title: Glucose 6-phosphate regulates hepatic glycogenolysis through inactivation of phosphorylase.
abstract: High glucose concentration suppresses hepatic glycogenolysis by allosteric inhibition and dephosphorylation (inactivation) of phosphorylase-a. The latter effect is attributed to a direct effect of glucose on the conformation of phosphorylase-a. Although glucose-6-phosphate (G6P), like glucose, stimulates dephosphorylation of phosphorylase-a by phosphorylase phosphatase, its physiological role in regulating glycogenolysis in intact hepatocytes has not been tested. We show in this study that metabolic conditions associated with an increase in G6P, including glucokinase overexpression and incubation with octanoate or dihydroxyacetone, cause inactivation of phosphorylase. The latter conditions also inhibit glycogenolysis. The activity of phosphorylase-a correlated inversely with the G6P concentration within the physiological range. The inhibition of glycogenolysis and inactivation of phosphorylase-a caused by 10 mmol/l glucose can be at least in part counteracted by inhibition of glucokinase with 5-thioglucose, which lowers G6P. In conclusion, metabolic conditions that alter the hepatic G6P content affect glycogen metabolism not only through regulation of glycogen synthase but also through regulation of the activation state of phosphorylase. Dysregulation of G6P in diabetes by changes in activity of glucokinase or glucose 6-phosphatase may be a contributing factor to impaired suppression of glycogenolysis by hyperglycemia.
authors.affiliation: Department of Diabetes, School of Clinical Medical Sciences, University of Newcastle upon Tyne, The Medical School, Newcastle upon Tyne NE2 4HH, U.K.
authors.forename: Susan
authors.initials: S
authors.lastname: Aiston
authors.forename: Birgitte
authors.initials: B
authors.lastname: Andersen
authors.forename: Loranne
authors.initials: L
authors.lastname: Agius
mesh_terms: D000818:Animals; D002210:Caprylates / Q000494:pharmacology; D002478:Cells, Cultured; D004098:Dihydroxyacetone / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006706:Homeostasis; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000096:biosynthesis*; D008297:Male; D008954:Models, Biological; D010762:Phosphorylase a / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values
chemical_list: D002210:Caprylates; D008112:Liver Glycogen; D019298:Glucose-6-Phosphate; D010762:Phosphorylase a; D005941:Glucokinase; D004098:Dihydroxyacetone; C031492:octanoic acid