Liver microsomal glucose-6-phosphatase is competitively inhibited by the lipid products of phosphatidylinositol 3-kinase.
We have studied the effect of various phospholipids on the activity of glucose-6-phosphatase (Glc6Pase) in untreated and detergent-treated rat liver microsomes. Glc6Pase is inhibited in the presence of phosphoinositides in a dose-dependent manner within a range of concentration 0.5-10 microM. The order of efficiency in untreated microsomes is: phosphatidylinositol (PI) 3,4,5P3 > PI3,4P2 = PI4,5P2 > PI3P = PI4P > PI. In contrast, Glc6Pase is not inhibited in the presence of phosphatidylserine, phosphatidylcholine, and phosphatidylethanolamine, diacylglycerol, and inositol 1,4, 5-trisphosphate at concentrations up to 100 microM. The mechanism of Glc6Pase inhibition by PI4,5P2, PI3,4P2, and PI3,4,5P3 is competitive in both untreated and detergent-treated microsomes. In untreated microsomes, the Ki for PI3,4,5P3 (1.7 +/- 0.3 microM, mean +/- S.D. n = 3) is significantly lower (p < 0.01) than that for PI3, 4P2 (5.0 +/- 0.8 microM) and for PI4,5P2 (4.7 +/- 0.7 microM). In detergent-treated microsomes, Glc6Pase is less sensitive to the inhibition and there is no difference anymore among the Ki values for the three compounds: 8.3 +/- 0.8, 11.1 +/- 0.5 and 8.9 +/- 0.4 microM for PI3,4,5P3, PI3,4P2, and PI4,5P2, respectively. This inhibition phenomenon might be of special importance with regards to the insulin's inhibition of hepatic glucose production.
Mithieux
G
G
Institut National de la Santé et de la Recherche Médicale, Unit 449, Faculty of Medicine R. T. H. Laënnec, 69372 Lyon Cédex 08, France. mithieux@cimac-res.univ-lyon1.fr
Daniele
N
N
Payrastre
B
B
Zitoun
C
C
D000818:Animals; D001667:Binding, Competitive; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors*; D007328:Insulin / Q000502:physiology; D007700:Kinetics; D050356:Lipid Metabolism; D008862:Microsomes, Liver / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats
D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D005952:Glucose-6-Phosphatase; D005947:Glucose