Exposure of perfused liver to hypotonic conditions modifies cellular nitrogen metabolism

Häussinger, Dieter; Läng, Florian

doi:10.1002/jcb.240430407

Cited by 40 publications

(17 citation statements)

References 16 publications

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“…These effects persist even after completion of volumeregulatory ion fluxes, indicating that the liver is left in an altered metabolic state. This is in line with the previous suggestion that alterations of liver cell volume act as an important trigger of liver cell function [10][11][12][13][14]. Also, glutamine leads to cell swelling [8,10] and inhibits proteolysis [2,4].…”

Section: Discussionsupporting

confidence: 91%

“…These effects were fully reversible upon re-exposure to normo-osmotic perfusion media. [10,[12][13][14][15]. On the other hand, exposure of perfused liver to hyperosmotic media (from 305 to 385 mosmol kg-') resulted in a 22 +2 % (n = 6) stimulation of branched-chain amino acid (leucine plus valine plus isoleucine) release from 168 + 5 to 203 + 7 nmol/min per g (n = 6), owing to a 15-26% increase in the release of the individual amino acids.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have indicated that amino acids, even at physiological concentrations [8], elicit liver cell swelling and volume-regulatory ion-flux responses [8-1 1]. Furthermore, cell swelling was recognized as an important trigger of hepatic metabolism [10][11][12][13][14]. The present study was undertaken to examine the effect of cell swelling on proteolysis and to determine whether the known anti-proteolytic effect of glutamine can be ascribed to glutamine-induced alterations of liver cell volume.…”

Section: Introductionmentioning

confidence: 99%

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Cell swelling inhibits proteolysis in perfused rat liver

Häussinger

Hallbrucker

Dahl

et al. 1990

Biochemical Journal

103

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Exposure of isolated single-pass-perfused rat liver to hypo-osmotic media resulted in liver cell swelling and an inhibition of release of branched-chain amino acids. Similarly, cell swelling inhibited [3H]leucine release from perfused livers from rats in which liver proteins were prelabelled in vivo by intraperitoneal injection of L-[4,5-3H]leucine 16-20 h before the experiment. The effects of cell swelling on [3H]leucine release were fully reversible. [3H]Leucine release was also inhibited when cell swelling was induced by addition of glutamine (0.5-2 mM). There was a close relationship between the inhibition of [3H]leucine release and the degree of liver cell swelling, regardless of whether cell swelling was induced by hypo-osmotic perfusion or addition of glutamine. The data suggest that the known anti-proteolytic effect of glutamine is in large part due to glutamine-induced hepatocyte swelling.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell swelling inhibits proteolysis in perfused rat liver

Häussinger

Hallbrucker

Dahl

et al. 1990

Biochemical Journal

103

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“…The effluent K t concentrations was continuously monitored with a K' -sensitive electrode (Radiometer, Munich, FRG); volume-regulatory K ' release was determined by planimetry of areas under curves [ l l , [14][15][16].…”

Section: Determinationsmentioning

confidence: 99%

Control of hepatic proteolysis by amino acids

Hallbrucker

Dahl

Läng

et al. 1991

European Journal of Biochemistry

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1. Proteolysis in isolated perfused rat liver was monitored as [3H]leucine release into effluent perfusate after in vivo labeling by intraperitoneal injection of [3H]leucine about 16 h prior to the perfusion experiment. Exposure of the livers to hypotonic perfusion media (175 -295 mOsmol . 1-I) increased liver mass due to cell swelling and inhibited [3H]leucine release. The extent of inhibition of [3H]leucine release was linearly related to the liver-mass increase, regardless of whether livers from fed or 24-h-starved rats were studied.2. Infusion of glycine (0.5-3 mmol . 1-I) or glutamine (0.5-3 mmol . 1-') during normotonic perfusions (305 mOsmol . 1-') led to a concentration-dependent increase of liver mass and inhibition of [3H]leucine release. The inhibition of [3H]leucine release was again strongly dependent upon the increase of liver mass, regardless of whether cell swelling was induced by glutamine or glycine in normotonic perfusions, by exposure of the liver to hypotonic media or whether amino-acid-induced cell swelling was modified by the nutritional state. The effects of glutamine and glycine on [3H]leucine release were additive to the same extent as that found when the liver-mass increase was observed.3. Alanine, serine and proline inhibited [3H]leucine release in parallel to the extent of amino-acid-induced liver-mass increase; however, the inhibition of [3H]leucine release was about twice that found when comparable degrees of cell swelling were induced either by hypotonic exposure or by addition of glutamine or glycine. The relationship between alanine-induced liver-mass increase and the inhibition of [3H]leucine release was also maintained in presence of aminooxyacetate (0.2 mmol . 1-I).4. Infusion of an amino acid mixture, roughly mimicking the concentrations found in portal venous blood, to livers from 24-h-starved or fed rats inhibited [3H]leucine release by 56.0 & 2.4% (n = 6) or 31.1 f 2.3% (n = 3), respectively, and increased liver mass by 5.0 & 0.1 YO (n = 6) or 2.2 f 0.3% (n = 3), respectively. Regardless of the nutritional state, there was a close relationship between the amino-acid-mixture-induced (and also phenylalanineinduced) increase of liver mass and the degree of inhibition of [3H]leucine release; however, the inhibition of [3H]leucine release was about fourfold higher than that found when comparable degrees of cell swelling were induced by hypotonic exposure. The amino-acid-mixture-induced inhibition of [3H]leucine release was reversed by hypertonic (385 mOsmol . 1-I) cell shrinkage and stimulated by glutamine/glycine-induced swelling to an cxtcnt predicted by the relationship between liver mass and anisotonic cell swelling.5. The data are consistent with the following: (a) a role of liver-cell volume in the control of hepatic proteolysis; (b) inhibition of proteolysis by glutamine and glycine can largely be ascribed to cell-volume changes, whereas the effects of alanine, serine, proline and especially of phenylalanine or of an amino acid mixture on proteolysis can only be explain...

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“…Following hypotonic exposure, perfused rat liver switches from net glutamine output to net uptake, resulting from a stimulation of glutaminase and a simultaneous inhibition of glutamine synthesis [3]. Further, hypotonicity decreases net lactate and glucose output due to an inhibition of net flux through the glycogenolytic and glycolytic pathways [12,141, activates glycogen phosphorylase [16], stimulates urea synthesis from alanine and glutamine [I 51, but inhibits urea synthesis from NH4C1 [15].…”

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confidence: 99%

Control of hepatic nitrogen metabolism and glutathione release by cell volume regulatory mechanisms

Häussinger

Läng

Bauers

et al. 1990

European Journal of Biochemistry

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1. Urea synthesis was studied in isolated perfused rat liver during cell volume regulatory ion fluxes following exposure of the liver to anisotonic perfusion media. Lowering of the osmolarity in influent perfusate from 305 mOsm/l to 225 mOsm/l (by decreasing influent [NaCl] by 40 mmol/l) led to an inhibition of urea synthesis from NH4CI (0.5 mmol/l) by about 60% and a decrease of hepatic oxygen uptake by 0.43 f 0.03 pmol g-min-[from 3.09 f 0.13 pmol g-' min-' to 2.66 0.12 pmol g -l min-' (n = 9)]. The effects on urea synthesis and oxygen uptake were observed throughout hypotonic exposure (225 mOsm/l). They persisted although volume regulatory K+ efflux from the liver was complete within 8 min and were fully reversible upon reexposure to normotonic perfusion media (305 mOsm/l). A 42% inhibition of urea synthesis from NH4Cl (0.5 mmol/l) during hypotonicity was also observed when the perfusion medium was supplemented with glucose (5 mmol/l). Urea synthesis was inhibited by only 10-20% in livers from fed rats, and was even stimulated in those from starved rats when an amino acid mixture (twice the physiological concentration) plus NH4C1 (0.2 mmol/l) was infused.2. The inhibition of urea synthesis from NH4C1 (0.5 mmol/l) during hypotonicity was accompanied by a threefold increase of citrulline tissue levels, a 50 -70% decrease of the tissue contents of glutamate, aspartate, citrate and malate, whereas 2-oxoglutarate, ATP and ornithine tissue levels, and the [3H]inulin extracellular space remained almost unaltered. Further, hypotonic exposure stimulated hepatic glutathione (GSH) release with a time course roughly paralleling volume regulatory K + efflux. NH4Cl stimulated lactate release from the liver during hypotonic but not during normotonic perfusion. In the absence of NH4Cl, hypotonicity did not significantly affect the lactate/pyruvate ratio in effluent perfusate. With NH4C1 (0.5 mmol/l) present, the lactate/pyruvate ratio increased from 4.3 to 8.2 in hypotonicity, whereas simultaneously the 3-hydroxybutyrate/acetoacetate ratio slightly, but significantly decreased.3. Addition of lactate (2.1 mmol/l) and pyruvate (0.3 mmol/l) to influent perfusate did not affect urea synthesis in normotonic perfusions, but completely prevented the inhibition of urea synthesis from NH4Cl (0.5 mmol/l) induced by hypotonicity. Restoration of urea production in hypotonic perfusions by addition of lactate and pyruvate was largely abolished in the presence of 2-cyanocinnamate (0.5 mmol/l). Addition of 3-hydroxybutyrate (0.5 mmol/l), but not of acetoacetate (0.5 mmol/l) largely reversed the hypotonicity-induced inhibition of urea synthesis from NH4Cl.4. The data are consistent with a cell-swelling-induced inhibition of the transfer of malate and reducing equivalents into the mitochondria1 compartment, thereby inhibiting urea synthesis due to a limitation of aspartate supply for argininosuccinate synthesis. They suggest that alterations of liver cell volume and/or volume regulatory responses exert marked effects on hepatic ammonia, amin...

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Exposure of perfused liver to hypotonic conditions modifies cellular nitrogen metabolism

Cited by 40 publications

References 16 publications

Cell swelling inhibits proteolysis in perfused rat liver

Cell swelling inhibits proteolysis in perfused rat liver

Control of hepatic proteolysis by amino acids

Control of hepatic nitrogen metabolism and glutathione release by cell volume regulatory mechanisms

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