Effect of alterations in vitro and in vivo of the cholesterol content in rat liver microsomes on the activity of 3-hydroxy-3-methylglutaryl-CoA reductase.
3-Hydroxy-3-methylglutaryl-CoA reductase, the regulatory enzyme of cholesterol synthesis in liver, is bound to the microsomal fraction. Lipoprotein-bound cholesterol (from human serum) in vitro inhibits the microsomal bound 3-hydroxy-3-methylglutaryl-CoA reductase. The solubilized enzyme, however, is not inhibited. Immunotitration of the microsomal enzyme with a monospecific antibody reveals that the loss in enzyme activity caused by cholesterol corresponds well with the lowering of the equivalence points. In contrast, the equivalence points of the solubilized enzyme remain unchanged. This indicates that the inhibitory effect of cholesterol is restricted to the microsomal bound enzyme. In vivo different physiological conditions lead to relatively small changes in the cholesterol content in the microsomes while drastic changes in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase are observed. When microsomes from these rats are incubated with exogenous cholesterol, the activity of the enzyme is always found to be decreased to the same extent independent of the physiological condition of the animals. The findings suggest that 3-hydroxy-3-methylglutaryl-CoA reductase may be "masked" by a cholesterol-mediated modification of the microsomal membrane.
D000818:Animals; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D004032:Diet; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases