title: Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase.
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.
authors: Department of Gastroenterology, Hepatology, and Infectious Diseases.
authors: Natalia
authors: N
authors: Qvartskhava
authors: Department of Gastroenterology, Hepatology, and Infectious Diseases, Department of Molecular Medicine II.
authors: Philipp A
authors: PA
authors: Lang
authors: Department of Gastroenterology, Hepatology, and Infectious Diseases.
authors: Boris
authors: B
authors: Görg
authors: Department of Gastroenterology, Hepatology, and Infectious Diseases.
authors: Vitaly I
authors: VI
authors: Pozdeev
authors: Department of Gastroenterology, Hepatology, and Infectious Diseases.
authors: Marina Pascual
authors: MP
authors: Ortiz
authors: Institute of Immunology, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany; and.
authors: Karl S
authors: KS
authors: Lang
authors: Cécile and Oskar Vogt Institute for Brain Research, and.
authors: Hans J
authors: HJ
authors: Bidmon
authors: Department of Gastroenterology, Hepatology, and Infectious Diseases.
authors: Elisabeth
authors: E
authors: Lang
authors: Department of Physiology, University of Tübingen, 72076 Tübingen, Germany.
authors: Christina B
authors: CB
authors: Leibrock
authors: Department of General Pediatrics, Neonatology, and Pediatric Cardiology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;
authors: Diran
authors: D
authors: Herebian
authors: Department of Gastroenterology, Hepatology, and Infectious Diseases.
authors: Johannes G
authors: JG
authors: Bode
authors: Department of Physiology, University of Tübingen, 72076 Tübingen, Germany.
authors: Florian
authors: F
authors: Lang
authors: Department of Gastroenterology, Hepatology, and Infectious Diseases, haeussin@uni-duesseldorf.de.
authors: Dieter
authors: D
authors: Häussinger
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018390:Gene Targeting; D005974:Glutamate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism*; D022124:Hyperammonemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D008124:Locomotion; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics
chemical_list: D005974:Glutamate-Ammonia Ligase
keywords: RNA oxidation; glutamine; hepatic encephalopathy; metabolic zonation; oxidative stress