Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis.

von Wilamowitz-Moellendorff A, Hunter RW, García-Rocha M, Kang L, López-Soldado I, Lantier L, Patel K, Peggie MW, Martínez-Pons C, Voss M, Calbó J, Cohen PT, Wasserman DH, Guinovart JJ, Sakamoto K
Diabetes. 2013 62 (12): 4070-82

PMID: 23990365 · PMCID: PMC3837029 · DOI:10.2337/db13-0880

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.

MeSH Terms (14)

Animals Blood Glucose Glucose Glucose-6-Phosphate Glycogen Synthase Hepatocytes Homeostasis Insulin Liver Liver Glycogen Mice Mice, Transgenic Muscle, Skeletal Phosphorylation

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