Premium
Pivotal role of glutamine synthetase in ammonia detoxification
Author(s) -
Hakvoort Theodorus B.M.,
He Youji,
Kulik Wim,
Vermeulen Jacqueline L.M.,
Duijst Suzanne,
Ruijter Jan M.,
Runge Jurgen H.,
Deutz Nicolaas E.P.,
Koehler S. Eleonore,
Lamers Wouter H.
Publication year - 2017
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28852
Subject(s) - glutamine synthetase , glutamine , urea cycle , hyperammonemia , glutaminase , glutamate dehydrogenase , urea , deamidation , biochemistry , medicine , ammonia , ornithine transcarbamylase , chemistry , catabolism , endocrinology , tyrosine aminotransferase , biology , metabolism , enzyme , amino acid , glutamate receptor , enzyme inducer , receptor , arginine
Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole‐body muscle‐to‐fat ratio with increased myostatin expression in muscle. Using GS‐knockout/liver and control mice and stepwise increments of enterally infused ammonia, we show that ∼35% of this ammonia is detoxified by hepatic GS and ∼35% by urea‐cycle enzymes, while ∼30% is not cleared by the liver, independent of portal ammonia concentrations ≤2 mmol/L. Using both genetic (GS‐knockout/liver and GS‐knockout/muscle) and pharmacological (methionine sulfoximine and dexamethasone) approaches to modulate GS activity, we further show that detoxification of stepwise increments of intravenously (jugular vein) infused ammonia is almost totally dependent on GS activity. Maximal ammonia‐detoxifying capacity through either the enteral or the intravenous route is ∼160 μmol/hour in control mice. Using stable isotopes, we show that disposal of glutamine‐bound ammonia to urea (through mitochondrial glutaminase and carbamoylphosphate synthetase) depends on the rate of glutamine synthesis and increases from ∼7% in methionine sulfoximine‐treated mice to ∼500% in dexamethasone‐treated mice (control mice, 100%), without difference in total urea synthesis. Conclusions: Hepatic GS contributes to both enteral and systemic ammonia detoxification. Glutamine synthesis in the periphery (including that in pericentral hepatocytes) and glutamine catabolism in (periportal) hepatocytes represents the high‐affinity ammonia‐detoxifying system of the body. The dependence of glutamine‐bound ammonia disposal to urea on the rate of glutamine synthesis suggests that enhancing peripheral glutamine synthesis is a promising strategy to treat hyperammonemia. Because total urea synthesis does not depend on glutamine synthesis, we hypothesize that glutamate dehydrogenase complements mitochondrial ammonia production. (H epatology 2017;65:281‐293).