Glycyl-dipeptides: new substrates for protein nutrition.
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Animals↗
Biomedical subjects
S A Adibi
Publications and source records attributed to S A Adibi.
Specificity and mechanism of influence of amino acid residues on hepatic clearance of oligopeptides.
We have investigated the influence of amino acid residues on hepatic clearance of oligopeptides by determining the rate of disappearance (nmol.(min.g liver)-1) of selective oligopeptides from the medium during isolated rat liver perfusion. (a) N terminus: the rate of disappearance of Ala-Leu was greater (p less than 0.01) than those of Gly-Leu, Phe-Leu, and Arg-Leu (208 +/- 13, 135 +/- 13, 116 +/- 12, and 127 +/- 12, respectively). (b) C terminus: the rate of disappearance of Leu-Ala (244 +/- 18) was significantly greater (p less than 0.01) than that of Leu-Gly (145 +/- 16). (c) Number of residues: with each increase in the number of alanine residues (2-4) there was a significant increase in the rate of peptide disappearance, and conversely, with each increase in the number of glycine residues (2-6) there was a significant decrease in the rate of peptide disappearance. Further studies showed no peptide transport by isolated liver plasma membrane vesicles and no significant correlation between the rates of peptide disappearance and hydrolase activities of the perfusion medium but highly significant correlation with hydrolase activity of plasma membrane. We conclude that certain amino acid residues, such as alanine, enhance hepatic clearance of oligopeptides by increasing their affinity as substrates for plasma membrane peptide hydrolases.
Alanine↗
Intravenously infused carnitine: influence on protein and branched-chain amino acid metabolism in starved and parenterally fed rats.
We studied the effect of intravenously infused carnitine (34 mumol.100 g-1.d-1) on protein and branched-chain amino acid (BCAA) metabolism in rats either starved for 3 d or parenterally fed for 7 d. Carnitine infusion did not significantly affect nitrogen balance, protein content of liver and muscle, plasma concentrations of BCAA and branched-chain keto acid, or leucine oxidation and incorporation into liver and muscle proteins of either starved or fed rats. Despite a two- to threefold increase in plasma carnitine level, tissue concentrations of carnitine and its acyl-derivatives were not significantly affected by carnitine infusion. Of the amount of carnitine infused, 91% was lost in the urine of starved rats and 87% in the urine of fed rats. We conclude that intravenous carnitine infusion does not affect protein and BCAA metabolism and that this lack of effect may be related to the failure of carnitine infusion to enrich tissue pools of carnitine.
3-Hydroxybutyric Acid↗
Metabolism of dipeptides and their constituent amino acids by liver, gut, kidney, and muscle.
Oligopeptides may enter the bloodstream from endogenous and exogenous sources. Using an organ-balance technique in conscious dogs, we investigated the role of individual organs in removal of two model oligopeptides (glycylleucine and glycylglycine) from plasma under steady-state conditions. Despite an identical infusion rate, arterial concentration of glycylglycine was twofold greater than that of glycylleucine. This appeared to be a result of greater fractional extraction of glycylleucine than glycylglycine by organs. Although all of the organs examined participated in removal of dipeptides from plasma, their roles varied. Liver, kidney, muscle, and gut accounted for the disappearance of 25, 24, 12, and 10% of the infused amount of glycylleucine, respectively. With glycylglycine as the substrate, disappearance across kidney accounted for 37% of the infused amount, whereas muscle, liver, and gut accounted for 18, 15, and 11%, respectively. Finally, we investigated glycine and leucine balances across organs with infusion of these amino acids in free and dipeptide forms. Glycine and leucine balances were uniquely more positive across muscle during the infusion of glycylleucine than the corresponding amino acid mixture. The possible mechanisms included release of products of glycylleucine hydrolysis by all organs except muscle. We conclude that molecular structure influences the organ extraction of dipeptides; if extraction, particularly by the liver, is not sufficiently rapid, kidney assumes a greater role than other organs in dipeptide removal from plasma.
Amino Acids↗
Regulation of leucine catabolism by caloric sources. Role of glucose and lipid in nitrogen sparing during nitrogen deprivation.
Previously we showed that hypocaloric amounts of glucose reduce leucine catabolism while an isocaloric amount of fat does not (1985. J. Clin. Invest. 76:737.). This study was designed to investigate whether the same difference exists when the entire caloric need is provided either as glucose or lipid. Rats were maintained for 3 d on total parenteral nutrition (350 cal/kg per d), after which the infusion of amino acids was discontinued and rats received the same amount of calories entirely as glucose or lipid for three more days. A third group of rats was infused with saline for 3 d. In comparison to glucose, lipid infusion resulted in higher urinary nitrogen excretion (55 +/- 3 vs. 37 +/- 2 mg N/24 h, P less than 0.05), muscle concentrations of tyrosine (95 +/- 8 vs. 42 +/- 8 microM, P less than 0.01), and leucine (168 +/- 19 vs. 84 +/- 16 microM, P less than 0.01), activity of BCKA dehydrogenase in muscle (2.2 +/- 0.2 vs. 1.4 +/- 0.04 nmol/mg protein per 30 min, P less than 0.05), and whole body rate of leucine oxidation (3.3 +/- 0.5 vs. 1.4 +/- 0.2 mumol/100 g per h, P less than 0.05). However, all these parameters were significantly lower in lipid-infused than starved rats. There was no significant difference between leucine incorporation into liver and muscle proteins of lipid and glucose-infused rats. On the other hand, starved rats showed a lower leucine incorporation into liver proteins. The data show that under conditions of adequate caloric intake lipid has an inhibitory effect on leucine catabolism but not as great as that of glucose. The mechanism of this difference may be related to a lesser inhibition of muscle protein degradation by lipid than glucose, thereby increasing the leucine pool, which in turn stimulates leucine oxidation.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Leucine catabolism and incorporation into tissue proteins in thyroparathyroidectomized rats.
We investigated parameters of leucine metabolism in thyroparathyroidectomized (TPX) and pair-fed control rats using a technique of continuous infusion of [l-14C]leucine. The rate of leucine turnover was significantly smaller in TPX than in control rats (42.5 +/- 2.6 vs 35.1 +/- 1.9 mumole/hr/100 g, mean +/- SEM, six rats). There was no significant difference between rates of alpha-decarboxylation of leucine by the two groups of rats. The protein incorporation of leucine was significantly smaller in the muscle of TPX than control rats (39 +/- 5 vs 24 +/- 4 pmole/mg protein, mean +/- SEM, six rats) but in liver it was not significantly different. Thyroparathyroidectomy also had no significant effect on concentration of either leucine or its ketoacid (alpha-ketoisocaproate) in plasma, liver, and muscle. We conclude that hypothyroidism does not alter catabolism of leucine but reduces its incorporation into muscle protein.
Animals↗
Development of hepatic cholestasis and fibrosis in patients with massive loss of intestine supported by prolonged parenteral nutrition.
We studied the effect of 1 yr of parenteral nutrition on liver function tests and, when indicated, liver histology and ultrastructure of 18 patients with no (n = 6), modest (n = 6), and massive (n = 6) loss of intestine. The resection was for Crohn's disease and infarction, respectively. The liver function tests remained normal in all patients with no loss and modest loss of intestine. Four patients with massive loss of intestine, 4-10 mo after initiation of parenteral nutrition, began to develop progressive, marked increases in serum alkaline phosphatase (2-10 times normal), glutamic oxaloacetic transaminase (7-20 times normal), and glutamic pyruvic transaminase (5-14 times normal) activity levels, and bilirubin concentration (5-22 times normal). Light microscopic examination of liver showed cholestasis, bile ductular proliferation, periportal inflammation, fibrosis, and mild steatosis. Electron microscopic examination of liver showed cholestasis with nonspecific organelle changes. None of the patients had any evidence of extrahepatic obstruction. Our data suggest that massive loss of intestine is a contributing factor to hepatic cholestasis and fibrosis in patients maintained on prolonged parenteral nutrition.
Cholestasis↗
Experimental basis for use of peptides as substrates for parenteral nutrition: a review.
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Amino Acids↗
Parenteral nutrition with an amino acid solution containing a mixture of dipeptides. Evidence for efficient utilization of dipeptides in man.
Ten healthy human subjects received parenteral nutrition consisting of 80 g of a dipeptide-amino acid mixture and 900 carbohydrate calories infused over a period of 12 h, and then fasted for another period of 12 h. The dipeptides included in the mixture were: glycyl-L-glutamine, glycyl-L-tyrosine, glycyl-L-leucine, glycyl-L-isoleucine, and glycyl-L-valine. Parenteral nutrition with the dipeptide-amino acid mixture was without any adverse reaction in any of the subjects. The urinary excretion of the 5 dipeptides during parenteral nutrition ranged between 1 and 2% of the amount infused. Plasma concentrations of dipeptides during parenteral nutrition, which ranged from 8-96 microM reflected their plasma half-lives. Glycyl-L-glutamine had the longest half-life, glycyl-L-leucine and glycyl-L-tyrosine the shortest half-lives. During parenteral nutrition there were increases in plasma amino acid concentrations including those of glutamine and tyrosine. Discontinuation of parenteral nutrition resulted in the disappearance of dipeptides from plasma, and the dissipation of increased plasma amino acid concentrations. In conclusion, the present results show efficient utilization of glycyl-dipeptides as substrates for parenteral nutrition in man. The results further show that the structure of amino acids in the C-terminal position has a significant influence on the metabolism of dipeptides.
Adult↗
Utilization of intravenously administered peptides: influence of molecular structure.
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Amino Acids↗
Metabolism of glycylleucine and its constituent amino acids by liver, muscle, kidney and gut in conscious dogs.
The role of liver, muscle, kidney and gut in the assimilation of intravenously administered glycylleucine was investigated in 8 mongrel dogs. The rates of disappearance of glycylleucine during its passage across liver, muscle, kidney and gut were 1487 +/- 80, 740 +/- 216, 1436 +/- 115, and 602 +/- 103 mumol/(min x kg B.W.), respectively. The infusion of glycylleucine greatly altered the fluxes of glycine and leucine across these organs. The major alterations included increases in the uptake of glycine by the liver and that of leucine by the muscle, and increases in release of leucine by liver and kidney. We conclude that all organs are involved in the assimilation of intravenously administered glycylleucine, but with varying importance. Although liver and kidney appear to be the dominant organs for the assimilation of glycylleucine, the metabolism of glycine is chiefly accomplished in the liver, and that of leucine is chiefly accomplished in the muscle.
Animals↗
Mechanism of hepatic assimilation of dipeptides. Transport versus hydrolysis.
To investigate dipeptide assimilation by the liver, a series of interrelated experiments were performed in rats. Partial hepatectomy prolonged the plasma half-life (min) of Gly-Ala (3.42 +/- 0.22 versus 4.90 +/- 0.35, p less than 0.05) but had no significant effect on plasma half-life of Gly-Leu, Gly-Pro, or Gly-Sar. We then investigated the rate of disappearance (mumol X (g liver X h)-1) of the above four dipeptides (initial concentration = 1 mM) from the medium during isolated liver perfusion. The order of dipeptide disappearance was: Gly-Leu (8.75 +/- 0.65) greater than Gly-Ala (3.36 +/- 0.46) greater than Gly-Pro (1.29 +/- 0.54) greater than Gly-Sar (0.35 +/- 0.12). This order of dipeptide disappearance corresponded exactly to the order of the rates of glycine accumulation in the medium during liver perfusion with the four dipeptides. Addition of glucagon had no effect on the disappearance rate of Gly-Ala from the medium, but reduced accumulation rates of glycine (3.39 +/- 0.30 versus 1.42 +/- 30, p less than 0.01) and alanine (4.42 +/- 0.66 versus 1.35 +/- 0.39, p less than 0.01). Finally, we found that hydrolysis by the liver plasma membranes and/or perfusion medium accounted for disappearance of dipeptides. In conclusion, the liver does not appear to have a transport system for dipeptides, but assimilates dipeptides by extracellular hydrolysis. Hydrolysis is achieved by enzymes either located on the plasma membranes or released from the cytosol. The amino acid residues released as the result of dipeptide hydrolysis are then taken up by the liver.
Animals↗
Kinetics and characteristics of absorption from an equimolar mixture of 12 glycyl-dipeptides in human jejunum.
We have investigated rates of dipeptide disappearance during jejunal perfusion with an equimolar mixture of 12 glycyl-dipeptides and compared amino acid absorption rates from this mixture with those from the corresponding free amino acid mixture in healthy volunteers. All dipeptides contained glycine in the N-terminal position, which was designed to favor peptide absorption rather than hydrolysis. At 2 mM concentration there was little difference in disappearance among dipeptides, but at 6 mM there was some selectivity: Gly-Phe and Gly-Met exhibited the fastest, and Gly-Arg and Gly-His the slowest rates of disappearance. However, between these ends of the spectrum there were only modest differences in disappearance among dipeptides (Gly-Ala, Gly-Thr, Gly-Leu, Gly-Ile, Gly-Val, Gly-Lys, Gly-Pro, Gly-Trp). The amino acid absorption rates were generally smaller but more selective from the free amino acid than from the dipeptide mixture. We conclude that (a) the C-terminal amino acid residue influences intestinal assimilation of glycyl-dipeptides and (b) the considerably greater absorption rate of amino acids from the dipeptide than from the amino acid mixture appears to be the result of uptake by a system that has a greater transport capacity than amino acid carrier systems, thus minimizing competition among its substrates.
Adult↗
Further characterization of a muscle factor which activates hepatic branched-chain ketoacid dehydrogenase.
A skeletal muscle factor which activates hepatic branched-chain keto acid dehydrogenase has been described. Since this factor is labile, the present study was designed to stabilize and characterize this factor. The muscle factor was stabilized by the addition of KCl and the protease inhibitor, antipain. Muscle factor activity was localized to the 100,000 g pellet fraction of muscle homogenate. The muscle factor was inactivated following trypsin or phospholipase A2 digestion.
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Inhibition of lipid accumulation and enhancement of energy expenditure by the addition of pyruvate and dihydroxyacetone to a rat diet.
To assess the effects of oral intake of pyruvate and dihydroxyacetone on body composition and metabolism, rats were divided into two groups and pair-fed one of the following isocaloric diets for 112 days. The control diet was a liquid diet with the following caloric composition: 14% protein, 28% fat, and 58% carbohydrate. The experimental diet was the same as the control diet except for the partial substitution of carbohydrate content with pyruvate and dihydroxyacetone. Rats receiving the experimental diet gained less weight than rats receiving the control diet. This reduction in body weight appeared to be largely the result of inhibition of lipid accumulation. The experimental diet reduced body fat content by 32% without any significant effect on either protein or water content. Rats receiving the experimental diet did not have increased loss of calories in the stool, but had greater rates of heat production and energy expenditure, which was accompanied by an elevated plasma level of thyroxine. Furthermore, rats receiving the experimental diet had a smaller rate of lipid synthesis in their adipose tissue, and a reduced plasma insulin level. The data suggest that inhibition of gain in weight with the addition of pyruvate and dihydroxyacetone to the diet is the result of an increased loss of calories as heat at the expense of storage as lipid.
Administration, Oral↗
Influence of molecular structure on half-life and hydrolysis of dipeptides in plasma: importance of glycine as N-terminal amino acid residue.
To investigate the effect of molecular structure on plasma disappearance and metabolism of dipeptides, rats were injected intravenously with individual dipeptides, and at various intervals after injection, dipeptide and amino acid concentrations were measured in plasma, tissues, and urine. In addition, plasma hydrolase activity against individual dipeptides was investigated. The half-lives of Ala-Leu, Ala-Tyr, and Ala-Gln were shorter than those of dipeptides with glycine substituting for alanine. Furthermore, the increases in plasma concentrations of leucine, tyrosine, and glutamine and rates of dipeptide hydrolysis by plasma enzymes were far greater with alanyl than glycyl dipeptides. In fact, Ala-Leu behaved like a mixture of corresponding free amino acids in raising the plasma concentration of leucine while Gly-Leu did not. There was no significant difference in either plasma half-life or hydrolysis when Leu-Gly and Leu-Ala were used as substrates, but both had rapid rates of hydrolysis in plasma. In comparison to Gly-Leu, Phe-Leu and Arg-Leu had shorter half-lives and greater rates of hydrolysis in plasma. On the other hand, Asp-Leu had a slower rate of plasma hydrolysis than Gly-Leu, but its excretion in the urine was much greater than that of Gly-Leu. In contrast to Gly-Leu and Ala-Leu, Gly-Pro was detected intracellularly in liver, muscle, and particularly, kidney. In fact, the intracellular concentration of Gly-Pro in kidney was either equal to or greater than Gly-Pro concentration in plasma. Increases in intracellular amino acid concentration after injection of individual dipeptides were considerably greater in the kidney than in either liver or muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗
Protein nutrition and amino acid metabolism after 4 weeks of total parenteral nutrition with a mixture of 14 dipeptides: serendipitous observations on effects of sepsis in baboons.
We investigated parameters of nutrition, metabolism, and organ function after 4 wk of total parenteral nutrition (TPN) in baboons receiving either dipeptides or amino acids as the nitrogen source. The two groups showed no significant difference with respect to gain in body weight, nitrogen balance, plasma and muscle concentrations of amino acids, plasma concentrations of proteins, and leucine incorporation into muscle protein. All dipeptides were efficiently utilized as evidenced by trace concentrations of dipeptides in plasma and urine; they produced no deleterious effect on the function of liver, kidney, or immune system. Development of infection in several baboons increased urinary excretion of urea nitrogen but had no effect on urinary excretion of dipeptides and amino acids with the single exception of taurine, which was greatly increased. In conclusion, the data show long-term efficacy and safety of the dipeptide mixture as the sole nitrogen source for TPN.
Amino Acids↗
Relation between plasma and tissue parameters of leucine metabolism in fed and starved rats.
By use of a primed continuous infusion of [1-14C]leucine, we investigated parameters of leucine metabolism in plasma, expired air, and tissues of fed and 48-h starved rats. The ratios of muscle to plasma specific activity of alpha-ketoisocaproate (KIC) in fed and starved rats were not significantly different from 1. The ratio of muscle to plasma specific activity of leucine was also not significantly different from 1 in fed rats, but was significantly lower than 1 in starved rats. The rate of leucine oxidation was 28-34% higher when calculation was based on plasma KIC rather than leucine specific activity. However, starvation significantly increased the rate of leucine oxidation with either specific activity. The rates of leucine incorporation into whole-body protein, calculated as the difference between plasma leucine turnover and oxidation, were unaffected by starvation, but the incorporations into total protein measured directly were significantly decreased in liver and muscle. We conclude that leucine or KIC specific activity in muscle is better predicted by plasma KIC than leucine specific activity, and the difference between rates of plasma leucine turnover and oxidation does not appear to be a valid measurement of leucine incorporation into whole-body protein.
Animals↗