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Biomedical subjects

S A Adibi

Publications and source records attributed to S A Adibi.

At least 73 records · Page 4Linked to original sources
PubMed1986

Mechanism of increased hepatic concentration of carnitine by clofibrate.

Our previous studies have shown that treatment of rats with clofibrate, a hypolipidemic drug, greatly increases the total concentration of carnitine in the liver (H. S. Paul and S. A. Adibi, J. Clin. Invest. 64: 405-412, 1979). In the present experiment we have investigated some possible mechanisms to account for this increase. Clofibrate treatment (30 mg/100 g rat/day for 2 wk) increased significantly the concentration (nmol/g, mean +/- SE, 6 rats) of both free (289 +/- 21 vs. 1,747 +/- 131) and acylcarnitine (87 +/- 11 vs. 412 +/- 42). These increases were not the result of redistribution of carnitine among tissues or due to a decrease in urinary excretion. In view of previous observations that thyroid hormones increase the hepatic concentrations of carnitine, and clofibrate treatment causes a hyperthyroid state in the liver, we investigated the effect of clofibrate in thyroidectomized rats. Clofibrate treatment of thyroidectomized rats also increased the concentration of free (423 +/- 25 vs. 1,460 +/- 123) and acylcarnitine (35 +/- 6 vs. 305 +/- 31) in the liver. Finally, clofibrate treatment significantly increased the urinary excretion of trimethyllysine, a precursor of carnitine (31 +/- 3 vs. 47 +/- 4 nmol/mg creatinine, mean +/- SE, 5 rats). Our data suggest that clofibrate treatment stimulates hepatic synthesis of carnitine by increasing the availability of its precursor, trimethyllysine. This effect of clofibrate is independent of thyroid hormone.

Animals↗
PubMed1986

A concentrated mixture of amino acids and dipeptides for total parenteral nutrition.

Using a subhuman primate (baboon) we have investigated the utility of a 20% mixture of amino acids and dipeptides as the nitrogen source for total parental nutrition. The mixture, besides containing all 8 essential amino acids and a number of non-essential amino acids (glutamate, aspartate, arginine, histidine, serine, ornithine and alanine), contained 6 dipeptides (Gly-Ile, Gly-Leu, Gly-Val, Gly-Tyr, Gly-Gln, and Ala-Gln) and acetyl-cysteine. A week of total parenteral nutrition was preceded by one week of oral feeding. The caloric intake and composition during the two periods was identical except for the nitrogen source, which was intact protein during the oral period, and the mixture of amino acids and dipeptides during the parenteral period. There was no significant difference between gain in body weight or nitrogen balance during the two periods. There were selective increases in plasma and muscle concentrations of amino acids during the parenteral period, which appeared to reflect the amino acid enrichment of the nitrogen source. The efficient utilization of dipeptides was evidenced by their small concentrations in plasma and urine. The urinary excretion of dipeptides was about 1% of the amount infused. This efficiency of dipeptide utilization persisted even when the infusion rate of the amino acid and dipeptide mixture was increased by 7-fold. There was no alteration in liver, kidney, and immune function during the parenteral period. The data indicate the efficacy and safety of the mixture of amino acids and dipeptides as the nitrogen source for parenteral nutrition.

Amino Acids↗
PubMed1985

Leucine metabolism in thyrotoxicosis: plasma aminogram and 3-methylhistidine excretion before and after treatment.

Previous studies have suggested increased protein catabolism and altered muscle metabolism in hyperthyroid patients. In this experiment we investigated parameters of protein and leucine metabolism before and after treatment of hyperthyroidism. While confined in a metabolic ward, patients' daily caloric intake was based on the resting energy expenditure and an allowance for 16 hours of light physical activity. We found no significant difference in plasma aminogram and urinary 3-methylhistidine excretion (an index of protein catabolism) before and after treatment. On the other hand, hyperthyroidism appeared to increase the rates of oxidation, turnover, and plasma clearance of endogenous leucine. However, only the 60% increase in the rate of leucine oxidation was statistically significant. We conclude that in spite of increased catabolism, basal levels of branched-chain amino acids are well maintained in plasma of hyperthyroid patients consuming a diet that compensates for their hypermetabolic state.

Adult↗
PubMed1985

Effect of starvation on amino acid and peptide transport and peptide hydrolysis in humans.

Jejunal disappearance rates of glycine (a model for neutral amino acid absorption), triglycine (a model for peptide transport), and tetraglycine (a model for brush-border membrane hydrolysis) were investigated by an in situ perfusion technique before and after 2 wk of starvation in seven obese volunteers. The three test solutions of glycine, triglycine, and tetraglycine were equivalent in glycine content. Before starvation glycine absorption was greatest from the triglycine solution and smallest from the glycine solution. Starvation significantly decreased glycine absorption from both glycine and triglycine solutions, but not from the tetraglycine solution. However, glycine absorption was still significantly greater from the triglycine and tetraglycine solutions than from the glycine solution. Starvation had no significant effect on the disappearance rate of triglycine, but it increased the disappearance rate of tetraglycine. We conclude that a) starvation has different effects on functions of mucosal brush-border membrane, for example, it reduces amino acid absorption but enhances peptide hydrolysis; and b) the greater amino acid absorption from peptides is maintained even after 2 wk of starvation, suggesting that peptides are superior to free amino acids as the nitrogen source for enteral nutrition if employed in malnutrition.

Absorption↗
PubMed1985

Effect of dietary fat, carbohydrate, and protein on branched-chain amino acid catabolism during caloric restriction.

To assess the effect of each dietary caloric source on the catabolism of branched-chain amino acids, we investigated the rate of leucine oxidation before and after obese volunteers consumed one of the following diets for one week: (a) starvation, (b) 300 or 500 cal of fat/d, (c) 300 or 500 cal of carbohydrate/d, (d) 300 or 500 cal of protein/d, (e) a mixture of carbohydrate (300 cal/d) and fat (200 cal/d), or (f) a mixture of carbohydrate (300 cal/d) and protein (200 cal/d). Starvation significantly increased the rate of leucine oxidation (1.4 +/- 0.11 vs. 1.8 +/- 0.16 mmol/h, P less than 0.01). The same occurred with the fat and protein diets. In sharp contrast, the 500-cal carbohydrate diet significantly decreased the rate of leucine oxidation (1.3 +/- 0.13 vs. 0.6 +/- 0.09 mmol/h, P less than 0.01). The same occurred when a portion of the carbohydrate diet was isocalorically replaced with either fat or protein. The cumulative nitrogen excretion during the fat diet and starvation was not significantly different. As compared with the fat diets, the carbohydrate diets on the average reduced the urinary nitrogen excretion by 12 g/wk. Nitrogen balance was positive during the consumption of the 500-cal protein diet, but negative during the consumption of carbohydrate-protein diet. The fat diets, like the protein diets and starvation, greatly increased plasma leucine (119 +/- 13 vs. 222 +/- 15 microM, P less than 0.01) and beta-hydroxybutyrate (0.12 +/- 0.02 vs. 4.08 +/- 0.43 mM, P less than 0.01) concentrations, and significantly decreased plasma glucose (96 +/- 4 vs. 66 +/- 3 mg/dl, P less than 0.01) and insulin (18 +/- 4 vs. 9 +/- 1 microU/ml, P less than 0.05) concentrations. These changes did not occur, or were greatly attenuated, when subjects consumed carbohydrate alone or in combination with fat or protein. We conclude that during brief caloric restriction, dietary lipid and protein, unlike carbohydrate, do not diminish the catabolism of branched-chain amino acids and the decrease in branched-chain amino acid oxidation is associated with protein sparing.

3-Hydroxybutyric Acid↗
PubMed1984

Partial substitution of amino acids of a parenteral solution with tripeptides: effects on parameters of protein nutrition in baboons.

We previously showed that triglycine and trileucine are efficiently utilized when infused intravenously (IV) in baboons who are fed a complete diet orally. In the present experiments we investigated the utilization of these tripeptides in the context of total parenteral nutrition. A group of subhuman primates (baboon) was subjected sequentially to two forms of total parenteral nutrition, each for a period of six days. The only difference between the two periods was that in one, all amino acids were given in free form, and in the other, the glycine and leucine components of the amino acid mixture were replaced with triglycine and trileucine, respectively. During both experimental periods the infusion solution provided daily 100 calories/kg body weight and 2.5 g amino acids/kg body weight. There were no significant differences between nitrogen balance, plasma amino acid concentrations, or urinary excretion of amino acids for the two forms of parenteral nutrition. The only exceptions were a greater plasma concentration of isoleucine and a greater urinary excretion of leucine during infusion of the partial peptide solution. Assimilation of triglycine and trileucine under the conditions of total parenteral nutrition was assessed by determining concentrations of these peptides in plasma and urine. Trileucine was not found in plasma, and only 1.8% of the amount of trileucine infused appeared as trileucine and dileucine in urine. Triglycine was detected in plasma and 17.1% of the amount of triglycine infused was excreted in urine as triglycine and diglycine. These data suggest that assimilation of trileucine and triglycine under the conditions of our experiment was sufficiently efficient to meet the daily need for an essential amino acid (leucine) and for nitrogen (glycine).

Amino Acids↗
PubMed1984

Influence of clofibrate on thyroid hormone and muscle protein turnover.

Clofibrate, a hypolipidemic agent, has been shown to increase muscle protein degradation. The possible role of thyroid hormones in this phenomena was examined. Clofibrate treatment of rats for 2 weeks resulted in a significant decrease in total thyroxine and triiodothyronine levels in serum. Reverse T3 and resin uptake values remained unchanged. When exogenous thyroxine was co-administered with clofibrate, serum TSH levels were suppressed, but the increased muscle protein degradation was not reversed. Equilibrium dialysis and Scatchard analysis of the binding of 125I-thyroxine to serum proteins indicated that clofibrate competitively inhibits the binding of thyroid hormone to serum proteins by decreasing its apparent binding affinity. In the presence of lower total thyroid hormone concentrations and an elevated free thyroxine fraction, the total free hormone levels are estimated to be in the normal range in the serum of clofibrate treated rats. Clofibrate seems to act like thyroid hormone since it binds to and displaces T4 from plasma proteins. Because free thyroid hormone levels are in the normal range, the thyroid hormone-like effects of clofibrate on the cell may be additive to the T4 effects, and are probably responsible for the hypermetabolic state seen in the muscle of clofibrate-treated animals. Our data suggest that the effects of clofibrate in muscle are complex. In addition to competitively altering the binding of thyroxine to serum proteins, this substance may also exert a hitherto unrecognized thyroid-hormone-like subcellular effect resulting in increased muscle protein degradation, and in augmented ouabain-sensitive ATPase activities.

Animals↗
PubMed1984

Interaction between transport of zinc and other solutes in human intestine.

To investigate the kinetics of zinc absorption, a jejunal segment from healthy human volunteers was intubated with a triple-lumen tube, and isotonic NaCl solutions containing 0, 0.1, 0.3, and 0.9 mM ZnCl2 were infused. There was secretion of zinc when zinc was not added to the test solution but absorption when zinc was added. Over the range of zinc concentrations infused, there were linear increases in the rate of zinc absorption. There was net absorption of sodium and water during the infusion of isotonic saline solution but no net absorption when zinc (0.9 mM) was added to this solution. This impairment was not prevented by adding glucose to the test solution, but the rate of zinc absorption was significantly enhanced in the presence of glucose. The rate of glucose absorption was not affected by adding zinc to a glucose-saline solution. Zinc absorption was significantly stimulated by the addition of glycylleucine to the test solution, whereas the corresponding mixture of glycine and leucine had no effect. The data allow the following conclusions: a) zinc absorption is selectively stimulated by organic solutes and b) zinc inhibits net absorption of sodium and water in the jejunum.

Adult↗
PubMed1984

Efficacy of a synthetic dipeptide mixture as the source of amino acids for total parenteral nutrition in a subhuman primate (baboon). Plasma concentration, metabolic clearance, and urinary excretion of a series of dipeptides.

To assess the efficacy and safety of oligopeptides as substrates for total parenteral nutrition, we investigated the effects of intravenous infusion of a synthetic dipeptide mixture, as compared with a corresponding amino acid mixture, on a range of parameters of nutrition, metabolism, and organ function in baboons. In all respects the two periods of total parenteral nutrition, each lasting for 1 wk, were identical except for the difference between the forms of amino acids in the parenteral solutions, being in free form in one period and in dipeptide form in the other. The dipeptide mixture was composed of a series of 12 dipeptides each containing glycine in the N-terminal position and either an essential or nonessential amino acid in the carboxyl position. The infusion of the dipeptide mixture and the amino acid mixture had similar effects on parameters of protein nutrition (e.g., nitrogen balance, plasma aminogram, urinary excretion of 3-methylhistidine) and metabolism (such as plasma concentrations of insulin, glucose, lipids). During infusion of the dipeptide mixture, rapid metabolic clearance resulted in a barely detectable concentration of most dipeptides in plasma. Total loss of dipeptides was 1.3% +/- 0.1% of the infused amount. The functions of liver, kidney, bone marrow, and the immune system remained the same before and during the two periods of treatment. In conclusion, the data showed that (a) there was efficient utilization of dipeptides when infused as a mixture and (b) parameters of nutrition, metabolism, and organ function were well maintained after 1 wk of total parenteral nutrition with the dipeptide mixture acting as the sole nitrogen source.

Amino Acids↗
PubMed1983

Mechanism of activation of hepatic branched-chain alpha-ketoacid dehydrogenase by a muscle factor.

We recently reported that a skeletal muscle factor specifically activates the branched-chain alpha-ketoacid (BCKA) dehydrogenase in liver mitochondria (Paul, H. S., and Adibi, S. A. (1982) J. Biol. Chem. 257, 12581-12588). The evidence suggested that the muscle factor may be a phosphatase or may stimulate the phosphatase in liver mitochondria, thus converting the inactive BCKA dehydrogenase into an active form. In the present study we have investigated these possibilities. The muscle factor did not increase the activity of BCKA dehydrogenase which was previously activated in vitro by preincubation of mitochondria or by the addition of Triton or Ca2+ to the incubation medium. The muscle factor had little or no stimulatory effect on BCKA dehydrogenase when this enzyme was activated in vivo by treatment of rats with streptozotocin or clofibrate. The addition of NaF (an inhibitor of phosphatase) to the incubation medium entirely abolished the stimulatory effect of the muscle factor on BCKA dehydrogenase. Elimination of phosphatase by partial purification of BCKA dehydrogenase resulted in loss of stimulation of the dehydrogenase by the muscle factor. These results suggest that the muscle factor activates the BCKA dehydrogenase in liver mitochondria by stimulating its associated phosphatase.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1983

Fasting-enhanced immune effector mechanisms in obese subjects.

Acute nutritional deprivation occurs frequently in clinical practice, yet little data exist on its effect on immune host defenses. To investigate this question, various immune parameters were studied in 15 obese subjects before and after a 14-day fast. Blood monocyte bactericidal activity and natural killer cell cytolytic activity were enhanced by fasting: monocyte killing increased in 12 of 14 subjects (p less than 0.05) and natural killer cell activity increased an average of 24 percent in 13 subjects tested (p less than 0.02). Starvation also enhanced parameters of humoral immunity as evidenced by increases in serum concentrations of IgG, IgA, and IgM (p less than 0.01). By contrast, lymphocyte blastogenic responses to the mitogen phytohemagglutinin were modestly decreased. Peripheral blood leukocyte counts, including neutrophils, T cells, and B cells, did not decrease significantly. These results indicate that fasting has differential influences on immune function rather than a uniformly deleterious effect. Of potential import, this nutritional alteration appears to actually enhance certain effector functions of the host defense system.

Adult↗
PubMed1983

Utilization of intravenously infused tripeptides in baboons: effect on plasma concentration and urinary excretion of amino acids.

When baboons, while consuming an adequate diet, were infused continuously for 3 days with parenteral solutions (1I/day) containing either triglycine (50 mM) or trileucine (5 mM) there was either no or very little accumulation of these peptides either in plasma or urine. The increases in plasma concentrations of glycine or leucine and urinary excretion rates of these amino acids during the infusion of the above tripeptides were similar to those found when baboons were infused with parenteral solutions containing either glycine (150 mM) or leucine (15 mM). These data show efficient utilization of tripeptides under the condition of continuous infusion and encourage further investigation of tripeptides as substrates for parenteral nutrition.

Amino Acids↗
PubMed1983

Clofibrate does not alter cyclic nucleotide metabolism in muscle.

Clofibrate is a hypolipidemic agent that causes muscle protein breakdown in rats, and an acute muscular syndrome in man. It also inhibits adenylate cyclase in fat tissue. Muscle protein metabolism has been shown to be regulated by cyclic nucleotides. In the present experiments were measured several parameters of cyclic nucleotide metabolism to determine the role that cyclic nucleotides play in clofibrate-induced muscle protein degradation. It was found that clofibrate treatment did not alter cyclic nucleotide levels, nor did it change the activities of basal or hormone-stimulated adenylate cyclase, or cyclic nucleotide phosphodiesterase in muscle. Our results suggest that muscle protein breakdown in clofibrate-treated rats is not regulated by cyclic nucleotides.

Adenylyl Cyclases↗
PubMed1982

Activation of hepatic branched chain alpha-keto acid dehydrogenase by a skeletal muscle factor.

These experiments were designed to determine whether there are tissue factors which affect the activity of branched chain alpha-keto acid (BCKA) dehydrogenase in the mitochondria of the same or different tissues. The activity of BCKA dehydrogenase was increased by the addition of the cytoplasmic fraction of the gastro-cnemius muscle to liver mitochondria. The specificity of the effect of the muscle factor was established by the fact that it only increased the BCKA dehydrogenase activity in liver mitochondria. The activity of this enzyme in mitochondria from skeletal muscle, heart, kidney, or brain was either not affected or inhibited by the muscle factor. Muscle factor also increased the activity of alpha-ketoglutarate dehydrogenase but decreased that of pyruvate dehydrogenase in liver mitochondria. This factor was found in a variety of skeletal muscles but not in smooth muscle such as uterus. A factor similar to that of muscle was not found in liver or kidney cytoplasm but was detected in plasma. There were similarities between the effects of muscle and plasma factors on the BCKA dehydrogenase activity in liver, kidney, heart, and skeletal muscle mitochondria. Studies concerning the properties and partial characterization of this factor revealed that it (a) is nondialyzable, (b) is a protein, (c) is heat labile, and (d) increases the activity of BCKA dehydrogenase by increasing the Vmax without a change in the apparent Km.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1982

Role of ATP in the regulation of branched-chain alpha-keto acid dehydrogenase activity in liver and muscle mitochondria of fed, fasted, and diabetic rats.

The activity of branched-chain alpha-keto acid (BCKA) dehydrogenase was increased after preincubation of liver and muscle mitochondria of control rats. Preincubation depleted mitochondrial ATP. Addition of ATP prevented the activation of BCKA dehydrogenase as well as reversed the activity of a fully activated enzyme to normal. Inhibition of phosphatase blocked the activation of BCKA dehydrogenase. There was a small or no increase in BCKA dehydrogenase activity when mitochondria from tissues of fasted, diabetic, and clofibrate-treated rats were preincubated. In fasted and diabetic rats, ATP was either less effective or failed to reverse the increased dehydrogenase activity in preincubated mitochondria. The concentration of ATP in liver and muscle mitochondria of diabetic rats was approximately one-half that of the control rats. We conclude that (a) in the fed state approximately 30-40% of BCKA dehydrogenase exists in the active form. The enzyme can be fully activated by preincubation of mitochondria which causes the depletion of ATP. Phosphatase is necessary for this activation. (b) In fasted, diabetic, and clofibrate-treated rats, approximately 70-100% of the enzyme exists in the active form which may be related to the mitochondrial depletion of ATP in vivo, and (c) while ATP can reverse the activation in control rats, it fails to do so in diabetic rats suggesting that other metabolic alterations may be involved in the regulation of BCKA dehydrogenase in diabetes.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗