The characteristics and site of inhibition of gluconeogenesis in rat liver cells by bacterial endotoxin. Stimulation of phosphofructokinase-1

Abstract

The characteristics and site of inhibition of gluconeogenesis by endotoxin were investigated in liver cells isolated from control and endotoxin-treated rats. Endotoxin treatment was associated with inhibition (40-50%) of gluconeogenesis from lactate plus pyruvate over a range of concentrations of substrate and of oleate and with or without glucose or glucagon. Similar inhibition was observed with asparagine, proline, glutamine, alanine and a substrate mixture, but not with glycerol, glyceraldehyde, dihydroxyacetone or endogenous substrates. There was no change in cellular ATP content or in the rates of ketogenesis or ureogenesis from asparagine, proline or glutamine. Other effects on isotopic fluxes, metabolite contents, enzyme activities and control coefficients were consistent with the suggestion that the effects of endotoxin on gluconeogenesis are exerted at the level of phosphofructokinase-1, and not at phosphoenolpyruvate carboxykinase, pyruvate kinase, pyruvate carboxylase or glucokinase.

Endotoxin stimulation of liver parenchymal cell phosphofructokinase activity requires nonparenchymal cells

“…Despite the 3 -4-fold increase in phosphofructokinase activity in parenchymal cells incubated with conditioned medium from LPS-stimulatcd liver non-parenchymal cells in this study, the rate of glucose accumulation was not significantly decreased under these conditions. This contrasts sharply with the observation that the apparent rate of net gluconeogenesis from 10 mM lactate and 1 mM pyruvate in parenchymal cells isolated from endotoxintreated rats (in which carbohydrate flux through phosphofructokinase is stimulated 3 -4-fold) is only 60% of the rate in parenchymal cells from control rats [4]. The results of the present study suggest that endotoxin stimulation of parenchymal cell phosphofructokinase activity can be dissociated from the decrease in parenchymal cell glucose output.…”

“…does not directly stimulate carbohydrate flux through phosphofructokinase in isolated rat liver parenchymal cells. The rate of parenchymal cell [3-3H]glucose detritiation is increased, however, during incubation with conditioned medium from LPS-stimulated liver non-parenchymal cells to a magnitude similar to the 3 -4-fold increase in phosphofructokinase activity reported in parenchymal cells isolated 18 h following endotoxin administration in vivo [4].…”

“…The initial hyperglycemia results from stimulation of liver parenchymal cell glycogenolysis and is mediated in part by prostaglandins secreted by liver nonparenchymal cells [S -71. The subsequent hypoglycemic phase of endotoxic shock has been suggested by Knowles et al [4] to result from stimulation of carbohydrate flux through hepatic phosphofructokinase and not by effects at phospho-enolpyruvate carboxykinase, pyruvate kinase, pyruvate carboxylase or glucokinase. We recently demonstrated that endotoxin administration to fasted rats results in a 2 -3-fold elevation in the level of fructose 2,6)P2] in liver within 3 h and that the level remains elevated for at least 24 h [8].…”

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

“…These findings confirm previous findings that LPS lowers blood glucose in animals and humans (35). Several mechanisms have been reported as to how LPS lowers blood glucose including enhanced systemic consumption of glucose (35), depletion of glycogen from liver and muscle (36), and impaired hepatic gluconeogenesis (37). Likely due to the extended time course of LPS-induced sickness in db/db mice (6), significant LPS-induced glucose lowering was seen in db/db mice at 8 h. Fig.…”

Primary Role of Interleukin-1α and Interleukin-1β in Lipopolysaccharide-Induced Hypoglycemia in Mice

“…It is also well known that LPS induces hypoglycemia in experimental animals as well as in humans (4,19,35). Incidentally, we have shown that various mitogenic substances other than LPS also induce hypoglycemia in mice (13).The mechanisms reported to underlie LPS-induced hypoglycemia include an enhanced systemic consumption of glucose (34), depletion of glycogen from liver and muscle (33,46), and impaired hepatic gluconeogenesis (18,26,33). The hyperthermic response often seen soon after LPS injection and the later hypothermic responses do not correspond well with the blood glucose changes induced by LPS (2, 28).…”