STUDIES RELATIVE TO THE MECHANISM OF ACTION OF 15-OXYGENATED STEROLS
MILLER, LARRY ROBERT
Doctor of Philosophy
5(alpha)-Cholest-8(14)-en-3(beta)-ol-15-one at 10('-4) M has been shown to inhibit the conversion of acetate, but not mevalonate, to nonsaponifiable lipids and digitoninprecipitable sterols by 10,000 x g supernatant preparations from rat liver homogenates. In addition, a variety of structurally related compounds were tested in this system. The direct addition of 5(alpha)-cholest-8(14)-en-3(beta)-ol-15-one to various cell-free preparations had no effect on the individual enzymes catalyzing the conversion of acetate to mevalonate. The administration of dietary 5(alpha)-cholest-8(14)-en-3(beta)-ol-15-one (0.1%) to male rats for eight days caused a significant decrease in serum cholesterol levels and an increase in the hepatic activities of acetoacetyl-CoA thiolase, HMG-CoA synthase, and HMG-CoA reductase. 14(alpha)-Ethyl-5(alpha)-cholest-7-en-3(beta),15-diol when administered by daily subcutaneous injections in triolein to male rats maintained on a Cholesterol-Free Test Diet has been shown to cause a 23 percent reduction in serum cholesterol levels after 13 days. A variety of oxygenated sterols containing a 15(alpha)-hydroxyl group were found to inhibit the conversion of acetate and mevalonate into digitonin-precipitable sterols by 10,000 x g supernatant preparations from rat liver homogenates. The structural parameters important in this inhibitory effect have been investigated. Cycloheximide at 10('-3) M has been found to inhibit the synthesis of digitonin-precipitable sterols from acetate, but not mevalonate, in 10,000 x g supernatant fractions of rat liver homogenates. This effect was not due to an inhibition of protein synthesis. The deprivation of food for 48 hours has been shown to cause a reduction in the activities of acetoacetyl-CoA thiolase, HMG-CoA synthase, and HMG-CoA reductase in rat liver.