5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation.
AMP-activated protein kinase (AMPK) controls glucose uptake and glycolysis in muscle. Little is known about its role in liver glucose uptake, which is controlled by glucokinase. We report here that 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), metformin, and oligomycin activated AMPK and inhibited glucose phosphorylation and glycolysis in rat hepatocytes. In vitro experiments demonstrated that this inhibition was not due to direct phosphorylation of glucokinase or its regulatory protein by AMPK. By contrast, AMPK phosphorylated liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase without affecting activity. Inhibitors of the endothelial nitric oxide synthase, stress kinases, and phosphatidylinositol 3-kinase pathways did not counteract the effects of AICAR, metformin, or oligomycin, suggesting that these signaling pathways were not involved. Interestingly, the inhibitory effect on glucose phosphorylation of these well-known AMPK activators persisted in primary cultured hepatocytes from newly engineered mice lacking both liver alpha1 and alpha2 AMPK catalytic subunits, demonstrating that this effect was clearly not mediated by AMPK. Finally, AICAR, metformin, and oligomycin were found to inhibit the glucose-induced translocation of glucokinase from the nucleus to the cytosol by a mechanism that could be related to the decrease in intracellular ATP concentrations observed in these conditions.
Guigas
Bruno
B
Hormone and Metabolic Research Unit, Institute of Cellular Pathology, UCL 7529, avenue Hippocrate 75, 1200 Brussels, Belgium. bruno.guigas@horm.ucl.ac.be
Bertrand
Luc
L
Taleux
Nellie
N
Foretz
Marc
M
Wiernsperger
Nicolas
N
Vertommen
Didier
D
Andreelli
Fabrizio
F
Viollet
Benoit
B
Hue
Louis
L
D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008954:Models, Biological; D009840:Oligomycins / Q000494:pharmacology; D025481:Phosphofructokinase-2 / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000494:pharmacology*
D009840:Oligomycins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000255:Adenosine Triphosphate; D008687:Metformin; D025481:Phosphofructokinase-2; D005941:Glucokinase; D000263:Adenylate Kinase; C031143:AICA ribonucleotide; D005947:Glucose