Protein turnover,synthesis and secretion of albumin in hepatocytes isolated from rats bearing walker 256 carcinoma

Summary Hepatocytes isolated from rats bearing line A of Walker 256 carcinoma (WA) were used to study the turnover of total liver protein and the synthesis of albumin in comparison with ad libitum (AL) and pair-fed (PF) healthy controls. The rates of total protein synthesis by hepatocytes of WA animals were 40 and 90% higher than in AL and PF controls, respectively. The degradation of fast-turnover proteins was not affected by nutrition or by the tumor, whereas the degradation of slow-turnover proteins was slightly but significantly increased—about 24% higher in hepatocytes from WA rats than in PF controls. The combination of the two processes, synthesis and degradation, was in favor of an increased synthesis which explains the increase in liver protein content observed in vivo in WA rats. Dietary restriction did not affect the synthesis and secretion of albumin, whereas the tumor significantly reduced its synthesis by about 30%. The plasma concentration of albumin in WA rats dropped by about the same percentage compared with AL and PF animals.     

Protein synthesis in the whole body,liver, skeletal muscle and kidney cortex of lambs infected by the nematode Trichostrongylus colubriformis

Jones W. O. and Symons L. E. A. 1982. Protein synthesis in the whole body, liver, skeletal muscle and kidney cortex of lambs infected by the nematode Trichostrongylus colubriformis. International Journal for Parasitology12: 295–301. Tyrosine flux and the synthesis of protein in the whole body, liver, skeletal muscle and kidney cortex and of albumin in lambs infected with Trichostrongylus colubriformis and uninfected lambs fed ad libitum or pair-fed with the infected group, were measured by constant infusion of ¹⁴C-l-tyrosine. Live weight gain was lower in the infected than in pairfed lambs, but rates of whole body protein synthesis were similar in both groups. On the other hand, compared with control lambs, there was a faster rate of protein synthesis per unit of protein consumed in infected but not in pair-fed lambs. Rates of protein synthesis per unit of body weight in infected were higher than in pair-fed lambs, but similar to the rate in control lambs. The fractional synthetic rates (FSR) of albumin and liver proteins and the amount of liver protein synthesized per day were increased by infection. The FSR and amount of protein synthesized per day were depressed in skeletal muscle and kidney cortex. Anorexia did not explain any of these changes. Infection caused a loss of protein from each of these tissues, but this loss was due to anorexia in only the liver. There was generally good correlation between concentration of RNA per g fresh weight or per mg nitrogen and the FSR of protein. However, although the $\text{RNA}\text{DNA}$ ratio correlated well with synthesis in skeletal muscle, it was poorly correlated for liver proteins. The relationship between the rate of growth and protein synthesis in infected lambs is discussed.     

Increased albumin plasma efflux contributes to hypoalbuminemia only during early phase of sepsis in rats

The mechanisms leading to hypoalbuminemia in sepsis were explored by measuring plasma volume, albumin distribution, plasma albumin transcapillary escape rate (TER), and efflux (TER x albumin intravascular pool). These parameters were quantified in infected rats, injected intravenously with live Escherichia coli, and pair-fed and well-fed rats using an injection of (35)S-albumin and measuring plasma and whole body albumin concentrations. Animals were studied on days 1, 6, and 10 after infection. In pair-fed rats, neither albumin distribution nor exchange rate between the intra- and extravascular compartments was modified. The increase of plasma volume after infection partly explained hypoalbuminemia. Infection resulted in a reduction of the total albumin pool of the body all along the experimental period, indicating a net loss of the protein. Albumin TER (%/day) was significantly increased 1 and 6 days after infection, but the absolute efflux was increased only on day 1. Normal values were observed on day 10. Therefore, an accelerated plasma efflux contributes to hypoalbuminemia only during the early period of sepsis. During this phase, the protein was retained in the extravascular space where it was probably catabolized. Later on, other factors are probably involved.     

Phospholipase C activation by ethanol in rat hepatocytes is unaffected by chronic ethanol feeding.

The activation of phosphoinositide-specific phospholipase C by ethanol was compared in hepatocytes isolated from ethanol-fed rats and from pair-fed control animals. Ethanol (100-300 mM) caused a dose-dependent transient increase in cytosolic free Ca2+ levels in indo-1-loaded hepatocytes from both groups of animals. The rate of Ca2+ increase was similar in hepatocytes from control and ethanol-fed rats, but the decay of the Ca2+ increase was somewhat slower in the latter preparation. The ethanol-induced Ca2+ increase caused activation of glycogen phosphorylase, with 50% response at 50 mM-ethanol and a maximal response at 150-200 mM-ethanol, not significantly different in hepatocytes from control and ethanol-fed animals. Ins(1,4,5)P3 formation in response to ethanol (300 mM) or vasopressin (2 nM or 40 nM) was also similar in the two preparations. It is concluded that long-term ethanol feeding does not lead to an adaptive response with respect to the ethanol-induced phospholipase C activation in rat hepatocytes. The ability of ethanol in vitro to decrease membrane molecular order in liver plasma membranes from ethanol-fed and control rats was measured by e.s.r. Membranes from ethanol-fed animals had a significantly lower baseline order parameter compared with control preparations (0.313 and 0.327 respectively), indicative of decreased membrane molecular order. Addition of 100 mM-ethanol significantly decreased the order parameter in control preparations by 2.1%, but had no effect on the order parameter of plasma membranes from ethanol-fed rats, indicating that the plasma membranes had developed tolerance to ethanol, similar to other membranes in the liver. Thus the membrane structural changes associated with this membrane tolerance do not modify the ethanol-induced activation of phospholipase C. The transient activation of phospholipase C by ethanol in hepatocytes may play a role in maintaining an adaptive phenotype in rat liver.     

Rates of sterol synthesis in the liver and extrahepatic tissues of the SHR/N-corpulent rat, an animal with hyperlipidemia and insulin-independent diabetes

The SHR/N-corpulent rat is a new genetically obese strain that exhibits both insulin-independent diabetes and hyperlipidemia. The present studies were undertaken to characterize various parameters of cholesterol metabolism in this model. At 11 weeks of age, the obese animals had markedly elevated plasma cholesterol, triglyceride, glucose, and insulin concentrations and elevated hepatic triglyceride concentrations compared to their lean littermates. The additional cholesterol in plasma was carried in the fractions of density less than 1.006, 1.020-1.055, 1.055-1.095, and 1.095-1.21 g/ml. In the obese rats the level of free cholesterol in the liver was decreased significantly while that of cholesteryl ester showed little change. Hepatic sterol synthesis was markedly suppressed in the obese animals. However, the rate of sterol synthesis in the small intestine and other extrahepatic tissues generally remained unchanged. Although hepatic synthesis was suppressed, whole animal sterol synthesis in the obese rats was similar to that in the lean controls. This resulted because, in the obese animals, not only was the reduced rate of hepatic synthesis partly balanced by a greater than 70% increase in liver mass, but the mass of the small intestine and adipose tissue was also increased more than 30% and 4-fold, respectively, thereby making these tissues quantitatively more important sites of sterol synthesis. When obese rats were pair-fed to the intake of their lean littermates for 10 weeks, there was only a modest reduction in body weight and plasma cholesterol concentration, and the rate of hepatic sterol synthesis remained very low. The suppression of synthesis in the liver also persisted when the obese rats were fed surfomer, a drug that specifically blocks cholesterol absorption. In contrast, feeding cholestyramine restored the rate of hepatic sterol synthesis to that found in lean animals. Bile acid pool size in the obese males and females was 2.5-fold greater than in their lean controls. The suppression of hepatic sterol synthesis in this model may be due to a change in the entero-hepatic circulation of bile acids arising from an expanded pool or, alternatively, it may represent a compensatory response to overproduction of sterol and its precursors in the intestinal and adipose compartments.     

Albumin synthesis and catabolism following partial hepatectomy in the rat. The effects of amino acids and adrenocortical steroids on albumin synthesis after partial hepatectomy.

Plasma albumin levels were measured in partially hepatectomized, sham operated and control rats. The levels fell in both the partially hepatectomized and sham operated groups; while the latter group returned to normal within a few days, the low plasma albumin in the partially hepatectomized animals was sustained. Albumin synthesis rates in the isolated perfused rat liver were measured in the three groups of animals at varying intervals after partial hepatectomy. There was a significant depression of albumin synthesis rate in terms of both liver and whole animal weights when compared to the sham operated and control animals. This depression was almost completely reversed by the addition of arginine, asparagine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan and valine added together to 10 times their normal plasma concentrations. The addition of hydrocortisone had no effect on the albumin synthesis rate after partial hepatectomy. Studies in vivo in the three groups of animals (partially hepatectomized, sham operated and control animals) revealed a fall in the albumin catabolic rate after partial hepatectomy coinciding with the fall in the albumin synthesis rate. An hypothesis whereby the amino acids may have their stimulatory effect is proposed.     

Plasma orosomucoid metabolism and susceptibility to malarial infection in rodents

The effects of Plasmodium berghei infection on liver function and plasma orosomucoid metabolism were investigated in Wistar rats. Infected rats with 20-25% parasitaemia manifested increased serum transaminase levels, hypoalbuminaemia and hypoproteinaemia. In spite of such indications of deranged liver function, the hepatic synthesis rate (as measured by 14C-amino acid incorporation) of seromucoids predominantly orosomucoid or alpha 1-acid glycoprotein) was increased by 73%. The circulating levels of this glycoprotein were also doubled in infected animals. The albumin synthesis rate was not increased. This preferential synthesis and increase in circulating levels of orosomucoid may have in vivo significance in malarial infection, in view of reports that orosomuocid has influence on in vitro invasion of red cells by malarial parasites.     

Zinc and insulin metabolism

A review of experimental studies of the effect of zinc nutrition on insulin metabolism is presented. In addition to a short introduction to the synthesis, secretion, and action of insulin, the effects of zinc deficiency—specifically on glucose tolerance, insulin secretion, insulin synthesis and storage, and on total insulin-like activity—are dealt with. The concentrations of zinc and chromium in serum, pancreas, and liver are compared to those of zinc-deficient animals and pair-fed controls. In contrast to pair-fed controls, zinc-deficient rats had unaltered proinsulin contents after glucose stimulation, but they showed a diminished glucose tolerance, lowered serum insulin content, and an elevated total insulin-like activity. The serum zinc concentration of the deficient animals was greatly reduced and did not change during glucose stimulation, whereas it rose in the case of the pair-fed controls. The serum chromium concentration increased in both groups in response to glucose stimulation. In the pancreas of the deficient animals, the zinc concentration was reduced 60% and it increased during the glucose tolerance test. In the liver there were no significant differences. The chromium concentrations were elevated in both the pancreas and liver of the zinc-deficient rats by 60 and 100%, respectively, and were not influenced by glucose injection. These studies show clearly that nutritional zinc deficiency influences insulin metabolism and action.     

Methionine transsulfuration is increased during sepsis in rats

Methionine transsulfuration in plasma and liver, and plasma methionine and cysteine kinetics were investigated in vivo during the acute phase of sepsis in rats. Rats were infected with an intravenous injection of live Escherichia coli, and control pair-fed rats were injected with saline. Two days after injection, the rats were infused for 6 h with [(35)S]methionine and [(15)N]cysteine. Transsulfuration was measured from the transfer rate of (35)S from methionine to cysteine. Liver cystathionase activity was also measured. Infection significantly increased (P < 0.05) the contribution of transsulfuration to cysteine flux in both plasma and liver (by 80%) and the contribution of transsulfuration to plasma methionine flux (by 133%). Transsulfuration measured in plasma was significantly (P < 0.05) higher in infected rats than in pair-fed rats (0.68 and 0.25 micromol. h(-1). 100 g(-1), respectively). However, liver cystathionase specific activity was decreased by 17% by infection (P < 0.05). Infection increased methionine flux (16%, P < 0.05) less than cysteine flux (38%, P < 0.05). Therefore, the plasma cysteine flux was higher than that predicted from estimates of protein turnover based on methionine data, probably because of enhanced glutathione turnover. Taken together, these results suggest an increased cysteine requirement in infection.     

The hypoalbuminaemia of ovine fascioliasis: the influence of protein intake on the albumin metabolism of infected and of pair-fed control sheep.

Studies using ¹²⁵I-albumin and ⁵¹Cr-labelled plasma proteins showed that the hypoalbuminaemia which developed in sheep during the migratory stage of Fasciola hepatica infections was brought about by a combination of reduced albumin synthesis and plasma volume expansion. It was suggested that these changes were a reflection of the attendant liver damage and possibly of preferential utilisation of amino acids for immunoglobulin production. During the biliary stage of the disease, when the animals developed even more marked hypoalbuminaemia, increased albumin degradation arising from excessive plasma leakage into the gut were the outstanding features. The severity of these changes was closely linked to the state of the albumin pools which in turn was related to such factors as the plane of nutrition, appetite and fluke burden of the host. More albumin was catabolised by sheep with low fluke burdens, and in animals with the same level of infection, greater rates of catabolism were associated with a high protein intake. Sheep which catabolised most albumin became the least hypoalbuminaemic and survived longest. These animals also synthesised most albumin. It was shown that by impairing albumin synthesis, inappetence was an important additional factor in the hypoalbuminaemia of heavy infections, particularly if superimposed on a low protein diet. Nevertheless, irrespective of the size of their adult fluke burden, chronically-infected sheep were able to synthesise more albumin than pair-fed controls.     

Chronic ethanol feeding inhibits plasma levels of insulin-like growth factor-1

The purpose of this study was to determine whether the generalized catabolic effects of chronic ethanol may be associated with a decline in plasma levels of insulin-like growth factor-1 (IGF-1). Male Sprague-Dawley rats were fed a liquid diet containing 5% ethanol or pair-fed a diet made isocaloric with maltose-dextrin. Animals were maintained on this diet for either 12 days or 4.5 months. Another group of animals were fed control diet ad libitum for 2 weeks. After 12 days of feeding, plasma concentrations of IGF-1 in ad libitum fed rats were 771 +/- 41 ng/ml which was greater than concentrations in either pair-fed (595 +/- 23 ng/ml) or ethanol-fed (680 +/- 40 ng/ml) rats (P less than 0.05). After 4.5 months of feeding, plasma levels of IGF-1 in ad libitum and pair-fed rats were similar to the 12 day study (736 +/- 56 and 607 +/- 26 ng/ml, respectively). However, a significant decrease in plasma levels of IGF-1 was observed in ethanol-fed animals over the 4.5 month period (551 +/- 28 ng/ml, P less than 0.05). Results of a similar study in rats fed a high-fat diet for 4.5 months were similar to those found with the low-fat diet. These results indicate that 1) dietary restriction of the type routinely used in this pair-feeding regimen decreases plasma levels of IGF-1, 2) chronic ethanol feeding further decreases plasma IGF-1 levels compared to pair-fed rats, 3) the effects of ethanol on IGF-1 concentrations are not modified by dietary fat, and 4) the effects on IGF-1 are not directly dependent on elevated plasma ethanol concentrations. Our results suggest that IGF-1 secreting cells in the liver may be progressively damaged by chronic ethanol feeding.     

Skeletal and heart muscle protein turnover during long-term exposure to high environmental temperatures in young rats

A study was undertaken to determine the long-term effects of a hot environment on protein turnover in skeletal and cardiac muscles of young homeothermic animals. Three groups of 36 male 28 day old rats were housed at 35 degrees C (hot group), 25 degrees C (control group), or 25 degrees C but pair-fed to the intake of the hot group (pair-fed group). Rates of protein synthesis and degradation were measured in vivo on days 5, 10, 15, and 20. By day 20, soleus and gastrocnemius (skeletal muscle) protein masses were 7 and 14% lower in the hot group and 31 and 21% lower in the pair-fed group compared with the control group (P < 0.05). The fractional rate of protein synthesis (k(syn)) was on average 11% lower (P < 0.05) in the hot group compared with control rats and was not different from pair-fed rats. The fractional rate of skeletal muscle protein degradation (k(deg)) in hot rats was slightly lower than in control rats; k(deg) was on average 18% higher (P < 0.05) in the pair-fed group compared with the hot group and this difference appeared to be most prominent on day 5. In heart, by day 20, protein mass was 30% lower in the hot group and 40% lower in the pair-fed group compared with control rats (P < 0.05). k(syn) was on average 19% lower (P < 0.05) in the hot group compared with the control group, but not different from pair-fed rats. In the heart there were no differences in k(deg) among treatments. Plasma triiodothyronine (T3) concentration was lower in the hot group, but not in the pair-fed group, compared with controls. In conclusion, chronic exposure to hot environments was associated with lower skeletal and cardiac muscle mass and protein turnover; lower protein mass in this tissue was due to decreased k(syn); this is consistent with lower plasma T3 concentrations. In pair-fed rats, k(syn) was also reduced, but interestingly k(deg) was not, resulting in a greater loss of skeletal muscle mass. These results suggest that heat exposure invokes physiological adaptations to preserve skeletal muscle mass despite decreased food intake. In the heart, loss of protein was a result of decreased k(syn), which can be primarily ascribed to lower food intake.     

Intense exercise stimulates albumin synthesis in the upright posture.

We tested the hypothesis that an elevation in albumin synthetic rate contributes to increased plasma albumin content during exercise-induced hypervolemia. Albumin synthetic rate was measured in seven healthy subjects at 1-5 and 21-22 h after 72 min of intense (85% peak oxygen consumption rate) intermittent exercise and after 5 h recovery in either upright (Up) or supine (Sup) postures. Deuterated phenylalanine (d(5)-Phe) was administrated by a primed-constant infusion method, and fractional synthetic rate (FSR) and absolute synthetic rate (ASR) of albumin were calculated from the enrichment of d(5)-Phe in plasma albumin, determined by gas chromatography-mass spectrometry. FSR of albumin in Up increased significantly (P < 0.05) from 4.9 +/- 0.9%/day at control to 7.3 +/- 0.9%/day at 22 h of recovery. ASR of albumin increased from 87.9 +/- 17.0 to 141.1 +/- 16.6 mg albumin. kg body wt(-1). day(-1). In contrast, FSR and ASR of albumin were unchanged in Sup (3.9 +/- 0.4 to 4.0 +/- 1.4%/day and 74.2 +/- 8.9 to 85.3 +/- 23.9 mg albumin. kg body wt(-1). day(-1) at control and 22 h of recovery, respectively). Increased albumin synthesis after upright intense exercise contributes to the expansion of greater albumin content and its maintenance. We conclude that stimuli related to posture are critical in modulating the drive for albumin synthesis after intense exercise.     

Albumin and transferrin synthesis during development in the rat

In this study, the incorporation of [(14)C]leucine into albumin and transferrin in early rat foetuses, vitelline plus amniotic membranes, chorioallantoic placenta and perinatal rat liver slices was measured and used to detect and compare the rates of synthesis of the two proteins. Albumin synthesis was detected in the body of foetuses from 13 days gestation onwards. Transferrin synthesis was detected only after day 15. Transferrin synthesis was demonstrable in the membranes but not in the chorioallantoic placenta of all the animals investigated, i.e. from 13 to 19 days gestation. Synthesis of albumin and transferrin by the liver of near-term and postnatal animals was shown to correlate with published data on the parenchymal cell number/unit wet wt. of liver. Near-term foetuses synthesized relatively more transferrin than albumin when compared with 10-day postnatal animals. The serum concentrations of the two plasma proteins were also determined. These increased before term whereas the rate of synthesis of albumin and transferrin declined. Postnatally, plasma albumin concentration increased but transferrin concentration decreased, yet the rates of synthesis of both proteins by the liver increased with age. This lack of correlation between the rates of synthesis of the two proteins and their respective plasma concentrations could be explained in part by their increased stability after birth. There was also evidence that the liver haemopoietic cells took up transferrin although they do not synthesize the protein. Thus the decrease in this population of cells during development could also contribute to the discrepancy between liver synthesis and serum concentrations of transferrin.     

Dietary zinc deficiency decreases plasma concentrations of vitamin E

Experiments were conducted to examine the effects of dietary zinc (Zn) upon plasma vitamin E (E) concentrations to test the hypothesis that there may be a significant dietary interaction between these two nutrients. Weanling female Sprague-Dawley rats were fed diets that were (i) Zn-deficient (less than 0.9 micrograms Zn/g diet) ad libitum; (ii) Zn-adequate (50.9 micrograms Zn/g diet), pair-fed to the Zn-deficient group; and (iii) Zn-adequate (50.9 micrograms Zn/g diet) ad libitum. Plasma E in Zn-deficient animals (4.02 +/- 1.20 micrograms/ml) was significantly reduced (P less than or equal to 0.05) compared with results in both Zn-adequate pair-fed (9.21 +/- 0.70 micrograms/ml) and Zn-adequate ad libitum-fed (9.47 +/- 0.90 micrograms/ml) animals. Zn deficiency in this model system also resulted in significant (P less than or equal to 0.05) reductions in femur and plasma Zn concentrations as well as in plasma retinol, plasma triglyceride, and plasma cholesterol concentrations. Plasma albumin and total plasma protein concentrations were normal in Zn-deficient animals. With dietary Zn deficiency, the decrease in plasma E appeared to be out of proportion to associated decreases in plasma triglyceride and plasma cholesterol concentrations. Since E is associated with plasma lipoproteins, these data suggest that lipid and/or E malabsorption may be a consequence of Zn deficiency. In response to increased dietary intake of E, increments of plasma E were lower in Zn-depleted than in Zn-adequate, pair-fed animals. These findings suggest that dietary Zn deficiency possibly may increase the nutritional requirement for E necessary to maintain adequate plasma concentrations.     

Effect of alimentary thiamine deficiency on the activity of gluconeogenic key enzymes in rat liver and kidney

Activity of the key enzymes of gluconeogenesis under alimentary thiamine deficiency (15 days of dietary treatment) was studied in the liver and kidney of fed and 48 h starved rats. As compared to pair-fed controls vitamin B1-deficiency was followed by a decrease of glucose 6-phosphatase and fructose 1,6-bisphosphatase activities in both organs; the activity of phosphoenolpyruvate carboxykinase was diminished only in the liver. Starvation of thiamine-deficient rats (as compared to pair-fed starved group) resulted in lower activation of these enzymes. The decrease of the enzyme activities in thiamine-deficient animals indicates that de novo glucose synthesis in the tissues is depressed, though thiamine-requiring enzymes are not directly involved in this process. Possible mechanisms of alterations described are discussed.     

Protein metabolism. 3. Relationship between albumin metabolism and elevated liver protein synthesis in the guinea pig infected with Trichostrongylus colubriformis

Studies of the incorporation of ¹⁴C-l-leucine into polypeptides by isolated liver ribosomes from guinea pigs confirmed previous in vivo studies that showed that Trichostrongylus colubriformis infection results in an elevated hepatic protein synthesis.The increased rate of protein synthesis was associated with the membrane-bound ribosomes that synthesize the circulating plasma proteins. Inappetance of infected animals was not resposible for the increased rate of synthesis by the membrane-bound ribosomes, but it was found that undernourishment may stimulate synthesis by free ribosomes.Plasma albumin turnover rate and loss into the intestine were both significantly increased in infected guinea pigs. It was concluded that these changes stimulated protein synthesis by membrane-bound ribosomes.The importance of elevated liver protein synthesis and loss of plasma protein in gastrointestinal nematode infections is discussed.     

Involvement of the liver in the regulation of tryptophan availability. Possible role in the responses of liver and brain to starvation

The concentrations of free and total (free plus albumin bound) tryptophan were measured in plasma of blood taken from the portal vein, hepatic vein and abdominal aorta of male rats, fed, and starved for one and three days. Liver and brain tryptophan concentrations were measured in similar groups of rats.On starvation, there was an increase in arterial plasma free tryptophan concentration which took place peripherally and was paralleled by an increase in brain tryptophan. In both the fed and starved rats, the portal vein concentrations of free tryptophan were high and as the blood flowed through the liver they were reduced to relatively low levels not directly related to the arterial values. All these changes were due to alterations in degree of binding of tryptophan to plasma albumin.The measurements of plasma total tryptophan concentrations showed that postabsorptively and during starvation there was a net uptake of tryptophan by the peripheral tissues (which included brain), but no overall fall in plasma concentration. At the same time, there was a net release from the liver, and to a lesser extent from the portal-drained tissues. The released tryptophan largely entered the albumin bound plasma pool. Accompanying the hepatic output was a fall in tryptophan concentration in the liver which was apparently caused by altered cell membrane transport.The results suggest (1) that the liver protects the brain from the high free tryptophan level in portal blood, (2) that the availability of tryptophan to the brain is maintained postabsorptively and during starvation by hepatic output into the albumin bound pool and (3) that this release of tryptophan from the liver and the fall in intracellular tryptophan concentration are initiated by altered membrane transport. The pattern of changes is consistent with a role for tryptophan in the mediation of changes in liver protein synthesis and gluconeogenesis and cerebral serotonin turnover on starvation.     

Cerebral Cortex Ammonia and Glutamine Metabolism in Two Rat Models of Chronic Liver Insufficiency-Induced Hyperammonemia: Influence of Pair-Feeding

Abstract: Enhanced cerebral cortex ammonia uptake, subsequent glutamine synthesis, and glutamine release into the bloodstream have been hypothesized to deplete cerebral cortex glutamate pools. We investigated this hypothesis in rats with chronic liver insufficiency-induced hyperammonemia and in pair-fed controls to rule out effects of differences in food intake. Cerebral cortex plasma flow and venous-arterial concentration differences of ammonia and amino acids, as well as cerebral cortex tissue concentrations, were studied 7 and 14 days after surgery in portacaval-shunted/bile duct-ligated, portacaval-shunted, and sham-operated rats, while the latter two were pair-fed to the first group, and in normal unoperated ad libitum-fed control rats. At both time points, arterial ammonia was elevated in the chronic liver insufficiency groups and arterial glutamine was elevated in portacaval shunt/biliary obstruction rats compared to the other groups. In the chronic liver insufficiency groups net cerebral cortex ammonia uptake was observed at both time points and was accompanied by net glutamine release. Also in these groups, cerebral cortex tissue glutamine, many other amino acid, and ammonia levels were elevated. Tissue glutamate levels were decreased to a similar level in all operated groups compared with normal unoperated rats, irrespective of plasma and tissue ammonia and glutamine levels. These results demonstrate that during chronic liver insufficiency-induced hyperammonemia, the rat cerebral cortex enhances net ammonia uptake and glutamine release. However, the decrease in tissue glutamate concentrations in these chronic liver insufficiency models seems to be related primarily to nutritional status and/or surgical trauma.