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: Natalia Qvartskhava, Philipp A Lang, Boris Görg, Vitaly I Pozdeev, Marina Pascual Ortiz, Karl S Lang, Hans J Bidmon, Elisabeth Lang, Christina B Leibrock, Diran Herebian, Johannes G Bode, Florian Lang, Dieter Häussinger
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 17 Pg. 5521-6 (Apr 28 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25870278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glutamate-Ammonia Ligase

Topics

• Animals
• Behavior, Animal
• Brain (metabolism, pathology, physiopathology)
• Disease Models, Animal
• Gene Targeting
• Glutamate-Ammonia Ligase (genetics, metabolism)
• Hyperammonemia (enzymology, genetics, pathology, physiopathology)
• Liver (enzymology, metabolism, physiopathology)
• Locomotion
• Memory
• Mice
• Mice, Knockout
• Oxidative Stress (genetics)