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Contributions of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 to the elevated glycolysis in hepatocytes from Zucker fa/fa rats

Lookup NU author(s): Victoria Payne, Dr Catherine Arden, Professor Loranne Agius

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Abstract

The insulin-resistant Zucker fa/fa rat has elevated hepatic glycolysis and activities of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 (PFK2). The latter catalyzes the formation and degradation of fructose-2,6-bisphosphate (fructose-2,6-P2) and is a glucokinasebinding protein. The contributions of glucokinase and PFK2 to the elevated glycolysis in fa/fa hepatocytes were determined by overexpressing these enzymes individually or in combination. Metabolic control analysis was used to determine enzyme coefficients on glycolysis and metabolite concentrations. Glucokinase had a high control coefficient on glycolysis in all hormonal conditions tested, whereas PFK2 had significant control only in the presence of glucagon, which phosphorylates PFK2 and suppresses glycolysis. Despite the high control strength of glucokinase, the elevated glycolysis in fa/fa hepatocytes could not be explained by the elevated glucokinase activity alone. In hepatocytes from fa/fa rats, glucokinase translocation between the nucleus and the cytoplasm was refractory to glucose but responsive to glucagon. Expression of a kinase-active PFK2 variant reversed the glucagon effect on glucokinase translocation and glucose phosphorylation, confirming the role for PFK2 in sequestering glucokinase in the cytoplasm. Glucokinase had a high control on glucose-6-phosphate content; however, like PFK2, it had a relative modest effect on the fructose-2,6-P2 content. However, combined overexpression of glucokinase and PFK2 had a synergistic effect on fructose-2,6-P2 levels, suggesting that interaction of these enzymes may be a prerequisite for formation of fructose-2,6-P2. Cumulatively, this study provides support for coordinate roles for glucokinase and PFK2 in the elevated hepatic glycolysis in fa/fa rats. Copyright © 2007 the American Physiological Society.


Publication metadata

Author(s): Payne VA, Arden C, Lange AJ, Agius L

Publication type: Article

Publication status: Published

Journal: American Journal of Physiology - Regulatory Integrative and Comparative Physiology

Year: 2007

Volume: 293

Issue: 2

Pages: R618-R625

Print publication date: 01/08/2007

ISSN (print): 0363-6119

ISSN (electronic): 1522-1490

Publisher: American Physiological Society

URL: http://dx.doi.org/10.1152/ajpregu.00061.2007

DOI: 10.1152/ajpregu.00061.2007

PubMed id: 17553851


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