TY - JOUR
T1 - Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits
AU - Ma, P. T S
AU - Gil, G.
AU - Sudhof, T. C.
AU - Bilheimer, D. W.
AU - Goldstein, J. L.
AU - Brown, M. S.
PY - 1986
Y1 - 1986
N2 - Through the use of quantitative solution hybridization assay with 32P-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.
AB - Through the use of quantitative solution hybridization assay with 32P-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.
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U2 - 10.1073/pnas.83.21.8370
DO - 10.1073/pnas.83.21.8370
M3 - Article
C2 - 3464957
AN - SCOPUS:0003042048
SN - 0027-8424
VL - 83
SP - 8370
EP - 8374
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -