Adaptative response of nitrogen metabolism in early endotoxemia: role of ornithine aminotransferase

Abstract

Arginine (Arg) and glutamine (Gln) utilization is greatly increased during catabolic stress. While the supply of both amino acids has been advocated in this situation, arginine administration is possibly associated with deleterious effects. From a metabolic point of view, these two amino acids are reciprocal precursors via ornithine aminotransferase (OAT). We hypothesized that OAT plays a key role in the interconversion between Arg and Gln. To test this hypothesis, we evaluated the influence of OAT activity in a model of septic shock induced by intraperitoneal injection of lipopolysaccharide (LPS) in wild-type (WT) and transgenic mice overexpressing OAT (OAT) in the liver, kidney and intestine, i.e. the three main organs of OAT expression. Plasma and tissue amino acid concentrations and tissue OAT expression and activity were measured. Five hours after LPS injection, WT and OAT mice showed a similar response to LPS in terms of inflammatory cytokine production and protein catabolism, suggesting that the interconversion between Arg and Gln through this pathway remains limited. Endotoxemia led to a significant decrease in plasma Orn levels and an increase in liver Orn levels. Of note, Orn levels were always lower in OAT mice. While only plasma Arg and Gln remained unaffected by LPS treatment, hepatic Gln was significantly increased without any difference between the two genotypes. In this model of early endotoxemia, arginine and glutamine maintained their metabolic homeostasis. Our results show an inhibition of OAT activity and expression in the liver following LPS treatment. These data highlight the importance of OAT in ornithine metabolism, especially in the liver, and suggest a post-transcriptional regulation of OAT by LPS in the liver.

Citrulline a More Suitable Substrate than Arginine to Restore NO Production and the Microcirculation during Endotoxemia

“…However, no deficit in the plasma arginine pool, comparable to the metabolic derangements reported in man, was found in these acute models [22], [45]–[48]. It should however be mentioned that one experimental animal study reported significant changes in the arginine flux in the early stages of endotoxemia [48]. Our new model was based on a pilot observation in mice that plasma arginine concentrations decreased below baseline from 12 hours after the onset of the continuous endotoxin infusion, which is supported by the observations of Braulio et al [31].…”

“…In these models, arginine as substrate for NO was identified as key factor in development of the microcirculatory and perfusion disturbances related to endotoxemia. However, no deficit in the plasma arginine pool, comparable to the metabolic derangements reported in man, was found in these acute models [22], [45]–[48]. It should however be mentioned that one experimental animal study reported significant changes in the arginine flux in the early stages of endotoxemia [48].…”

“…We, therefore, consider that this prolonged endotoxemia model mimics the human metabolic situation during endotoxemia-induced inflammatory conditions, in which we demonstrated a deficiency in arginine availability and associated decreased NO production during prolonged endotoxemia [44]. Thus far, disturbances in the arginine-NO metabolism were mainly studied in acute murine endotoxemia models [22], [45]–[48]. In these models, arginine as substrate for NO was identified as key factor in development of the microcirculatory and perfusion disturbances related to endotoxemia.…”

Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways

“…Conversely, OAT activity is decreased by glucocorticoids [154,155], and by lipopolysaccharide (LPS) [156]. In mice and rats, it presents circadian variations, with a decrease along the day, by control of the translation step, but with no change in the mRNA levels [17,149,157], and with an effect of the dark/light transitions [158].…”

“…Ventura et al [156] showed that the adaptive response of nitrogen metabolism in early endotoxemia is associated with a physiological inhibition of liver OAT, the latter being responsible for increased Orn in the liver. This OAT inhibition could be considered as a protective mechanism, sparing Orn for other metabolic pathways (Pro and polyamine synthesis).…”