Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism

Poll, Marcel C. G. van de; Siroen, Michiel P. C.; Leeuwen, Paul A. M. van; Soeters, Peter B.; Melis, Gerdien C.; Boelens, Petra G.; Deutz, Nicolaas E. P.; Dejong, Cornelis H. C.

doi:10.1093/ajcn/85.1.167

Cited by 158 publications

(135 citation statements)

References 27 publications

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“…Yet increased use of glutamine by GALT should increase its oxidation. Alternatively, increased splanchnic glutamine extraction may serve to enhance arginine availability, via citrulline synthesis (7,13,15,44,45,48,49), or the synthesis of glutathione, an antioxidant tripeptide involved in the maintaining of redox status in the intestinal mucosa, particularly under septic conditions (3,20,25,42).…”

Section: Discussionmentioning

confidence: 99%

Corticosteroids increase glutamine utilization in human splanchnic bed

Thibault

Welch²,

Mauras³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Thibault R, Welch S, Mauras N, Sager B, Altomare A, Haymond M, Darmaun D. Corticosteroids increase glutamine utilization in human splanchnic bed. Am J Physiol Gastrointest Liver Physiol 294: G548-G553, 2008. First published December 27, 2007 doi:10.1152/ajpgi.00461.2007.-Glutamine is the most abundant amino acid in the body and is extensively taken up in gut and liver in healthy humans. To determine whether glucocorticosteroids alter splanchnic glutamine metabolism, the effect of prednisone was assessed in healthy volunteers using isotope tracer methods. Two groups of healthy adults received 5-h intravenous infusions of L-[1-14 C]leucine and L-[ 2 H5]glutamine, along with q. 20 min oral sips of tracer doses of L-[1-13 C]glutamine in the fasting state, either 1) at baseline (control group; n ϭ 6) or 2) after a 6-day course of 0.8 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 prednisone (prednisone group; n ϭ 8). Leucine and glutamine appearance rates (Ra) were determined from plasma [1-14 C]ketoisocaproate and [ 2 H5]glutamine, respectively, and leucine and glutamine oxidation from breath 14 CO2 and 13 CO2, respectively. Splanchnic glutamine extraction was estimated by the fraction of orally administered [ 13 C]glutamine that failed to appear into systemic blood. Prednisone treatment 1) did not affect leucine Ra or leucine oxidation; 2) increased plasma glutamine Ra, mostly owing to enhanced glutamine de novo synthesis (medians Ϯ interquartiles, 412 Ϯ 61 vs. 280 Ϯ 190 mol ⅐ kg Ϫ1 ⅐ h Ϫ1 , P ϭ 0.003); and 3) increased the fraction of orally administered glutamine undergoing extraction in the splanchnic territory (means Ϯ SE 64 Ϯ 6 vs. 42 Ϯ 12%, P Ͻ 0.05), without any change in the fraction of glutamine oxidized (means Ϯ SE, 75 Ϯ 4 vs. 77 Ϯ 4%, not significant). We conclude that high-dose glucocorticosteroids increase in splanchnic bed the glutamine requirements. The role of such changes in patients receiving chronic corticoid treatment for inflammatory diseases or suffering from severe illness remains to be determined. nutrition; protein metabolism; stable isotopes; stress; gut GLUTAMINE PLAYS AN IMPORTANT role in the maintenance of intestinal function (39,43,46). Glutamine indeed is both a preferred fuel (9, 47) for enterocytes and a precursor for the intestinal synthesis of purines, pyrimidines (9), and glutathione (37), and it may regulate gut protein synthesis (21,30,32). In addition, glutamine is a major donor of carbon for gluconeogenesis (19). This explains why glutamine is extensively extracted in the splanchnic tissues in several animal species (39,47).In humans, the concomitant infusion of two tracers of glutamine (one infused intravenously, the other one enterally) can be used to assess the extraction of glutamine by the splanchnic bed. By using this technique, ϳ50 to 75% of enterally administered glutamine undergoes first-pass extraction within the splanchnic bed, presumably by the gut and liver, in healthy humans (4, 17, 18, 34). Additionally, the major fate of splanchnic glutamine after enteral administration was oxidation, ...

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Section: Discussionmentioning

confidence: 99%

Corticosteroids increase glutamine utilization in human splanchnic bed

Thibault

Welch²,

Mauras³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…However, while oral L-arginine supplementation can increase circulating [L-arginine] [4,5], and therefore one of the substrates for nitric oxide synthase, whether oral Larginine supplementation increases nitric oxide biomarkers (nitrate and nitrite) and improves exercise performance is controversial [4,[6][7][8][9], see 10 for review]. These conflicting findings might be linked, at least in part, to significant pre-systemic [11,12] and systemic [11,[13][14][15][16] breakdown of orally ingested L-arginine.…”

Section: Introductionmentioning

confidence: 99%

Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans

et al. 2016

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“…Approximately 40% of ingested oral Arg is catabolized by intestinal bacteria and arginases on the first pass (13, 67), with a further 10 -15% of systemic Arg extracted and metabolized by the liver (13,44,48,59,71). While acute (57) and short-term (35) Arg ingestion have been shown to increase plasma Arg concentration ([Arg]), the intracellular utilization of this additional substrate by NOS might be restricted by the competition between Arg, asymmetric dimethylarginine (ADMA), and other Arg analogs for the transporter y ϩ carrier hCAT-2B (14).…”

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confidence: 99%

“…Consequently, the majority of an oral Cit bolus passes into the systemic circulation (43). Cit is then extracted by the kidneys to be converted, in sequence, to argininosuccinate and Arg by the enzymes arginoinosuccinate synthase and arginoinosuccinate lyase, respectively (15,24,59,65,70). Synthesis of Arg from Cit is prevalent in other tissues (15,23,70), and this process is facilitated since Cit does not compete with ADMA for cell transport (50, 69).…”

mentioning

confidence: 99%

“…An advantage of oral Cit treatment is that, unlike Arg, catabolism of Cit in the intestines is limited, since Cit is not metabolized by arginases and bacteria, and the activity of arginoinosuccinate synthase, the enzyme that initiates Cit metabolism, is low in enterocytes (68). Moreover, and also in contrast to Arg, Cit is not extracted from the systemic circulation for clearance by the liver (59,65). Consequently, the majority of an oral Cit bolus passes into the systemic circulation (43).…”

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confidence: 99%

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l-Citrulline supplementation improves O₂ uptake kinetics and high-intensity exercise performance in humans

Bailey

Blackwell

Lord

et al. 2015

Journal of Applied Physiology

107

119

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Bailey SJ, Blackwell JR, Lord T, Vanhatalo A, Winyard PG, Jones AM. L-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans. J Appl Physiol 119: 385-395, 2015. First published May 28, 2015 doi:10.1152/japplphysiol.00192.2014.-The purpose of this study was to compare the effects of L-citrulline (Cit) and L-arginine (Arg) supplementation on nitric oxide (NO) biomarkers, pulmonary O2 uptake (V O2) kinetics, and exercise performance. In a randomized, placebo (Pla)-controlled, crossover study, 10 healthy adult men completed moderate-and severe-intensity cycling exercise on days 6 and 7 of a 7-day supplementation period with Pla, Arg (6 g/day), and Cit (6 g/day). Compared with Pla, plasma Arg concentration was increased by a similar magnitude with Arg and Cit supplementation, but plasma Cit concentration was only increased (P Ͻ 0.001) with Cit supplementation. Plasma nitrite (NO 2 Ϫ ) concentration was increased with Arg supplementation (P Ͻ 0.05) and tended to increase with Cit supplementation (P ϭ 0.08) compared with Pla (83 Ϯ 25, 106 Ϯ 41, and 100 Ϯ 38 nM with Pla, Arg, and Cit, respectively); however, mean arterial blood pressure was only lower (P Ͻ 0.05) after Cit supplementation. The steady-state V O2 amplitude during moderateintensity cycle exercise was not significantly different between supplements, but Cit lowered the V O2 mean response time (59 Ϯ 8 and 53 Ϯ 5 s with Pla and Cit, respectively, P Ͻ 0.05) during severe-intensity exercise, improved tolerance to severe-intensity exercise (589 Ϯ 101 and 661 Ϯ 107 s with Pla and Cit, respectively), and increased the total amount of work completed in the exercise performance test (123 Ϯ 18 and 125 Ϯ 19 kJ with Pla and Cit, respectively, P Ͻ 0.05). These variables were not altered by Arg supplementation (P Ͼ 0.05).In conclusion, these results suggest that short-term Cit, but not Arg, supplementation can improve blood pressure, V O2 kinetics, and exercise performance in healthy adults. nitric oxide; blood pressure; near-infrared spectroscopy; metabolism; fatigue THE MULTIFACETED PHYSIOLOGICAL signaling molecule nitric oxide (NO) can be synthesized endogenously through the nitratenitrite (NO 2 Ϫ )-NO pathway (37) and through the five-electron oxidation of L-arginine (Arg) in a reaction catalyzed by the NO synthase (NOS) enzymes (55). While studies have shown that dietary nitrate supplementation can increase NO biomarkers, reduce blood pressure, and improve exercise economy/efficiency and exercise tolerance in healthy adults (see Ref. 4 for review), the extent to which these variables are impacted by dietary Arg supplementation is less clear (see Ref. 1 for review). However, when Arg treatment increases NO biomarkers, exercise economy and exercise performance are improved (5, 52), whereas exercise economy and exercise performance are not improved when Arg treatment does not influence NO synthesis (9,31,35,60). Therefore, while there is some evidence to suggest that Arg treatment might improve physiological responses ...

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Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism

Cited by 158 publications

References 27 publications

Corticosteroids increase glutamine utilization in human splanchnic bed

Corticosteroids increase glutamine utilization in human splanchnic bed

Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans

l-Citrulline supplementation improves O₂ uptake kinetics and high-intensity exercise performance in humans

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Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism

Cited by 158 publications

References 27 publications

Corticosteroids increase glutamine utilization in human splanchnic bed

Corticosteroids increase glutamine utilization in human splanchnic bed

Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans

l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans

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Product

Resources

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l-Citrulline supplementation improves O₂ uptake kinetics and high-intensity exercise performance in humans