STUDIES ON THE SITE OF THE FEEDBACK CONTROL OF CHOLESTEROL SYNTHESIS*†

Abstract

It is well established that despite variations in exogenous cholesterol, plasma cholesterol levels vary only slightly in most animals. This homeostasis of body cholesterol is in part due to the fact that increased cholesterol intake causes a depression in hepatic cholesterogenesis. The purpose of the present investigation has been to determine the site in cholesterol synthesis at which this homeostatic control is exerted. Utilizing rat liver slices, the influence of cholesterol feeding on the conversion of acetate-C14 to cholesterol, mevalonic-Cl4 to squalene, and squalene-C14 to cholesterol has been determined. While cholesterol feeding depressed the conversion of acetate-Cl4 to cholesterol by a factor of from 10-300, the reactions beyond mevalonic acid were not greatly influenced by dietary cholesterol. It was therefore concluded, as has been also shown in liver homogenates by Gould et al. (Biochem. J. 66:51p. 1957) and Bucher et al. (J. B. C. 234:262, 1959), that the site of the cholesterol feedback control must lie in reactions prior to utilization of mevalonic acid. These 4 reactions are as follows: acetate [image]acetyl CoA [image] acetoacetyl CoA [image][beta]-hydroxy- [beta]-methyl-[beta]-glutaryl CoA (HMG CoA) [image] mevalonic acid. Since acetoacetyl CoA is an intermediate in lipogenesis as well as in cholesterol synthesis, the fact that cholesterol feeding was of no influence on lipogenesis eliminates reactions 1 and 2 as sites of the cholesterol feedback regulation. Reaction 3 is required for ketone body synthesis as well as for cholesterogenesis and since the synthesis of ketone bodies is not affected by dietary cholesterol, reaction 3 is likewise not the site of the block. It has been concluded therefore that reaction 4 involving the conversion of [beta]-hydroxy-[beta]- methyl-[beta]-glutaryl CoA to mevalonate is the site at which cholesterol synthesis is controlled by dietary cholesterol. The similarities between the bacterial systems and the cholesterol feedback system are discussed, and it is suggested that such feedback mechanisms may be more widespread in biological systems than has hitherto been recognized.