Modulation of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase by lipid inhibitors, substrates, and cytosolic factors

Oleic acid and oleoyl coenzyme A were found to be inhibitors of microsomal and purified 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) activities. Inhibition of the microsomal enzyme was time-dependent and complete in 10 min. The addition of oleic acid, but not of oleoyl-CoA, resulted in gross morphological changes in the microsomal vesicles. Purification of the enzyme increased its sensitivity to both inhibitors, indicating that the microsomal membrane was not a necessary component of the inhibition. Either of the two substrates, HMG-CoA or NADPH, could prevent the inhibition significantly when present prior to addition of the lipids. Phosphatidylcholine or bovine serum albumin, both capable of binding to the lipids, were able to prevent the the inhibition but were unable to reverse it. By contrast, crude rat liver cytosol reversed the inhibition completely. In the absence of NADPH, the incubation of purified enzyme with HMG-CoA resulted in inhibition of the enzyme; on the other hand, incubation of the purified reductase with NADPH, in the absence of HMG-CoA, resulted in an activation of the enzyme.