Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis
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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 G6Pmediated 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.
Originalsprog | Engelsk |
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Tidsskrift | Diabetes |
Vol/bind | 62 |
Udgave nummer | 12 |
Sider (fra-til) | 4070-4082 |
Antal sider | 13 |
ISSN | 0012-1797 |
DOI | |
Status | Udgivet - 1 dec. 2013 |
Eksternt udgivet | Ja |
ID: 239216185