Mevinolin, an Inhibitor of Cholesterol Synthesis, Induces mRNA for Low Density Lipoprotein Receptor in Livers of Hamsters and Rabbits

Through the use of a quantitative solution hybridization assay with32P-labeled cDNA probes, we found that mevinolin, an inhibitor of cholesterol synthesis, elevates the level of mRNA for the low density lipoprotein receptor in livers of hamsters and rabbits. In hamsters the maximal effect (3-fold increase) occurred at 0.1% mevinolin in the diet for 10 days. The same dose produced a maximal induction (10-fold) of mRNA levels for 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of cholesterol synthesis, and a maximal decrease (80%) in plasma cholesterol. The drug lowered the level of all cholesterol-carrying lipoproteins in plasma. In normal rabbits, mevinolin produced a 90% reduction in plasma low density lipoprotein-cholesterol levels, which was associated with a 2.5-fold increase in low density lipoprotein receptor mRNA levels. A similar induction of receptor mRNA occurred in livers of Watanabe-heritable hyperlipidemic rabbits, although the plasma cholesterol was not reduced to normal, presumably because the receptors produced by the mutant mRNA function poorly. These data are consistent with the hypothesis that mevinolin and other inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase lower plasma cholesterol levels in part by stimulating production of mRNA for the low density lipoprotein receptor in liver.