Ornithine transcarbamylase (OTC; EC 2.1.3.3) is a ubiquitous enzyme found in almost all organisms... more Ornithine transcarbamylase (OTC; EC 2.1.3.3) is a ubiquitous enzyme found in almost all organisms, including vertebrates, microorganisms, and plants. Anabolic, mostly trimeric OTCs catalyze the production of L-citrulline from L-ornithine which is a part of the urea cycle. In eukaryotes, such OTC localizes to the mitochondrial matrix, partially bound to the mitochondrial inner membrane and part of channeling multi-enzyme assemblies. In mammals, mainly two organs express OTC: the liver, where it is an integral part of the urea cycle, and the intestine, where it synthesizes citrulline for export and plays a major role in amino acid homeostasis, particularly of L-glutamine and L-arginine. Here, we give an overview on OTC genes and proteins, their tissue distribution, regulation, and physiological function, emphasizing the importance of OTC and urea cycle enzymes for metabolic regulation in human health and disease. Finally, we summarize the current knowledge of OTC deficiency, a rare X-...
Sepsis considerably alters the intestinal barrier functions, which in turn modify the absorption ... more Sepsis considerably alters the intestinal barrier functions, which in turn modify the absorption and bioavailability of nutrients. However, the effects of septic shock on aminoacid (AAs) bioavailability are poorly documented. The aim of this study was to compare the bioavailability of citrulline, arginine and glutamine during endotoxemia. Thirty-six rats were randomised into two groups: control and lipopolysaccharides (LPS). The LPS group received an intraperitoneal injection of endotoxins (7·5 mg/kg). After 12 h, each group was again randomised into three subgroups, each of which received an oral bolus of citrulline, arginine or glutamine (5·7 mmol/kg). Blood samples were collected at various times from 0 to 600 min after AA administration. The concentrations of citrulline, arginine, glutamine and their metabolites arginine and ornithine were measured to determine pharmacokinetic parameters Area Under Curve (AUC), C(max) and T(max). The AUC values of citrulline decreased in LPS rats [citrulline, control: 761 ± 67 and LPS: 508 ± 72 μmol min/mL (P = 0·02)]. Maximum concentrations of citrulline were also significantly decreased by endotoxemia (P = 0·01). The pharmacokinetic parameters of arginine and glutamine were not significantly modified by endotoxemia. The AUC value of arginine from citrulline conversion was diminished in endotoxemic rats. The other pharmacokinetic parameters of arginine were not significantly modified after arginine or citrulline supply in either group (control or LPS). Endotoxemia affects the bioavailability of AAs differently according to the amino acid considered. This feature may be important for nutritional strategy in ICU patients.
Citrulline has anti-inflammatory properties and exerts beneficial effects on various impaired fun... more Citrulline has anti-inflammatory properties and exerts beneficial effects on various impaired functions in aging. However, there are few data on citrulline action on immune function in aged populations. The objective of the study was to evaluate citrulline ability, after in vivo and in vitro administration, to modulate macrophage functions in aged rats and the possible pathways involved. Twenty-one-month-old Sprague-Dawley rats (n = 27) received a citrulline supplementation at 5 g/kg/d for 5 days, or an isonitrogenous diet, and peritoneal macrophages were cultured with or without LPS. In the in vitro study, macrophages from 22-month-old rats (n = 16) were cultured with or without LPS, citrulline and inhibitors of different inflammatory pathways (n = 8/conditions). Nitric oxide (NO) and tumor necrosis factor α (TNFα) production were measured in both in vivo and in vitro studies. Citrulline decreased NO production variability by peritoneal macrophages after in vivo administration (p = 0.0034) and downregulated NO production by 22% after in vitro administration (95% CI: [6%; 35%]; p = 0.0394), without any direct effect on TNFα production. None of the transductional pathways explored seem to be involved. Citrulline slightly modulates NO production in vivo and in vitro, suggesting a possible action through modulation of arginine metabolism in macrophages rather than a direct transductional effect. The pleiotropic effects of citrulline in aging could be due, at least in part, to the anti-inflammatory effect of citrulline.
A citrulline (CIT)-enriched diet improves locomotor activity in aged rats, but the underlying mec... more A citrulline (CIT)-enriched diet improves locomotor activity in aged rats, but the underlying mechanism is unknown. The aim of this study was to determine the effect of CIT administration on locomotor activity and dopamine activity in healthy aged rats. Sixty adult (3-mo-old) and aged (20-mo-old) rats were divided into four groups (n = 15 each) stratified by age (adult versus old) and diet (control versus CIT; i.e., Ad-Control, Ad-CIT, Old-Control, Old-CIT) and fed for 4 d on either a CIT-enriched diet (5 g/kg daily; Ad-CIT and Old-CIT) or an isonitrogeneous control diet (Ad-Control and Old-Control). Locomotor activity was evaluated in a Y-maze. On day 5, animals were sacrificed and brain (striatum) was removed to determine total and phosphorylated forms of tyrosine hydroxylase (TH) by immunohistochemistry. CIT restored locomotor activity in aged rats (arm visits: Old-CIT 28 ± 1 versus Old-Control 23 ± 1; P < 0.05), associated with an increase in total TH (Old-CIT 668 ± 27 versus Old-Control 529 ± 22; P < 0.05) and phosphorylated forms of TH (Old-CIT 1012 ± 39 versus Old-Control 589 ± 69; P < 0.05). In aged rats, CIT is able to stimulate locomotor activity via the dopaminergic pathway.
American Journal of Physiology - Endocrinology And Metabolism, 2016
Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has con... more Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated ( P < 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P < 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to ...
Clinical nutrition (Edinburgh, Scotland), Jan 24, 2016
Immune-enhancing diet (IED) utilization in critically ill septic patients is still debated. A new... more Immune-enhancing diet (IED) utilization in critically ill septic patients is still debated. A new concept of IED has been proposed combining extra glutamine sequentially with either antioxidants or other amino acids, in order to match patient requirements according to their response to injury. We evaluated whether this new IED elicits a more favorable response to stress when compared with two existing IEDs both enriched in arginine but with different levels of anti-oxidants, in a validated rat model combining head injury (HI) and infectious complications. Forty-eight HI rats were randomized into four groups (n = 11-13 per group) to receive, for 4 days, standard enteral nutrition (S), one of the two existing IEDs (IED1, IED2), or the new IED (IED3; providing glutamine and antioxidants for two days and glutamine and specific amino acids for two days). Two days after HI, the rats received an enteral bolus of luminescent Escherichia coli Xen14 to induce infection, and bacterial dissemin...
Ornithine transcarbamylase (OTC; EC 2.1.3.3) is a ubiquitous enzyme found in almost all organisms... more Ornithine transcarbamylase (OTC; EC 2.1.3.3) is a ubiquitous enzyme found in almost all organisms, including vertebrates, microorganisms, and plants. Anabolic, mostly trimeric OTCs catalyze the production of L-citrulline from L-ornithine which is a part of the urea cycle. In eukaryotes, such OTC localizes to the mitochondrial matrix, partially bound to the mitochondrial inner membrane and part of channeling multi-enzyme assemblies. In mammals, mainly two organs express OTC: the liver, where it is an integral part of the urea cycle, and the intestine, where it synthesizes citrulline for export and plays a major role in amino acid homeostasis, particularly of L-glutamine and L-arginine. Here, we give an overview on OTC genes and proteins, their tissue distribution, regulation, and physiological function, emphasizing the importance of OTC and urea cycle enzymes for metabolic regulation in human health and disease. Finally, we summarize the current knowledge of OTC deficiency, a rare X-...
Sepsis considerably alters the intestinal barrier functions, which in turn modify the absorption ... more Sepsis considerably alters the intestinal barrier functions, which in turn modify the absorption and bioavailability of nutrients. However, the effects of septic shock on aminoacid (AAs) bioavailability are poorly documented. The aim of this study was to compare the bioavailability of citrulline, arginine and glutamine during endotoxemia. Thirty-six rats were randomised into two groups: control and lipopolysaccharides (LPS). The LPS group received an intraperitoneal injection of endotoxins (7·5 mg/kg). After 12 h, each group was again randomised into three subgroups, each of which received an oral bolus of citrulline, arginine or glutamine (5·7 mmol/kg). Blood samples were collected at various times from 0 to 600 min after AA administration. The concentrations of citrulline, arginine, glutamine and their metabolites arginine and ornithine were measured to determine pharmacokinetic parameters Area Under Curve (AUC), C(max) and T(max). The AUC values of citrulline decreased in LPS rats [citrulline, control: 761 ± 67 and LPS: 508 ± 72 μmol min/mL (P = 0·02)]. Maximum concentrations of citrulline were also significantly decreased by endotoxemia (P = 0·01). The pharmacokinetic parameters of arginine and glutamine were not significantly modified by endotoxemia. The AUC value of arginine from citrulline conversion was diminished in endotoxemic rats. The other pharmacokinetic parameters of arginine were not significantly modified after arginine or citrulline supply in either group (control or LPS). Endotoxemia affects the bioavailability of AAs differently according to the amino acid considered. This feature may be important for nutritional strategy in ICU patients.
Citrulline has anti-inflammatory properties and exerts beneficial effects on various impaired fun... more Citrulline has anti-inflammatory properties and exerts beneficial effects on various impaired functions in aging. However, there are few data on citrulline action on immune function in aged populations. The objective of the study was to evaluate citrulline ability, after in vivo and in vitro administration, to modulate macrophage functions in aged rats and the possible pathways involved. Twenty-one-month-old Sprague-Dawley rats (n = 27) received a citrulline supplementation at 5 g/kg/d for 5 days, or an isonitrogenous diet, and peritoneal macrophages were cultured with or without LPS. In the in vitro study, macrophages from 22-month-old rats (n = 16) were cultured with or without LPS, citrulline and inhibitors of different inflammatory pathways (n = 8/conditions). Nitric oxide (NO) and tumor necrosis factor α (TNFα) production were measured in both in vivo and in vitro studies. Citrulline decreased NO production variability by peritoneal macrophages after in vivo administration (p = 0.0034) and downregulated NO production by 22% after in vitro administration (95% CI: [6%; 35%]; p = 0.0394), without any direct effect on TNFα production. None of the transductional pathways explored seem to be involved. Citrulline slightly modulates NO production in vivo and in vitro, suggesting a possible action through modulation of arginine metabolism in macrophages rather than a direct transductional effect. The pleiotropic effects of citrulline in aging could be due, at least in part, to the anti-inflammatory effect of citrulline.
A citrulline (CIT)-enriched diet improves locomotor activity in aged rats, but the underlying mec... more A citrulline (CIT)-enriched diet improves locomotor activity in aged rats, but the underlying mechanism is unknown. The aim of this study was to determine the effect of CIT administration on locomotor activity and dopamine activity in healthy aged rats. Sixty adult (3-mo-old) and aged (20-mo-old) rats were divided into four groups (n = 15 each) stratified by age (adult versus old) and diet (control versus CIT; i.e., Ad-Control, Ad-CIT, Old-Control, Old-CIT) and fed for 4 d on either a CIT-enriched diet (5 g/kg daily; Ad-CIT and Old-CIT) or an isonitrogeneous control diet (Ad-Control and Old-Control). Locomotor activity was evaluated in a Y-maze. On day 5, animals were sacrificed and brain (striatum) was removed to determine total and phosphorylated forms of tyrosine hydroxylase (TH) by immunohistochemistry. CIT restored locomotor activity in aged rats (arm visits: Old-CIT 28 ± 1 versus Old-Control 23 ± 1; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), associated with an increase in total TH (Old-CIT 668 ± 27 versus Old-Control 529 ± 22; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) and phosphorylated forms of TH (Old-CIT 1012 ± 39 versus Old-Control 589 ± 69; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). In aged rats, CIT is able to stimulate locomotor activity via the dopaminergic pathway.
American Journal of Physiology - Endocrinology And Metabolism, 2016
Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has con... more Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature has consistently shown CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both interorgan and intraorgan trafficking and metabolism, we combined three approaches: in vivo, ex vivo, and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle. Interestingly, the increase in S6K1 phosphorylation was positively correlated ( P < 0.05) with plasma CIT concentration. In a model of isolated incubated skeletal muscle from malnourished rats, CIT enhanced MPS (from 30 to 80% CIT vs. Ctrl, P < 0.05), and the CIT effect was abolished in the presence of wortmannin, rapamycin, and PD-98059. In vitro, on myotubes in culture, CIT led to ...
Clinical nutrition (Edinburgh, Scotland), Jan 24, 2016
Immune-enhancing diet (IED) utilization in critically ill septic patients is still debated. A new... more Immune-enhancing diet (IED) utilization in critically ill septic patients is still debated. A new concept of IED has been proposed combining extra glutamine sequentially with either antioxidants or other amino acids, in order to match patient requirements according to their response to injury. We evaluated whether this new IED elicits a more favorable response to stress when compared with two existing IEDs both enriched in arginine but with different levels of anti-oxidants, in a validated rat model combining head injury (HI) and infectious complications. Forty-eight HI rats were randomized into four groups (n = 11-13 per group) to receive, for 4 days, standard enteral nutrition (S), one of the two existing IEDs (IED1, IED2), or the new IED (IED3; providing glutamine and antioxidants for two days and glutamine and specific amino acids for two days). Two days after HI, the rats received an enteral bolus of luminescent Escherichia coli Xen14 to induce infection, and bacterial dissemin...
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