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      In vivo regulation of rat liver 3-hydroxy-3-methylglutaryl-coenzyme A reductase: enzyme phosphorylation as an early regulatory response after intragastric administration of mevalonolactone.

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          Abstract

          Although substantial evidence supports the conclusion that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34] is the major regulatory enzyme in cholesterol biosynthesis, the molecular events involved in the in vivo regulation of this enzyme have remained obscure. To study this problem, rats were given a single 100-mg dose of mevalonolactone by intragastric tube. The rats were sacrificed 20 or 60 min later, and liver microsomes were prepared by ultracentrifugation. Two phases of inhibition of microsomal HMG-CoA reductase were observed. The first phase of inhibition, observed 20 min after mevalonolactone administration, was completely reversed by preincubation of the microsomes with purified phosphoprotein phosphatase. The second phase of inhibition, observed 60 min after mevalonolactone administration, was not reversed by phosphoprotein phosphatase. The reactivation of liver microsomal HMG-CoA reductase by phosphoprotein phosphatase was blocked by potassium fluoride or by phosphoprotein phosphatase inhibitor. Results obtained by immunotitration also showed that microsomal HMG-CoA reductase obtained from animals killed 20 min after mevalonolactone administration was significantly activated by phosphoprotein phosphatase treatment of the microsomes. These findings demonstrate that phosphorylation of rat liver HMG-CoA reductase is an early in vivo regulatory response after intragastric administration of mevalonolactone.

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          Author and article information

          Journal
          Proc. Natl. Acad. Sci. U.S.A.
          Proceedings of the National Academy of Sciences of the United States of America
          0027-8424
          0027-8424
          Nov 1980
          : 77
          : 11
          Article
          10.1073/pnas.77.11.6429
          350298
          6256737
          983e0fbe-99eb-4224-8bc2-ad2e21852a43
          History

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