The control of hepatic glycogen metabolism in an in vitro model of sepsis

Abstract

Culturing hepatocytes with a combination of LPS, TNF-alpha, IL-1beta and IFN-gamma resulted in an inhibition of glucose output from glycogen and prevented the repletion of glycogen in freshly cultured cells. The reduced glycogen mobilisation correlated with the lower cell glycogen content and reduced rate of glycogen synthesis from [U-(14)C]glucose rather than alterations in either total phosphorylase or phosphorylase a activity. There was no change in the percentage of glycogen exported as glucose nor the production of lactate plus pyruvate indicating that redistribution of the Gluc-6-P cannot explain the failure of the liver to export glucose. Although changes in glycogen mobilisation correlated with NO production, inhibition of NO synthase by inclusion of L-NMMA in the culture medium failed to prevent the inhibition of either glycogen accumulation or mobilisation by the proinflammatory cytokines, precluding the involvement of NO in this response. LPS plus cytokine treatment had no effect on total glycogen synthase activity although the activity ratio was lowered, indicative of increased phosphorylation. The inhibition of glycogen synthesis correlated with a fall in the intracellular concentrations of Gluc-6-P and UDP-glucose and in the absence of measured changes in kinase activity, it is suggested that the fall in Gluc-6-P reduces both substrate supply and glycogen synthase phosphatase activity. The fall in Gluc-6-P coincided with a reduction in total glucokinase and hexokinase activity within the cells, but no significant change in either the translocation of glucokinase or glucose-6-phosphatase activity. This demonstrates direct cytokine effects on glycogen metabolism independent of changes in glucoregulatory hormones.

Liver Metabolomic Changes Identify Biochemical Pathways in Hemorrhagic Shock

“…UDP-Glucose is present only as a glycogen precursor and is not formed in the degradation of glycogen into glucose [29]. Other studies have also shown that an increase in UDP-glucose concentration correlates with an increase in glycogen synthase activity and glycogen concentration [30,31]. Glycogen synthesis occurs when there are high concentrations of glucose within the hepatocyte but the source of this glucose can be extracellular and not strictly due to gluconeogenesis.…”

General Review on In Vitro Hepatocyte Models and Their Applications

“…Thus, in vitro models of sepsis created by treating hepatocytes with proinflammatory cytokines have been used to demonstrate direct cytokine effects on glycogen metabolism (67) and evaluate the effects of several catecholamines that are used to treat sepsis patients (68).…”

A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia

“…Endotoxin administration results in hyperglycemia, followed by manifest hypoglycemia (11,39). Severe hypoglycemia defined as blood glucose levels < 40 mg/dl (10).…”