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

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Abstract
3-Hydroxy-3-methylglutaryl-CoA [HMG-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 HMG-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 HMG-CoA reductase are observed. When microsomes from these rats are incubated with exogenous cholesterol, the activity of the enzyme is always decreased to the same extent independent of the physiological condition of the animals. HMG-CoA reductase may be masked by a cholesterol-mediated modification of the microsomal membrane.