Disruption of the allosteric phosphorylase a regulation of the hepatic glycogen-targeted protein phosphatase 1 improves glucose tolerance in vivo.
Type 2 diabetes is characterised by elevated blood glucose concentrations, which potentially could be normalised by stimulation of hepatic glycogen synthesis. Under glycogenolytic conditions, the interaction of hepatic glycogen-associated protein phosphatase-1 (PP1-G(L)) with glycogen phosphorylase a is believed to inhibit the dephosphorylation and activation of glycogen synthase (GS) by the PP1-G(L) complex, suppressing glycogen synthesis. Consequently, the interaction of G(L) with phosphorylase a has emerged as an attractive anti-diabetic target, pharmacological disruption of which could provide a novel mechanism to lower blood glucose levels by increasing hepatic glycogen synthesis. Here we report for the first time the in vivo consequences of disrupting the G(L)-phosphorylase a interaction, using a mouse model containing a Tyr284Phe substitution in the phosphorylase a-binding region of the G(L) protein. The resulting G(L)(Y284F/Y284F) mice display hepatic PP1-G(L) activity that is no longer sensitive to allosteric inhibition by phosphorylase a, resulting in increased GS activity under glycogenolytic conditions, demonstrating that regulation of G(L) by phosphorylase a operates in vivo. G(L)(Y284F/Y284F) and G(L)(Y284F/+) mice display improved glucose tolerance compared with G(L)(+/+) littermates, without significant accumulation of hepatic glycogen. The data provide the first in vivo evidence in support of targeting the G(L)-phosphorylase a interaction for treatment of hyperglycaemia. During prolonged fasting the G(L)(Y284F/Y284F) mice lose more body weight and display decreased blood glucose levels in comparison with their G(L)(+/+) littermates. These results suggest that, during periods of food deprivation, the phosphorylase a regulation of G(L) may prevent futile glucose-glycogen cycling, preserving energy and thus providing a selective biological advantage that may explain the observed conservation of the allosteric regulation of PP1-G(L) by phosphorylase a in mammals.
Kelsall
Ian R
IR
Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, Scotland, UK.
Rosenzweig
Doron
D
Cohen
Patricia T W
PT
D000494:Allosteric Regulation; D000818:Animals; D001835:Body Weight; D003433:Crosses, Genetic; D005215:Fasting / Q000097:blood; D005260:Female; D018390:Gene Targeting; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D025001:Glycogen Phosphorylase, Liver Form / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008099:Liver / Q000201:enzymology; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011817:Rabbits; D015431:Weight Loss
D008112:Liver Glycogen; D025001:Glycogen Phosphorylase, Liver Form; D006006:Glycogen Synthase; D054645:Protein Phosphatase 1; D005947:Glucose