Feedback Control of Mevalonate Synthesis by Dietary Cholesterol

1. By means of a gas-liquid chromatographic technique the effect of exogenous cholesterol on the incorporation of acetate-2- 14 C into β-hydroxy-β-methylglutarate and mevalonate has been measured both in cell-free systems of liver and in intact liver cells. 2. It has been shown that mevalonate synthesis is markedly suppressed by cholesterol feeding while the synthesis of β-hydroxy-β-methylglutarate is unaffected by this regimen. These results are consistent with the conclusion that the major site of the cholesterol feedback system is located at the reaction responsible for the conversion of β-hydroxy-β-methylglutarate to mevalonate; namely β-hydroxy-β-methylglutaryl reductase. 3. The intracellular localization of mevalonate synthesis and its feedback control have been likewise examined. Mevalonate was found to be synthesized in both microsomal and soluble fractions of the liver cell; however, the major site of mevalonate synthesis, and hence of feedback control of cholesterol synthesis, is localized to the membranous fraction of the microsomes.