Liver microsomal glucose-6-phosphatase is competitively inhibited by the lipid products of phosphatidylinositol 3-kinase

Abstract

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 μM. 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 μM. 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 K(i) for PI3,4,5P3 (1.7 ± 0.3 μM, mean ± S.D. n = 3) is significantly lower (p < 0.01) than that for PI3,4P2 (5.0 ± 0.8 μM) and for PI4,5P2 (4.7 ± 0.7 μM). In detergent-treated microsomes, Glc6Pase is less sensitive to the inhibition and there is no difference anymore among the K~ values for the three compounds: 8.3 ± 0.8, 11.1 ± 0.5 and 8.9 ± 0.4 μM 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.