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(Received for publication, May 22, 1996, and in revised form, July 8, 1996)
From the In a previous study (O'Doherty, R. M., Lehman,
D. L., Seoane, J., Gómez-Foix, A. M., Guinovart, J. J., and
Newgard, C.B. (1996) J. Biol. Chem. 271, 20524-20530), we demonstrated that adenovirus-mediated overexpression
of glucokinase but not hexokinase I has a potent enhancing effect on
glycogen synthesis in primary hepatocytes. In an effort to understand
the underlying mechanism of this differential effect of the two
hexokinase isoforms, we have investigated changes in key intracellular
metabolites and the activation state of glycogen synthase in cells
treated with recombinant adenoviruses expressing the liver isoform of
glucokinase (AdCMV-GKL) or hexokinase I (AdCMV-HKI). Glucose
6-phosphate (Glu-6-P) levels are elevated from approximately 1.5 nmol/mg protein to 8-10 nmol/mg protein in both AdCMV-GKL- and
AdCMV-HKI-treated hepatocytes as glucose is raised from 1 to 5 mM, levels four times higher than those in untreated cells.
In AdCMV-GKL-treated cells, Glu-6-P continues to accumulate at glucose
levels greater than 5 mM, reaching a maximum of 120 nmol/mg
protein in cells incubated at 25 mM glucose, a value 10 and
50 times greater than the maximal levels achieved in AdCMV-HKI-treated
and untreated cells, respectively. In parallel with the changes
observed in Glu-6-P levels, increases in UDP-Glc in AdCMV-HKI- and
AdCMV-GKL-treated cells were most pronounced at low (1-5
mM) and high (25 mM) glucose levels,
respectively. Despite the significant increases in Glu-6-P and UDP-Glc
achieved in AdCMV-HKI-treated cells, only AdCMV-GKL-treated cells
exhibited increases in glycogen synthase activity ratio and
translocation of the enzyme from a soluble to a particulate form
relative to untreated control cells. We conclude that Glu-6-P produced
by overexpressed glucokinase is glycogenic because it effectively
promotes activation of glycogen synthase. Glu-6-P produced by
overexpressed hexokinase, in contrast, appears to be unable to exert
the same regulatory effects, probably due to the different subcellular
distribution of the two glucose-phosphorylating enzymes.
Volume 271, Number 39,
Issue of September 27, 1996
pp. 23756-23760
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
,
Departament de Bioquímica i Biologia
Molecular, Facultat de Química, Universitat de Barcelona,
E08028 Barcelona, Spain and § Departments of Biochemistry
and Internal Medicine, Gifford Laboratories for Diabetes Research,
University of Texas Southwestern Medical Center,
Dallas, Texas 75235
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