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

Alexander von Wilamowitz-Moellendorff, 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 (Lead / Corresponding author)

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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.
Original languageEnglish
Pages (from-to)4070-4082
Number of pages13
JournalDiabetes
Volume62
Issue number12
DOIs
Publication statusPublished - Dec 2013

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    von Wilamowitz-Moellendorff, A., Hunter, R. W., García-Rocha, M., Kang, L., López-Soldado, I., Lantier, L., Patel, K., Peggie, M. W., Martínez-Pons, C., Voss, M., Calbó, J., Cohen, P. T. W., Wasserman, D. H., Guinovart, J. J., & Sakamoto, K. (2013). Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis. Diabetes, 62(12), 4070-4082. https://doi.org/10.2337/db13-0880