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 mu M. The order of efficiency in untreated microsomes is: phosphatidylinositol (PI) 3,4,5P(3) > PI3,4P(2) = PI4,5P(2) > 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 mu M The mechanism of Glc6Pase inhibition by PI4,5P(2), PI3,4P(2), and PI3,4,5P(3) is competitive in both untreated and detergent-treated microsomes. In untreated microsomes, the K-i for PI3,4,5P(3) (1.7 +/- 0.3 mu M, mean +/- S.D. n = 3) is significantly lower (p < 0.01) than that for PI3,4P(2) (5.0 +/- 0.8 mu M) and for PI4,5P(2) (4.7 +/- 0.7 mu M). In detergent-treated microsomes, Glc6Pase is less sensitive to the inhibition and there is no difference anymore among the K-i values for the three compounds: 8.3 +/- 0.8, 11.1 +/- 0.5 and 8.9 +/- 0.4 mu M for PI3,4,5P(3), PI3,4P(2), and PI4,5P(2), respectively. This inhibition phenomenon might be of special importance with regards to the insulin's inhibition of hepatic glucose production.