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Hepatic glycogen synthesis is highly sensitive to phosphorylase activity: Evidence from metabolic control analysis

Lookup NU author(s): Dr Susan Aiston, Dr Laura Hampson, Professor Loranne Agius

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Abstract

We used metabolic control analysis to determine the flux control coefficient of phosphorylase on glycogen synthesis in hepatocytes by titration with a specific phosphorylase inhibitor (CP-91149) or by expression of muscle phosphorylase using recombinant adenovirus. The muscle isoform was used because it is catalytically active in the b-state. CP-91149 inactivated phosphorylase with sequential activation of glycogen synthase. It increased glycogen synthesis by 7-fold at 5 mM glucose and by 2-fold at 20 mM glucose with a decrease in the concentration of glucose causing half-maximal rate (S 0.5) from 26 to 19 mM. Muscle phosphorylase was expressed in hepatocytes mainly in the b-state. Low levels of phosphorylase expression inhibited glycogen synthesis by 50%, with little further inhibition at higher enzyme expression, and caused inactivation of glycogen synthase that was reversed by CP-91149. At endogenous activity, phosphorylase has a very high (greater than unity) negative control coefficient on glycogen synthesis, regardless of whether it is determined by enzyme inactivation or overexpression. This high control is attenuated by glucokinase overexpression, indicating dependence on other enzymes with high control. The high control coefficient of phosphorylase on glycogen synthesis affirms that phosphorylase is a strong candidate target for controlling hyperglycemia in type 2 diabetes in both the absorptive and postabsorptive states.


Publication metadata

Author(s): Hampson L; Aiston S; Agius L; Gomez-Foix AM; Guinovart JJ

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2001

Volume: 276

Issue: 26

Pages: 23858-23866

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology

URL: http://dx.doi.org/10.1074/jbc.M101454200

DOI: 10.1074/jbc.M101454200

PubMed id: 11309391


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