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Increased sensitivity of glycogen synthesis to phosphorylase-a and impaired expression of the glycogen-targeting protein R6 in hepatocytes from insulin-resistant Zucker fa/fa rats

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



Hepatic insulin resistance in the leptin-receptor defective Zucker fa/fa rat is associated with impaired glycogen synthesis and increased activity of phosphorylase-a. We investigated the coupling between phosphorylase-a and glycogen synthesis in hepatocytes from fa/fa rats by modulating the concentration of phosphorylase-a. Treatment of hepatocytes from fa/fa rats and Fa/? controls with a selective phosphorylase inhibitor caused depletion of phosphorylase-a, activation of glycogen synthase and stimulation of glycogen synthesis. The flux-control coefficient of phosphorylase on glycogen synthesis was glucose dependent and at 10 mm glucose was higher in fa/fa than Fa/? hepatocytes. There was an inverse correlation between the activities of glycogen synthase and phosphorylase-a in both fa/fa and Fa/? hepatocytes. However, fa/fa hepatocytes had a higher activity of phosphorylase-a, for a corresponding activity of glycogen synthase. This defect was, in part, normalized by expression of the glycogen-targeting protein, PTG. Hepatocytes from fa/fa rats had normal expression of the glycogen-targeting proteins GL and PTG but markedly reduced expression of R6. Expression of R6 protein was increased in hepatocytes from Wistar rats after incubation with leptin and insulin. Diminished hepatic R6 expression in the leptin-receptor defective fa/fa rat may be a contributing factor to the elevated phosphorylase activity and/or its high control strength on glycogen synthesis. © 2006 The Authors.

Publication metadata

Author(s): Arden C, Green AR, Hampson LJ, Aiston S, Harndahl L, Greenberg CC, Brady MJ, Freeman S, Poucher SM, Agius L

Publication type: Article

Publication status: Published

Journal: FEBS Journal

Year: 2006

Volume: 273

Issue: 9

Pages: 1989-1999

Print publication date: 01/04/2006

ISSN (print): 1742-464X

ISSN (electronic): 1742-4658

Publisher: Wiley


DOI: 10.1111/j.1742-4658.2006.05215.x

PubMed id: 16640562


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