Glucose-6-Phosphate–Mediated Activation of Liver Glycogen Synthase Plays a Key Role in Hepatic Glycogen Synthesis

• DOI: 10.2337/db13-0880
• Publication Date: 2013-08-30T02:11:30Z
• Authors: Alexander von Wil...; Roger W. Hunter; Mar García-Rocha; Li Kang; Iliana López-Soldado; Louise Lantier; Kashyap Patel; Mark W. Peggie; Carlos Martínez-Pons; Martin Voss; Joaquim Calbó; Patricia T.W. Cohen; David H. Wasserman; Joan J. Guinovart; Kei Sakamoto
• Keywords: Blood Glucose; 0301 basic medicine; 570; Glucose-6-Phosphate; Mice, Transgenic; Liver Glycogen; Mice; 03 medical and health sciences; Glucose; Glycogen Synthase; Liver; 616; Hepatocytes; Animals; Homeostasis; Insulin; Phosphorylation; Muscle, Skeletal; Original Research

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 (Arg582) required for activation of GYS2 by G6P. We then used GYS2 Arg582Ala 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.