Independent and combined actions of interleukin-1β, tumor necrosis factor α, and glucagon on amino acid metabolism in the isolated perfused rat liver

Abstract

Conflicting reports concerning the hepatic effects of interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) in the metabolic response to injury led us to investigate the influence of physiological concentrations of these cytokines on amino acid metabolism in the isolated perfused rat liver. IL-1β was ineffective at a concentration of 1 ng/mL, whereas TNFα (0.7 ng/mL) reduced the uptake of some of the main gluconeogenic amino acids (alanine, −55.3 ± 4.9 v −72.9 ± 13.7 nmol·min −1·g −1 in controls, P < .05) without affecting urea synthesis. TNFα also increased glucose uptake by 237% and inhibited that of free fatty acids (−1.6 ± 1.4 v −9.9 ± 6.7 nmol·min −1·g −1 in controls, P < .05). IL-1β and TNFα potentiated glucagon-induced total amino acid uptake by 56% and 87%, respectively. They also affected glucagon-activated gluconeogenesis, leading to an initial potentiation of glucose release. Thereafter, IL-1β inhibited glucagon action, leading to an hepatic uptake of glucose. These results indicate that (1) in the conditions of the study, IL-1β has no direct effect on hepatic amino acid exchanges and utilization; (2) TNFα, which exerted an inhibitory effect on these parameters, could be involved in the reduced amino acid exchanges during the end stage of sepsis; (3) the TNFα-induced increase in glucose uptake could be related to an inhibition of gluconeogenesis and/or to the activation of glucose utilization by Kupffer cells; (4) IL-1β and TNFα both potentiate the action of glucagon on hepatic amino acid uptake and utilization; and (5) complex interactions between Kupffer cells and hepatocytes on the one hand and between cytokines and hormones on the other hand could account for the differences in hepatic metabolism according to the stage of the response to injury.