gastroenterology, Hepatology, and Infectious Diseases.
2
Department of Gastroenterology, Hepatology, and Infectious Diseases, Department of Molecular Medicine II.
3
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany; and.
4
Cécile and Oskar Vogt Institute for Brain Research, and.
5
Department of Physiology, University of Tübingen, 72076 Tübingen, Germany.
6
Department of General Pediatrics, Neonatology, and Pediatric Cardiology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;
7
Department of Gastroenterology, Hepatology, and Infectious Diseases, haeussin@uni-duesseldorf.de.

Abstract

Urea cycle defects and acute or chronic liver failure are linked to systemic hyperammonemia and often result in cerebral dysfunction and encephalopathy. Although an important role of the liver in ammonia metabolism is widely accepted, the role of ammonia metabolizing pathways in the liver for maintenance of whole-body ammonia homeostasis in vivo remains ill-defined. Here, we show by generation of liver-specific Gln synthetase (GS)-deficient mice that GS in the liver is critically involved in systemic ammonia homeostasis in vivo. Hepatic deletion of GS triggered systemic hyperammonemia, which was associated with cerebral oxidative stress as indicated by increased levels of oxidized RNA and enhanced protein Tyr nitration. Liver-specific GS-deficient mice showed increased locomotion, impaired fear memory, and a slightly reduced life span. In conclusion, the present observations highlight the importance of hepatic GS for maintenance of ammonia homeostasis and establish the liver-specific GS KO mouse as a model with which to study effects of chronic hyperammonemia.

KEYWORDS:

RNA oxidation; glutamine; hepatic encephalopathy; metabolic zonation; oxidative stress

PMID:
25870278
PMCID:
PMC4418919
DOI:
10.1073/pnas.1423968112
[Indexed for MEDLINE]
Free PMC Article

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