Regulation of cholesterol synthesis in normal and malignant tissue

The rate of cholesterol synthesis in mammalian liver is regulated by the activity of the microsomal enzyme, β hydroxy β methylglutaryl coenzyme. A reductase (HMG CoA reductase). When an animal consumes cholesterol in the diet, the level of activity of this enzyme and the rate of cholesterol synthesis decline in a parallel fashion. In all hepatomas so far studied, this feedback control of HMG CoA reductase activity is absent. The authors report that solubilized and highly purified HMG CoA reductase from normal liver and hepatoma tissue have identical properties. This observation, coupled with other data reviewed, suggests that in normal liver the activity of HMG CoA reductase is controlled by alterations in synthesis and degradation of the enzyme rather than by direct allosteric effects on enzyme activity. The regulation of the synthesis of this enzyme was studied in normal human fibroblasts cultured in vitro. Evidence is presented to indicate that in such cells the rate of synthesis, and hence the activity of HMG CoA reductase, is regulated by specific lipoprotein fractions. This tissue culture system offers a model for the further exploration of the nature of the defective control of HMG CoA reductase activity in malignancy and in other pathological states.