Feedback Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Livers of Mice Treated with Mevinolin, a Competitive Inhibitor of the Reductase
Open Access
- 1 November 1980
- journal article
- research article
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 66 (5) , 1094-1100
- https://doi.org/10.1172/jci109938
Abstract
Compactin (ML-236B) and the related compound, mevinolin, are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-controlling enzyme in cholesterol synthesis. Previous studies have shown that administration of compactin to cultured cells elicits a compensatory increase in the amount of HMG CoA reductase in the cells. A similar increase in HMG CoA reductase has been reported in livers of rats and mice that have been treated with compactin. In this study, we explore the mechanism for the mevinolin-mediated increase in hepatic HMG CoA reductase in mice that have been fed a control diet and a 2% cholesterol diet. Administration of mevinolin to mice on a control diet produced a 6- to 10-fold increase in the amount of HMG CoA reductase in liver microsomes. When mice were fed the cholesterol-enriched diet, cholesterol accumulated in the liver and HMG CoA reductase declined by 90%. The administration of mevinolin to cholesterol-fed mice produced a three to eightfold increase in HMG CoA reductase. Despite the abundant amount of cholesterol that was already present in the livers of the mevinolin-treated, cholesterol-fed animals, their elevated HMG CoA reductase could be rapidly suppressed by the subcutaneous injection of small amounts of mevalonate, the product of HMG CoA reductase. These data are compatible with the existence in mouse liver of a multivalent feedback regulatory mechanism for HMG CoA reductase in which suppression of the enzyme requires both a sterol and a nonsterol substance derived from mevalonate. By blocking mevalonate synthesis, mevinolin activates this regulatory mechanism, and this in turn causes an increase in hepatic HMG CoA reductase. The ability to suppress the elevated HMG CoA reductase with mevalonate may prove useful in potentiating the effectiveness of mevinolin as a hypocholesterolemic agent.Keywords
This publication has 18 references indexed in Scilit:
- Active and inactive forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the liver of the rat. Comparison with the rate of cholesterol synthesis in different physiological states.Journal of Biological Chemistry, 1979
- Inhibition of cholesterol synthesis with compactin renders growth of cultured cells dependent on the low density lipoprotein receptor.Journal of Biological Chemistry, 1979
- Reversible modulation of liver hydroxymethylglutaryl CoA reductaseLife Sciences, 1978
- 3-Hydroxy-3-methylglutaryl coenzyme A reductase: regulation of enzymatic activity by phosphorylation and dephosphorylation.Proceedings of the National Academy of Sciences, 1978
- Inhibitory Effects on Lipid Metabolismn in Cultured Cells of ML‐236B, a Potent Inhibitor of 3‐Hydroxt‐3‐methylglutaryl‐Cornzyme‐A ReductaseEuropean Journal of Biochemistry, 1978
- Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductaseJournal of Biological Chemistry, 1978
- Control of 3-hydroxy-3-methylglutaryl coenzyme A reductase by endogenously synthesized sterols in vitro and in vivo.Journal of Biological Chemistry, 1977
- INTERCONVERSION OF ACTIVE AND INACTIVE FORMS OF RAT-LIVER HYDROXYMETHYLGLUTARYL-COA REDUCTASE1977
- Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactumJournal of the Chemical Society, Perkin Transactions 1, 1976
- Role of the low density lipoprotein receptor in regulating the content of free and esterified cholesterol in human fibroblasts.Journal of Clinical Investigation, 1975