Regulation of isoprenoid metabolism in rat liver: near constant chain lengths of dolichyl phosphate and ubiquinone are maintained during greatly altered rates of cholesterogenesis

When rat liver slices were incubated with varying concentrations of [3H]mevalonolactone, the chain lengths of radiolabeled dolichyl phosphate and ubiquinone varied according to the initial mevalonolactone concentration, indicating that product chain length is dependent on the level of isoprenoid diphosphate intermediates. However, when livers were analyzed from rats which had been maintained on diets of either colestipol (which induces cholesterogenesis 3-fold), or normal chow, or cholesterol (which suppresses cholesterogenesis to 5% of normal) there were only minor changes in the isoprene distribution of either dolichyl phosphate or ubiquinone. In contrast, when rats were maintained on 2% cholesterol plus mevalonolactone (conditions prone to increase the levels of intermediates), the isoprene distributions of both of these compounds were greatly shifted to the higher homologs. However, under none of these conditions were the hepatic levels of these compounds changed significantly. It is concluded that under conditions of greatly altered cholesterogenesis, regulatory mechanisms exist which stabilize the levels of isoprenoid diphosphate intermediates, and that even when levels are increased (e.g., by dietary manipulation), the effect is only to alter isoprene distribution and not the rate of synthesis of dolichyl phosphate and ubiquinone.