In vivo modulation of rat liver 3-hydroxy-3-methylglutaryl-coenzyme A reductase, reductase kinase, and reductase kinase kinase by mevalonolactone.

It has been previously demonstrated that the enzymic activity of rat liver 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.34) is modulated in vitro and in vivo by a bicyclic cascade system involving reversible phosphorylation of HMG-CoA reductase and reductase kinase. In the present study, administration of mevalonolactone to rats caused a rapid inhibition of HMG-CoA reductase activity. The initial short-term (20-min) reversible inhibition (38%) of enzyme activity was due to increased phosphorylation of HMG-CoA reductase. The inhibition of HMG-CoA reductase activity by increased phosphorylation was associated with an increased activity and phosphorylation (2- to 3-fold) of reductase kinase. The increased phosphorylation of reductase kinase was catalyzed by reductase kinase kinase, which was significantly elevated (3- to 4-fold) after the administration of mevalonolactone to rats. The mechanism for the in vivo activation of reductase kinase kinase is as yet unknown. Mevalonolactone administration was also associated with a significant inhibition of phosphoprotein phosphatase activity, which dephosphorylates both HMG-CoA reductase (activation) and reductase kinase (inactivation). These results indicate that mevalonolactone administration to rats in vivo was associated with an inhibition of HMG-CoA reductase activity by two mechanisms: (i) an increase in the degree of phosphorylation of both HMG-CoA reductase and reductase kinase due to increased activity of reductase kinase kinase; (ii) a decrease in the dephosphorylation of both HMG-CoA reductase and reductase kinase secondary to inhibition of phosphoprotein phosphatase activity. These combined effects favor an increase in the steady-state level of the phosphorylated forms of both HMG-CoA reductase and reductase kinase, resulting in a net reduction in the enzymic activity of HMG-CoA reductase and mevalonate formation. These results demonstrate that the activity of reductase kinase kinase is modulated in vivo, providing a mechanism for the regulation of the activities of both reductase kinase and HMG-CoA reductase.