METABOLIC EFFECTS OF STRESS MEDIATORS ON CULTURED-HEPATOCYTES

Stress mediators play a major role in inducing the hypermetabolic stre ss state in the liver after major injuries. The majority of studies on the effect of mediators on hepatocytes have focused on single factor effects or on the effect of very complex additives (e.g., serum), and there are no reports which have rigorously identified specific interac tions between stress mediators, We used a factorial design experimenta l approach to evaluate the effects of a four to five day exposure to h ormone (glucagon, hydrocortisone, and epinephrine) and cytokine [tumor necrosis factor-alpha (TNF-alpha) interteukin-1 beta (IL-1 beta) and interleukin-6 (IL-6)] stress mediators on stable cultures of rat hepat ocytes. Both individual-factor effects and two factor interactions on the metabolism elf urea, glucose, lactate, ketone bodies, albumin, and fibrinogen were evaluated. The cultured hepatocyte model exhibited ph ysiologic responses to the applied stress mediators. While hydrocortis one and epinephrine had no effect, glucagon induced an increase in glu cose and urea synthesis. Interleukin-6 increased fibrinogen and decrea sed albumin production. Furthermore, IL-6 and glucagon caused an incre ase in the ketone-body ratio (KBR = [acetoacetate]/[beta-hydroxybutyra te]), which is in equilibrium with the intramitochondrial NAD(+)/NADH. Turner necrosis factor-alpha and IL-1 beta, on the other hand, decrea sed the KBR. An important two-factor interaction between IL-1 beta and IL-6 was identified, namely that it-lp effectively negates the positi ve effect of IL-6 on the KBR when both are present. These results prov ide further understanding of the effect of stress mediators on hepatic function and metabolism. These effects may have important implication s in the pathogenesis of progressive organ dysfunction which often fol lows prolonged inflammatory states triggered by major injuries. (C) 19 98 John Wiley & Sons, Inc.