A potential role for fructose-2,6-bisphosphate in the stimulation of hepatic glucokinase gene expression.
The effects of fructose-2,6-bisphosphate (F-2,6-P(2)) on hepatic glucokinase (GK) and glucose-6-phosphatase (G-6-Pase) gene expression were investigated in streptozotocin-treated mice, which exhibited undetectable levels of insulin. Hepatic F-2,6-P(2) levels were manipulated by adenovirus-mediated overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Streptozotocin treatment alone or with infusion of control adenovirus leads to a dramatic decrease in hepatic F-2,6-P(2) content compared with normal nondiabetic mice. This is accompanied by a 14-fold decrease in GK and a 3-fold increase in G-6-Pase protein levels, consistent with a diabetic phenotype. Streptozotocin-treated mice that were infused with adenovirus-overexpressing an engineered 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase with high kinase activity and little bisphosphatase activity showed high levels of hepatic F-2,6-P(2). Surprisingly, these mice had a 13-fold increase in GK protein and a 2-fold decrease in G-6-Pase protein compared with diabetic controls. The restoration of GK is associated with increases in the phosphorylation of Akt upon increasing hepatic F-2,6-P(2) content. Moreover, the changes in levels of F-2,6-P(2) and Akt phosphorylation revealed a pattern similar to that of streptozotocin mice treated with insulin, indicating that increasing hepatic content of F-2,6-P(2) mimics the action of insulin. Because G-6-Pase gene expression was down-regulated only after the restoration of euglycemia, the effect of F-2,6-P(2) was indirect. Also, the lowering of blood glucose by high F-2,6-P(2) was associated with an increase in hepatic nuclear factor 1-alpha protein, a transcription factor involved in G-6-Pase gene expression. In conclusion, F-2,6-P(2) can stimulate hepatic GK gene expression in an insulin-independent manner and can secondarily affect G-6-Pase gene expression by lowering the level of plasma glucose.
Wu
Chaodong
C
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, 321 Church Street SE, Minneapolis, MN 55455, USA.
Okar
David A
DA
Stoeckman
Angela K
AK
Peng
Li-Jen
LJ
Herrera
Amy H
AH
Herrera
Julio E
JE
Towle
Howard C
HC
Lange
Alex J
AJ
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D005635:Fructosediphosphates / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006706:Homeostasis; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D009687:Nuclear Proteins; D025481:Phosphofructokinase-2 / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection
D001786:Blood Glucose; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005635:Fructosediphosphates; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D007328:Insulin; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; C027652:fructose 2,6-diphosphate; D025481:Phosphofructokinase-2; D005941:Glucokinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005952:Glucose-6-Phosphatase