In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Studies in normal subjects.

Abstract

In vivo regulation of microsomal HMG CoA reductase activity was investigated in freshly isolated mononuclear leukocytes from 26 healthy adult males. Reductase activity exhibited a diurnal rhythm and decreased during fasting. Enzyme activity was also modulated in vivo by alterations in dietary and plasma cholesterol, suggesting the existence of an operative cholesterol feedback regulatory system. A single, high cholesterol meal decreased reductase activity within 2 h. In addition, rapid depletion of circulating cholesterol levels by plasmapheresis led to an approximately twofold elevation in enzyme activity within 90 min of treatment. Finally, reductase activity was inhibited by dichloroacetate, a compound known to lower plasma cholesterol in man and inhibit the human leukocyte enzyme in vitro. The regulatory mechanisms controlling HMG CoA reductase activity in the human mononuclear leukocyte in vivo thus are similar to those that modulate the mammalian liver enzyme in vivo. Assessment of mononuclear leukocyte reductase activity may provide insight into the in vivo regulation of human cholesterol metabolism.