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

Abstract

Despite wide variations in dietary cholesterol, most animals are capable of maintaining the cho- lesterol of their plasma at relatively constant levels.Insight into the means by which this homeo- statis of plasma cholesterol is accomplished was first provided when Gould and associates (3-5), Tom- kins, Sheppard and Chaikoff (6) and Frantz, Schneider and Hinkelman (7) independently dem- onstrated that cholesterol synthesis in the liver varies inversely with the level of dietary choles- terol.Since all endogenous plasma cholesterol probably originates in the liver (8-10), it is likely that the constancy of plasma cholesterol is the result of this reciprocal relationship between dietary cholesterol and hepatic cholesterogenesis.The mechanism by which exogenous choles- terol is able to suppress cholesterol synthesis in the liver is not as yet understood.Previous stud- ies of this problem have been carried out by Gould and Popja'k (11) who presented preliminary evi- dence indicating that the conversion of mevalonic acid to cholesterol in liver homogenates is not im- paired by cholesterol feeding.Similarly, since completion of our study, Bucher, McGarrahan, Gould and Loud (12, 13), employing an approach similar to that used here, have clearly demon- strated that in homogenates the reactions in- volved in the conversion of mevalonic acid to cholesterol are not greatly influenced by dietary cholesterol.These experiments (11-13), as well as the present investigation, provide evidence that the site of control of cholesterol synthesis is located proximal to the utilization of mevalonic acid.The present report describes studies which