期刊
DIABETES
卷 62, 期 12, 页码 4070-4082出版社
AMER DIABETES ASSOC
DOI: 10.2337/db13-0880
关键词
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资金
- Diabetes UK
- British Heart Foundation
- British Medical Research Council (MRC)
- MRC
- Wellcome Trust [093991/Z/10/Z]
- National Institutes of Health [R37 DK050277, U24 DK059637]
- Ministry of Science and Innovation, Spain [BFU2011-30554]
- Autonomous Government of Catalonia [2009SGR-1176]
- Fundacion Marcelino Botin
- CIBERDEM (Instituto de Salud Carlos III)
- AstraZeneca
- Boehringer Ingelheim
- GlaxoSmithKline
- Merck Co. Inc.
- Merck KGaA
- Pfizer
- Wellcome Trust [093991/Z/10/Z] Funding Source: Wellcome Trust
- MRC [MC_U127015389] Funding Source: UKRI
- British Heart Foundation [PG/09/059/27851] Funding Source: researchfish
- Diabetes UK [07/0003529] Funding Source: researchfish
- Medical Research Council [MC_U127015389] Funding Source: researchfish
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.
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