FATTY ACYL-COA ESTERS INHIBIT GLUCOSE-6-PHOSPHATASE IN RAT-LIVER MICROSOMES

In native rat liver microsomes glucose 6-phosphatase activity is depen dent not only on the activity of the glucose-6-phosphatase enzyme (whi ch is lumenal) but also on the transport of glucose-6-phosphate, phosp hate and glucose through the respective translocases T1, T2 and T3. By using enzymic assay techniques, palmitoyl-CoA or CoA was found to inh ibit glucose-6-phosphatase activity in intact microsomes. The effect o f CoA required ATP and fatty acids to form fatty acyl esters. Increasi ng concentrations (2-50 mu M) of CoA (plus ATP and 20 mu M added palmi tic acid) or of palmitoyl-CoA progressively decreased glucose-6-phosph atase activity to 50% of the control value. The inhibition lowered the V-max. without significantly changing the K-m. A non-hydrolysable ana logue of palmitoyl-CoA also inhibited, demonstrating that binding of p almitoyl-CoA rather than hydrolysis produces the inhibition. Light-sca ttering measurements of osmotically induced changes in the size of rat liver microsomal vesicles pre-equilibrated in a low-osmolality buffer demonstrated that palmitoyl-CoA alone or CoA plus ATP and palmitic ac id altered the microsomal permeability to glucose 6-phosphate, but not to glucose or phosphate, indicating that T1 is the site of palmitoyl- CoA binding and inhibition of glucose-6-phosphatase activity in native microsomes. The type of inhibition found suggests that liver microsom es may comprise vesicles heterogeneous with respect to glucose-6-phosp hate translocase(s), i.e. sensitive or insensitive to fatty acid ester inhibition.