HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/2/R618    most recent 00061.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Payne, V. A. Articles by Agius, L. Search for Related Content PubMed PubMed Citation Articles by Payne, V. A. Articles by Agius, L.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

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

¹Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; ²Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota

Submitted 13 March 2007 ; accepted in final form 29 May 2007

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 glucokinase-binding 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.

liver; glucose metabolism; fructose-2,6-bisphosphate

This article has been cited by other articles:

				L. Agius Targeting Hepatic Glucokinase in Type 2 Diabetes: Weighing the Benefits and Risks Diabetes, January 1, 2009; 58(1): 18 - 20. [Full Text] [PDF]

				M. H. Mukhtar, V. A. Payne, C. Arden, A. Harbottle, S. Khan, A. J. Lange, and L. Agius Inhibition of glucokinase translocation by AMP-activated protein kinase is associated with phosphorylation of both GKRP and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R766 - R774. [Abstract] [Full Text] [PDF]