Functional hepatocyte heterogeneity in glutamate, aspartate and α-ketoglutarate uptake: A histoautoradiographical study

Stoll, Barbara J.; McNelly, Sabine; Buscher, Hans-Peter; Häussinger, Dieter

doi:10.1002/hep.1840130208

Cited by 73 publications

(23 citation statements)

References 23 publications

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“…Previous liver perfusion experiments revealed that when Asn is added to the perfusate, there is an increased rate of ureogenesis in the Ctrn-KO mice (42) accompanied by increased hepatic Asp and ammonia concentrations (55), suggesting that Asn is stimulating ureogenesis through its conversion to Asp and ammonia. This was not true of added Asp under similar conditions (55) because of its impermeability into periportal hepatocytes (57). A survey of various mammalian and avian species has shown that human and mouse liver have comparable asparagine synthetase activities but that mouse liver has a thousandfold increased activity of asparaginase compared with that of human (58).…”

Section: Discussionmentioning

confidence: 99%

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Saheki

Iijima

et al. 2007

Journal of Biological Chemistry

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Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol.Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD ؉ ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.

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Section: Discussionmentioning

confidence: 99%

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Saheki

Iijima

et al. 2007

Journal of Biological Chemistry

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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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“…The transferred anions are then channelled into various metabolic pathways, either towards complete oxidation, incorporation into glucose and liver glycogen or use for glutamine synthesis in perivenous hepatocytes (Stoll et al 1991). This last point is noteworthy because it suggests that organic anions might exert an alkalinising effect not only through HCO 3 -generation, but also through glutamine production (by being used in the kidneys for HCO 3 -and NH 4 + formation).…”

Section: Metabolismmentioning

confidence: 99%

Organic anions and potassium salts in nutrition and metabolism

et al. 2004

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The present review examines the importance of dietary organic anions in preventive nutrition. Organic anions are chiefly supplied by plant foods, as partially neutralised K salts such as potassium citrate, potassium malate and, to a lesser extent, oxalate or tartrate salts. Animal products may also supply K anions, essentially as phosphate, but also as lactate as a result of fermentative or maturation processes, but these K salts have little alkalinising significance. Citrate and malate anions are absorbed in the upper digestive tract, while a substantial proportion is probably metabolised in the splanchnic area. Whatever their site of metabolism, these anions finally yield KHCO 3 which is used by the kidneys to neutralise fixed acidity. This acidity essentially reflects the oxidation of excess S amino acids to sulfate ions, which is mainly related to the dietary protein level. Failure to neutralise acidity leads to low-grade metabolic acidosis, with possible long-term deleterious effects on bone Ca status and on protein status. Furthermore, low-grade acidosis is liable to affect other metabolic processes, such as peroxidation of biological structures. These metabolic disturbances could be connected with the relatively high incidence of osteoporosis and muscle-protein wasting problems observed in ageing individuals in Europe and Northern America. Providing a sufficient supply of K organic anions through fruit and vegetable intake should be recommended, fostering the actual motivational campaigns ('five (or ten) per d') already launched to promote the intake of plant foods rich in complex carbohydrates and various micronutrients.

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Functional hepatocyte heterogeneity in glutamate, aspartate and α-ketoglutarate uptake: A histoautoradiographical study

Cited by 73 publications

References 23 publications

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Citrin/Mitochondrial Glycerol-3-phosphate Dehydrogenase Double Knock-out Mice Recapitulate Features of Human Citrin Deficiency

Pivotal role of glutamine synthetase in ammonia detoxification

Organic anions and potassium salts in nutrition and metabolism

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