Lovastatin treatment inhibits sterol synthesis and induced HMG-CoA reductase activity in mononuclear leukocytes of normal subjects

B. G. Stone, C. D. Evans, W. F. Prigge, W. C. Duane, R. L. Gebhard

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Abstract

The mechanism by which competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase decrease serum cholesterol is incompletely understood. The few available data in humans suggest that chronic administration of the competitive inhibitor, lovastatin, decreases serum cholesterol with little or no change in total body sterol synthesis. To further define the effect of lovastatin on cholesterol synthesis in normal subjects, we investigated the effect of a single oral dose of lovastatin and a 4-week treatment period of lovastatin on mononuclear leukocyte (ML) sterol synthesis as a reflection of total body sterol synthesis. In parallel, we measured serum lipid profiles and HMG-CoA reductase activity in ML microsomes that had been washed free of lovastatin. ML sterol synthesis did not significantly decrease (23 ± 5%, mean ± SEM) at 3 h after a single 40-mg dose of lovastatin. With a single oral 80-mg dose, ML sterol synthesis decreased by 57 ± 10% (P < 0.05) and remained low for the subsequent 6 h. With both doses, total HMG-CoA reductase enzyme activity in microsomes prepared from harvested mononuclear leukocytes was induced 4.8-fold (P < 0.01) over baseline values. Both the 20-mg bid dose and the 40-mg bid dose of lovastatin administered for a 4-week period decreased serum cholesterol by 25-34%. Lovastatin at 20 mg bid decreased ML sterol synthesis by 23 ± 6% (P < 0.02) and increased ML HMG-CoA reductase 3.8 times (P < 0.001) the baseline values. Twenty-four hours after stopping lovastatin, ML sterol synthesis and HMG-CoA reductase enzyme activity had returned to the baseline values. The higher dose of lovastatin (40 mg bid) decreased ML sterol synthesis by 16 ± 3% (P < 0.05) and induced HMG-CoA reductase to 53.7 times (P < 0.01) the baseline value at 4 weeks. Stopping this higher dose effected a rebound in ML sterol synthesis to 140 ± 11% of baseline (P < 0.01), while HMG-CoA reductase remained 12.5 times baseline (P < 0.01) over the next 3 days. No rebound in serum cholesterol was observed. From these data we conclude that in normal subjects lovastatin lowers serum cholesterol with only a modest effect on sterol synthesis. The effect of lovastatin on sterol synthesis in mononuclear leukocytes is tempered by an induction of HMG-CoA reductase enzyme quantity, balancing the enzyme inhibition by lovastatin. The speed (within 3 h) and the magnitude of enzyme induction (53.7-fold) with lovastatin administration demonstrate the exquisite nature of the feedback regulation mechanism of HMG-CoA reductase enzyme in human mononuclear leukocytes.

Original languageEnglish (US)
Pages (from-to)1943-1952
Number of pages10
JournalJournal of Lipid Research
Volume30
Issue number12
StatePublished - Dec 1 1989

Keywords

  • HMG-CoA reductase inhibitors
  • cholesterol synthesis
  • hydroxymethylgutaryl CoA reductase regulation
  • hypercholesterolemia

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