Overexpression of protein targeting to glycogen (PTG) in rat hepatocytes causes profound activation of glycogen synthesis independent of normal hormone- and substrate-mediated regulatory mechanisms.
Protein targeting to glycogen (PTG), also known as PPP1R5, is a widely expressed member of a growing family of proteins that target protein phosphatase-1 (PP-1) to glycogen particles. Because PTG also binds to glycogen synthase and phosphorylase kinase, it has been suggested that it serves as a "scaffold" for efficient activation of glycogen synthesis. However, very little is known about the metabolic effects of PTG. In this study, we have used recombinant adenovirus to overexpress PTG in primary rat hepatocytes, a cell type with high glycogenic capacity. We find that overexpression of PTG potently activates glycogen synthesis in cultured hepatocytes. Surprisingly, the glycogenic effect of PTG is observed even in the complete absence of carbohydrates or insulin in the culture medium. Furthermore, glycogenolytic agents such as forskolin or glucagon are largely ineffective at activating glycogen degradation in PTG overexpressing hepatocytes, even though large increases in cAMP levels are demonstrated. These metabolic effects of PTG overexpression are accompanied by a 3.6-fold increase in glycogen synthase activation state and a 40% decrease in glycogen phosphorylase activity. Our results are consistent with a model in which PTG overexpression "locks" the hepatocyte in a glycogenic mode, presumably via its ability to promote interaction of enzymes of glycogen metabolism with PP-1.
Gifford Laboratories for Diabetes Research and the Departments of Biochemistry and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
H K
HK
Berman
R M
RM
O'Doherty
P
P
Anderson
C B
CB
Newgard
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers; D005947:Glucose / Q000378:metabolism; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008112:Liver Glycogen / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D013379:Substrate Specificity
D017931:DNA Primers; D007328:Insulin; D008112:Liver Glycogen; D011506:Proteins; D000242:Cyclic AMP; D005947:Glucose