Regulation of flux through glutaminase and glutamine synthetase in isolated perfused rat liver

Häussinger, D; Gerok, W.; Sies, Helmut

doi:10.1016/0304-4165(83)90214-3

Cited by 122 publications

(81 citation statements)

References 14 publications

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“…There is also uncertainty in the literature as to where LGA localizes (Table 2). Early reports consistently found LGA activity in mitochondria, but a study by Olalla and colleagues shows the protein to localize to the nucleus in mammalian brain tissue [40,[55][56][57]. While this report is at odds with previous literature and the predicted localization of either LGA isoform, no study has yet been published which either disputes or supports these findings.…”

Section: Gls 5ǵcontrasting

confidence: 68%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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Many cancer cells exhibit an altered metabolic phenotype, in which glutamine consumption is upregulated relative to healthy cells. This metabolic reprogramming often depends upon mitochondrial glutaminase activity, which converts glutamine to glutamate, a key precursor for biosynthetic and bioenergetic processes. Two isozymes of glutaminase exist, a kidney-type (GLS) and a liver-type enzyme (GLS2 or LGA). While a majority of studies have focused on GLS, here we summarize key findings on both glutaminases, describing their structure and function, their roles in cancer and pharmacological approaches to inhibiting their activities.

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Section: Gls 5ǵcontrasting

confidence: 68%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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“…The periportal localization of production, together with its efficient utilization by urea and glutamine synthesis, keeps the concentration of free ammonia low in the effluent when the flow of the perfusate is from portal to caval vein. However, if the direction of perfusion is changed to retrograde (flow from caval to portal vein), ammonia that is formed under these conditions is apparently not utilized, but washed out of the liver and can be taken as a measure of ammonia production (Haussinger, 1983). As indicated in Table 2, the concentration of ammonia in the effluent was greatly affected by the direction of the perfusate flow, a result similar to that obtained by Haussinger (1983).…”

Section: Results and Discussion Protein Degradationmentioning

confidence: 62%

“…It has been shown (Haiussinger, 1983;Poso et al, 1986) that ammonia is largely produced in the periportal part of the liver acinus, where most of it is incorporated into urea. Further removal of ammonia occurs in the periveneous region by the reaction catalysed by glutamine synthetase (Haussinger, 1983;Gebhardt & Mecke, 1983). The periportal localization of production, together with its efficient utilization by urea and glutamine synthesis, keeps the concentration of free ammonia low in the effluent when the flow of the perfusate is from portal to caval vein.…”

Section: Results and Discussion Protein Degradationmentioning

confidence: 99%

“…However, if the direction of perfusion is changed to retrograde (flow from caval to portal vein), ammonia that is formed under these conditions is apparently not utilized, but washed out of the liver and can be taken as a measure of ammonia production (Haussinger, 1983). As indicated in Table 2, the concentration of ammonia in the effluent was greatly affected by the direction of the perfusate flow, a result similar to that obtained by Haussinger (1983). When 50 mM-ethanol was present in the medium during antegrade (flow from portal to caval vein) perfusions, the output of ammonia was raised 3-fold (Table 2).…”

Section: Results and Discussion Protein Degradationmentioning

confidence: 99%

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Inhibition of intracellular protein degradation by ethanol in perfused rat liver

Pösö¹,

Surmacz²,

Mortimore³

1987

Biochemical Journal

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Ethanol (50 mM) inhibited proteolysis in the perfused rat liver during stringent amino acid deprivation and also in the presence of normal and 10 times normal concentrations of plasma amino acids. The concentration-response curve of ethanol reached a plateau after 5 mm in both the presence and the absence of normal plasma amino acids, suggesting inhibition by oxidation products of ethanol. Intracellular glutamine, tyrosine and proline increased in concentration with ethanol, but the increases were too small to explain the observed inhibition of proteolysis. The uptake of 1251-asialofetuin was slightly decreased and the output of ammonia increased in the presence of ethanol. These, together with a significant suppression of basal proteolysis in the presence of amino acids, suggest that lysosomal function was directly affected. Electron-microscopic examination of lysosomal components showed that the aggregate volume of autophagosomes (initial vacuoles) were significantly smaller in livers perfused with ethanol than in controls. However, the equivalent volume of autolysosomes (degradative vacuoles) was the same in both groups. According to these results, ethanol inhibits protein degradation in the liver by two discrete mechanisms: one decreasing the formation of autophagic vacuoles and the other involving lysosomotropic inhibition, possibly via ammonia.

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“…44,51 It is noteworthy that D-galactosamine does not show a preferential target zone of damage along the hepatic acinus. 53 Because urea synthesis and glutamine synthesis are expressed in different regions of the hepatic acinus, 54 different results may be obtained when using hepatotoxins that exhibit regio-selectivity, such as acetaminophen. 55 Metabolic flux analysis, which balances the major input and output metabolites according to well-known stoichiometric constraints, was able to systematically identify pathway fluxes that were altered by D-galactosamine treatment.…”

Section: Discussionmentioning

confidence: 99%

Intrahepatic amino acid and glucose metabolism in a ?-galactosamine–induced rat liver failure model

et al. 2001

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A better understanding of the hepatic metabolic pathways affected by fulminant hepatic failure (FHF) would help develop nutritional support and other nonsurgical medical therapies for FHF. We used an isolated perfused liver system in combination with a mass-balance model of hepatic intermediary metabolism to generate a comprehensive map of metabolic alterations in the liver in FHF. To induce FHF, rats were fasted for 36 hours, during which they received 2 D-galactosamine injections. The livers were then perfused for 60 minutes via the portal vein with amino acid-supplemented Eagle minimal essential medium containing 3% wt/ vol bovine serum albumin and oxygenated with 95% O 2 /5% CO 2 . Control rats were fasted for 36 hours with no other treatment before perfusion. FHF rat livers exhibited reduced amino acid uptake, a switch from gluconeogenesis to glycolysis, and a decrease in urea synthesis, but no change in ammonia consumption compared with normal fasted rat livers. Mass-balance analysis showed that hepatic glucose synthesis was inhibited as a result of a reduction in amino acid entry into the tricarboxylic acid cycle by anaplerosis. Furthermore, FHF inhibited intrahepatic aspartate synthesis, which resulted in a 50% reduction in urea cycle flux. Urea synthesis by conversion of exogenous arginine to ornithine was unchanged. Ammonia removal was quantitatively maintained by glutamine synthesis from glutamate and a decrease in the conversion of glutamate to ␣-ketoglutarate. Mass-balance analysis of hepatic metabolism will be useful in characterizing changes during FHF, and in elucidating the effects of nutritional supplements and other treatments on hepatic function. (HEPATOLOGY 2001;34:360-371.)Since the late 1980s, orthotopic liver transplantation has become the only widely accepted treatment for fulminant hepatic failure (FHF). [1][2][3][4] Because of the severe shortage in donor organs, various alternatives aimed at providing a "substitute" liver, such as xenogeneic whole liver perfusion 5 and extracorporeal bioartificial liver devices, 6,7 are being developed. Such systems, which can be used as a bridge to transplantation or provide temporary relief during the most acute phase of hepatic failure, are promising, although technically complex and expensive. It has been hypothesized that hepatic encephalopathy may result from the elevation of circulating levels of putative toxins such as ammonia, mercaptans, short-chain fatty acids, [8][9][10] and an abnormal amino acid profile. [11][12][13] In FHF patients, alterations in amino acid concentrations in systemic plasma have been characterized by several investigators, 14,15 which led to the use of solutions rich in branchedchain amino acids (BCAA) for the treatment of hepatic encephalopathy. 16,17 These approaches, which were largely unsuccessful, aimed at counteracting the observed shifts in metabolite levels in the systemic circulation; however, systemic changes in metabolite levels do not solely reflect alterations in liver function, but also changes in whole-b...

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Regulation of flux through glutaminase and glutamine synthetase in isolated perfused rat liver

Cited by 122 publications

References 14 publications

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

Inhibition of intracellular protein degradation by ethanol in perfused rat liver

Intrahepatic amino acid and glucose metabolism in a ?-galactosamine–induced rat liver failure model

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