Influence of endotoxin treatment on dexamethasone induction of hepatic phosphoenolpyruvate carboxykinase

Abstract

Decreased glucocorticoid binding has been observed at a time after endotoxin (3 to 6 h) when imparied liver enzyme induction is known to occur. This study was undertaken to characterize the early time course of hypoglycemia and decreased liver phosphoenolpyruvate carboxykinase (PEPCK) activity in intact and adrenalectomized mice given endotoxin. In addition, altered steroid induction of hepatic PEPCK was examined in adrenalectomized mice given dexamethasone at intervals before and after a median lethal dose of endotoxin. Intact mice demonstrated a dramatic hyperglycemia at 1 h after endotoxin treatment, a response absent in adrenalectomized mice. Plasma glucose levels were significantly reduced from control values at 3 and 6 h posttreatment, with the most pronounced endotoxin-induced hypoglycemia seen in adrenalectomized mice. Hepatic PEPCK activity in intact mice given endotoxin was decreased at 3 and 6 h after treatment, although no change from basal, noninduced levels was seen in poisoned adrenalectomized mice. The increased increment in hepatic PEPCK activity due to fasting of intact control mice was reproduced in adrenalectomized control mice by the administration of dexamethasone. Furthermore, the induction of hepatic PEPCK by dexamethasone was inhibited by 1 h after endotoxin treatment, with enzyme activity falling to basal, noninduced levels by 6 h posttreatment. At these same time intervals after endotoxin treatment, no evidence of histopathology in the liver or adrenal glands was seen. These results coincide with changes in steroid binding seen previously and indicate that endotoxin treatment produces significant alterations in glucocorticoid action at the subcellular or molecular level.

Down regulation of hepatic glucocorticoid receptors after endotoxin treatment

“…Further evidence that the endotoxin effects reported here are related to glucocorticoid mechanisms of action was presented by McCal-lum et al (19) who studied hypoglycemia in adrenalectomized mice given endotoxin. An initial hyperglycemia (1 h after treatment), preceding a severe hypoglycemia seen after endotoxin treatment of intact mice, was absent in adrenalectomized mice.…”

“…Results from previous studies have demonstrat-614 STITH AND McCALLUM ed less specific binding of [3H]dexamethasone in liver cytosol prepared from endotoxin-treated mice than in untreated controls at a time when the animals exhibit hypoglycemia and diminished hepatic phosphoenolpyruvate carboxykinase activity (19,20). This study was undertaken to characterize further the changes in [3H]dexamethasone binding associated with endotoxemia.…”

Identification of tumor necrosis factor as a transcriptional regulator of the phosphoenolpyruvate carboxykinase gene following endotoxin treatment of mice

“…Berry et al (5) first observed in mice an inhibitory effect of endotoxin on the glucocorticoid induction of the rate-limiting enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK). We observed subsequently that mice given a 50% (LD50) lethal dose of Salmonella typhimurium endotoxin were hyperglycemic at 1 h after treatment; however, the animals became hypoglycemic at 3 and 6 h (39). Coincident with this pattern, hepatic PEPCK activity decreased as early as 3 h after endotoxin.…”

“…Liver cytosol preparations were obtained by homogenizing livers in 0.25 mM Tris-sucrose (pH 7.4) containing 5 mM dithiothreitol and centrifuging them at 468,000 x g for 10 min in a TL-100 tabletop ultracentrifuge (Beckman Instruments, Inc., Palo Alto, Calif.). PEPCK enzyme activity was measured by a 14C radiometric method as described previously (39). Units of enzyme activity correspond to nanomoles of oxaloacetate formed from phosphoenolpyruvate per 15 min per milligram of cytosol protein.…”

Endogenous and exogenous glucocorticoids have different roles in modulating endotoxin lethality in D-galactosamine-sensitized mice

“…However, other studies suggest additional potentially relevant targets for beneficial effects of glucocorticoids. These include, for example, increased expression of phosphoenolpyruvate carboxykinase in the liver (13,15) and regulation of arachidonic acid metabolism (22,24). Adrenalectomy and hypophysectomy, which serve to deplete endogenous sources of glucocorticoids, have effects opposite those of glucocorticoids, including increased sensitivity to the lethal effects of endotoxin (3,17,21,26), lowering of hepatic phosphoenolpyruvate carboxykinase (15), and increased serum TNF-ct levels in endotoxin-challenged animals (17,26).…”