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PMID:17553851

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Citation

Payne, VA, Arden, C, Lange, AJ and Agius, L (2007) Contributions of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 to the elevated glycolysis in hepatocytes from Zucker fa/fa rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293:R618-25

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-P(2)) 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-P(2) content. However, combined overexpression of glucokinase and PFK2 had a synergistic effect on fructose-2,6-P(2) levels, suggesting that interaction of these enzymes may be a prerequisite for formation of fructose-2,6-P(2). Cumulatively, this study provides support for coordinate roles for glucokinase and PFK2 in the elevated hepatic glycolysis in fa/fa rats.

Links

PubMed Online version:10.1152/ajpregu.00061.2007

Keywords

Animals; Cells, Cultured; Gene Expression Regulation, Enzymologic; Glucagon/metabolism; Glucagon/pharmacology; Glucokinase/genetics; Glucokinase/metabolism; Glucose/metabolism; Glucose/pharmacology; Glycolysis/physiology; Hepatocytes/cytology; Hepatocytes/drug effects; Hepatocytes/enzymology; Insulin Resistance/physiology; Male; Phosphofructokinase-2/genetics; Phosphofructokinase-2/metabolism; Rats; Rats, Zucker; Recombinant Proteins/genetics; Recombinant Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:F263

involved_in

GO:0006003: fructose 2,6-bisphosphate metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:HXK4

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:HXK4

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:HXK4

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:HXK4

involved_in

GO:0042327: positive regulation of phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:HXK4

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:HXK4

involved_in

GO:0006003: fructose 2,6-bisphosphate metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:HXK4

involved_in

GO:0006006: glucose metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:HXK4

involved_in

GO:0045821: positive regulation of glycolytic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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