Feedback Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Livers of Mice Treated with Mevinolin, a Competitive Inhibitor of the Reductase

Abstract

A B S T R A C T 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 mevinolinmediated 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 Dr. Toru Kita is the recipient of a travel grant from the Japan Research Foundation for Clinical Pharmacology.

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

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Role of RhoA activation in the growth and morphology of a murine prostate tumor cell line

“…Lovastatin was a gift from Merck Research Laboratories, Rahway, NJ, USA and was prepared as described by Kita et al (1980). Brie¯y, lovastatin (90 mg) was dissolved in warm (558C) ethanol (1.8 ml) by dropwise addition of 0.6 N NaOH (0.9 ml) and 18 ml water.…”

Deficient post-translational processing of Rap 1A in variant HL-60 cells

“…Translation reactions were performed either with methionine free amino acid mix and 35 S-methionine (1.2 mCi/ml) or with cold amino acid mixtures for the phosphopeptide mapping experiments described in Figure 3. Mevalonic acid, generated from mevalonic acid lactone by alkaline hydrolysis (Kita et al, 1980), was added at 10 mM to provide maximal isoprenylation and 20 mM S-adenosylmethionine was added during the last 30 min of incubation to provide optimal carboxyl methylation (Hancock et al, 1991;Hancock, 1995). The products of the transcription/translation reactions were phosphorylated by the C subunit of A-kinase either with non-radioactive ATP or, for the phosphopeptide maps, with 50 mCi of [g-32 P]ATP.…”