1. Glucose-6-phosphate--mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis
- Author
-
von Wilamowitz-Moellendorff, Alexander, Hunter, Roger W., Garcia-Rocha, Mar, Kang, Li, Lopez-Soldado, Iliana, Lantier, Louise, Patel, Kashyap, Peggie, Mark W., Martinez-Pons, Carlos, Voss, Martin, Calbo, Joaquim, Cohen, Patricia T.W., Wasserman, David H., Guinovart, Joan J., and Sakamoto, Kei
- Subjects
Blood sugar -- Physiological aspects ,Glycogen -- Physiological aspects -- Synthesis ,Liver -- Physiological aspects ,Glucose metabolism -- Research ,Health - 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 glyeogen 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.sup.582) required for activation of GYS2 by G6P. We then used GYS2 [Arg.sup.582] Ala knockin (+/R582A) mice in which G6Pmediated GYS2 activation had been profoundly hnpaired (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.sup.+/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., The liver plays a central role in maintaining blood glucose homeostasis by uptake of glucose in the postprandial state and conversion to glycogen and triglyceride and by production of glucose [...]
- Published
- 2013
- Full Text
- View/download PDF