title: Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis.
abstract: The liver responds to an increase in blood glucose levels in the postprandial state by uptake of glucose and conversion to glycogen. Liver glycogen synthase (GYS2), a key enzyme in glycogen synthesis, is controlled by a complex interplay between the allosteric activator glucose-6-phosphate (G6P) and reversible phosphorylation through glycogen synthase kinase-3 and the glycogen-associated form of protein phosphatase 1. Here, we initially performed mutagenesis analysis and identified a key residue (Arg(582)) required for activation of GYS2 by G6P. We then used GYS2 Arg(582)Ala knockin (+/R582A) mice in which G6P-mediated GYS2 activation had been profoundly impaired (60-70%), while sparing regulation through reversible phosphorylation. R582A mutant-expressing hepatocytes showed significantly reduced glycogen synthesis with glucose and insulin or glucokinase activator, which resulted in channeling glucose/G6P toward glycolysis and lipid synthesis. GYS2(+/R582A) mice were modestly glucose intolerant and displayed significantly reduced glycogen accumulation with feeding or glucose load in vivo. These data show that G6P-mediated activation of GYS2 plays a key role in controlling glycogen synthesis and hepatic glucose-G6P flux control and thus whole-body glucose homeostasis.
authors.affiliation: Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee, Scotland, U.K.
authors.forename: Alexander
authors.initials: A
authors.lastname: von Wilamowitz-Moellendorff
authors.forename: Roger W
authors.initials: RW
authors.lastname: Hunter
authors.forename: Mar
authors.initials: M
authors.lastname: García-Rocha
authors.forename: Li
authors.initials: L
authors.lastname: Kang
authors.forename: Iliana
authors.initials: I
authors.lastname: López-Soldado
authors.forename: Louise
authors.initials: L
authors.lastname: Lantier
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.forename: Mark W
authors.initials: MW
authors.lastname: Peggie
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-Pons
authors.forename: Martin
authors.initials: M
authors.lastname: Voss
authors.forename: Joaquim
authors.initials: J
authors.lastname: Calbó
authors.forename: Patricia T W
authors.initials: PT
authors.lastname: Cohen
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Guinovart
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008112:Liver Glycogen; D019298:Glucose-6-Phosphate; D006006:Glycogen Synthase; D005947:Glucose