期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：17
页码：5521-5526
DOI：10.1073/pnas.1423968112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAmmonia 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. 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.
