Colocalization in pericentral hepatocytes in adult mice and similarity in developmental expression pattern of ornithine aminotransferase and glutamine synthetase mRNA.

Kuo, Frank C.; Hwu, Wuh‐Liang; Valle, David; Darnell, James

doi:10.1073/pnas.88.21.9468

Cited by 61 publications

(40 citation statements)

References 17 publications

(19 reference statements)

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“…Perfusion of the liver with "%C-labelled arginine or ornithine resulted in production of "%CO # [178], reflecting conversion of arginine or ornithine into glutamate via P5C ( Figure 5) and the subsequent oxidation of glutamate via the citric acid cycle. Because similar results were obtained when the liver was perfused in the antegrade or retrograde direction, O'Sullivan et al [178] inferred that arginase must be co-expressed with hepatic OAT, which is expressed in perivenous, but not periportal, hepatocytes [266]. Although the isoenzyme of arginase expressed in perivenous hepatocytes has not been identified, it is likely to be type II arginase, which would be co-localized in the mitochondrion with OAT.…”

Section: Arginase and Glutamate Synthesismentioning

confidence: 87%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,421

2,036

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Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified

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Section: Arginase and Glutamate Synthesismentioning

confidence: 87%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,421

2,036

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“…Although GS was selectively deleted in perivenous hepatocytes (Fig. 2C), ornithine aminotransferase (OAT), as well as Rhesus family B glycoprotein, which show similar acinar localization as GS, were still detectable in these specialized cells (27,28) (Fig. 2 C and D).…”

Section: Resultsmentioning

confidence: 99%

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Qvartskhava

Lang

Görg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.hepatic encephalopathy | metabolic zonation | oxidative stress | RNA oxidation | glutamine

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“…(26) Pericentral hepatocytes are, therefore, 20-fold more efficient per cell at removing ammonia than periportal hepatocytes. Accordingly, the downstream, pericentral hepatocytes are well equipped to remove residual ammonia from the hepatic circulation (4,27) because they express the ammonia transporters RhBG (28) and APQ9, (29) the glutamate transporter SLC1A2, (30,31) the glutamate-producing enzyme ornithine aminotransferase, (32) the glutamine-producing enzyme GS, (33,34) and the glutamine transporter SLC38A3. (35) PERIPORTAL UREA SYNTHESIS FROM AMMONIA FUNCTIONS AT 10% OF ITS CAPACITY The K 0.5 of ammonia for urea formation in perfused rat liver is 1-2.5 mmol/L (36,37) so that at 200-400 lmol/L ammonia in the portal vein detoxification of ammonia to urea proceeds at only 10% of its maximum rate under normal circumstances.…”

Section: Gs Activity Provides For Systemic High-affinity Ammonia Detomentioning

confidence: 99%

Pivotal role of glutamine synthetase in ammonia detoxification

et al. 2016

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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 (GSknockout/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 lmol/hour in control mice. Using stable isotopes, we show that disposal of glutaminebound 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. (HEPATOLOGY 2017;65:281-293). G lutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. (Note: NH 3 is protonated for 98% to NH 4 1 at physiological pH. We use the term "ammonia" to refer to the sum of NH 3 and NH 4 1 unless specified as either "NH 3 " or "NH 41 .") Glutamine serves, with alanine, as a major nontoxic interorgan ammonia shuttle in the body (1) and as an aminomoiety donor for the synthesis of nucleotides, amino acids, amino-sugars, and oxidized nicotinamide adenine dinucleotide. Its intracellular turnover rate exceeds that of all other amino acids. GS deficiency causes only moderate hyperammonemia, but affected humans and mice suffer from encephalopathy and die neonatally. (2,3) GS is predominantly expressed in the nervous system, kidney, and liver, that is, in established glutamine-consuming organs, (4)(5)(6) whereas skeletal muscle, with a much lower expression but large mass, is considered the main net ...

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Colocalization in pericentral hepatocytes in adult mice and similarity in developmental expression pattern of ornithine aminotransferase and glutamine synthetase mRNA.

Cited by 61 publications

References 17 publications

Arginine metabolism: nitric oxide and beyond

Arginine metabolism: nitric oxide and beyond

Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase

Pivotal role of glutamine synthetase in ammonia detoxification

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