Cholesterol and mevalonate metabolism: a time course study in vivo

Abstract

SUMMARY Within 30 minutes after injecting ~~-mevalonate-2-C1~ into young rats, the total body nonsaponifiable fraction contained 47.6% of the biologically active Cz4-mevalonate. Time course data suggest that at this time utilization of tracer MVA was essentially complete. Urinary radioactivity accounted for slightly more than one-half of the dose. The metabolism of nonsaponifiable fractions of liver and gut may be related by two processes having similar but reciprocal half times. Kidney tissue was found to contain the greater part of the radioactivity previously associated with carcass nonsaDonifiable fractions. A small but consistent amount of label was found in the saponifiable fractions. The problem of cholesterol and fatty acid biosynthesis, transport, and turnover has been under investigation in this laboratory for some time (1 to 5), the larger part of these studies having been made with acetate-l-C14 as the labeling agent. The mult,iple pathways available for acetate metabolism tend to obscure the information desired on any single pathway, particularly if the time periods involved allow for recycling of the tracer. It appears well established that mevalonic acid (MVA) is a unique and a more direct precursor of squalene and cholesterol in mammalian systems (6 to 15) than is acetate. While most of these studies have been made with homogenates, we have compared acetate and mevalonate as tracers in a liver slice system (l). In the homogenate and liver slice systems, using C14-acetate and C14-mevalonate as tracers, it is possible to obtain definitive information largely on biosynthetic pathways. We have shown that the in vivo and in vitro methods are not directly comparable for studies on cholesterol metabolism (16), and that both in vivo cholesterol transport and turnover may be important facets of cholesterol metabolism (2). The present experiments were designed to utilize the more selective labeling of cholesterol by mevalonate in studies on cholesterol biosynthesis and turnover in