Ammonia and Glutamine Metabolism During Liver Insufficiency: The Role of Kidney and Brain in Interorgan Nitrogen Exchange

Dejong, C.H.C.; Deutz, Nicolaas E. P.; Soeters, Peter B.

doi:10.3109/00365529609094733

Cited by 30 publications

(12 citation statements)

References 111 publications

(143 reference statements)

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“…Glutamine synthetase adds ammonia to glutamate to form glutamine Dejong et al, 1996;Nissim et al, 1996;Norenberg et al, 1997;Sonnenwald et al, 1997]. Glutamine is the major inter-organ carrier of ammonia and can transport ammonia that is generated, for example, in skeletal muscle or the intestinal lumen to the liver for detoxification.…”

Section: A Pathways Of Glutamate Metabolismmentioning

confidence: 99%

Disorders of glutamate metabolism

Kelly

Stanley

2001

Ment. Retard. Dev. Disabil. Res. Rev.

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The significant role the amino acid glutamate assumes in a number of fundamental metabolic pathways is becoming better understood. As a central junction for interchange of amino nitrogen, glutamate facilitates both amino acid synthesis and degradation. In the liver, glutamate is the terminus for release of ammonia from amino acids, and the intrahepatic concentration of glutamate modulates the rate of ammonia detoxification into urea. In pancreatic beta-cells, oxidation of glutamate mediates amino acid-stimulated insulin secretion. In the central nervous system, glutamate serves as an excitatory neurotransmittor. Glutamate is also the precursor of the inhibitory neurotransmittor GABA, as well as glutamine, a potential mediator of hyperammonemic neurotoxicity. The recent identification of a novel form of congenital hyperinsulinism associated with asymptomatic hyperammonemia assigns glutamate oxidation by glutamate dehydrogenase a more important role than previously recognized in beta-cell insulin secretion and hepatic and CNS ammonia detoxification. Disruptions of glutamate metabolism have been implicated in other clinical disorders, such as pyridoxine-dependent seizures, confirming the importance of intact glutamate metabolism. This article will review glutamate metabolism and clinical disorders associated with disrupted glutamate metabolism.

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Section: A Pathways Of Glutamate Metabolismmentioning

confidence: 99%

Disorders of glutamate metabolism

Kelly

Stanley

2001

Ment. Retard. Dev. Disabil. Res. Rev.

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“…A tentative hypothesis would be that RhAG, in the Rh complex, promotes export of ammonium accumulated into erythrocytes. RhAG might also promote erythrocytemediated retention of ammonium from the plasma and its release to detoxifying organs such as the liver and brain 14 . Our results will certainly lead to new studies of human Rh null patients, such as the analysis of ammonium concentrations in plasma and erythrocytes and of possible perturbation in labile nitrogen metabolism.…”

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confidence: 99%

The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast

et al. 2000

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The Rhesus blood-group antigens are defined by a complex association of membrane polypeptides that includes the non-glycosylated Rh proteins (RhD and RhCE) and the RHag glycoprotein, which is strictly required for cell surface expression of these antigens. RhAG and the Rh polypeptides are erythroid-specific transmembrane proteins belonging to the same family (36% identity). Despite their importance in transfusion medicine, the function of RhAG and Rh proteins remains unknown, except that their absence in Rh(null) individuals leads to morphological and functional abnormalities of erythrocytes, known as the Rh-deficiency syndrome. We recently found significant sequence similarity between the Rh family proteins, especially RhAG, and Mep/Amt ammonium transporters. We show here that RhAG and also RhGK, a new human homologue expressed in kidney cells only, function as ammonium transport proteins when expressed in yeast. Both specifically complement the growth defect of a yeast mutant deficient in ammonium uptake. Moreover, ammonium efflux assays and growth tests in the presence of toxic concentrations of the analogue methylammonium indicate that RhAG and RhGK also promote ammonium export. Our results provide the first experimental evidence for a direct role of RhAG and RhGK in ammonium transport. These findings are of high interest, because no specific ammonium transport system has been characterized so far in human.

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“…The interorgan exchange of glutamine and ammonia is severely altered in experimental animals with liver failure. 5,6 Ammonia metabolism has been studied in individual organs of patients with cirrhosis, but quantification is sparse, as is its relation with amino acid metabolism. Furthermore, to our knowledge no quantitative data are available on interorgan ammonia and amino acid metabolism in patients with cirrhosis.…”

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confidence: 99%

Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS

et al. 2002

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Ammonia is central to the pathogenesis of hepatic encephalopathy. This study was designed to determine the quantitative dynamics of ammonia metabolism in patients with cirrhosis and previous treatment with a transjugular intrahepatic portosystemic stent shunt (TIPSS). We studied 24 patients with cirrhosis who underwent TIPSS portography. Blood was sampled and blood flows were measured across portal drained viscera, leg, kidney, and liver, and arteriovenous differences across the spleen and the inferior and superior mesenteric veins. The highest amount of ammonia was produced by the portal drained viscera. The kidneys also produced ammonia in amounts that equaled total hepatosplanchnic area production. Skeletal muscle removed more ammonia than the cirrhotic liver. The amount of nitrogen that was taken up by muscle in the form of ammonia was less than the glutamine that was released. The portal drained viscera consumed glutamine and produced ammonia, alanine, and citrulline. Urea was released in the splenic and superior mesenteric vein, contributing to whole-body ureagenesis in these cirrhotic patients. In conclusion, hyperammonemia in metabolically stable, overnight-fasted patients with cirrhosis of the liver and a TIPSS results from portosystemic shunting and renal ammonia production. Skeletal muscle removes more ammonia from the circulation than the cirrhotic liver. Muscle releases excessive amounts of the nontoxic nitrogen carrier glutamine, which can lead to ammonia production in the portal drained viscera (PDV) and kidneys. Urinary ammonia excretion and urea synthesis appear to be the only way to remove ammonia from the body.

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Ammonia and Glutamine Metabolism During Liver Insufficiency: The Role of Kidney and Brain in Interorgan Nitrogen Exchange

Cited by 30 publications

References 111 publications

Disorders of glutamate metabolism

Disorders of glutamate metabolism

The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast

Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS

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