Use of cholesterol precursors to assess changes in cholesterol synthesis under non‐steady‐state conditions

Abstract

Quantification of plasma levels of an early and late intermediate on the cholesterol pathway, mevalonic acid (MVA) and lathosterol respectively, provides a useful method of estimating cholesterol synthesis in humans. The aim of this study was to assess further their roles as indices of cholesterol synthesis under non-steady-state conditions. The short-term effects of pharmacological inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on both variables were determined in four normolipidaemic subjects during and after treatment with simvastatin 20 mg daily. Plasma MVA was measured using gas chromatography–mass spectrometry, and lathosterol using gas chromatography. A single dose of 20 mg of simvastatin decreased plasma MVA after 2 h and decreased the lathosterol–cholesterol (L/C) ratio after 4 h. Treatment with simvastatin 20 mg daily for 9 days decreased both variables by approximately 50%, the nadir of plasma MVA occurring on the second day and of the L/C ratio on the fifth day, and resulted in a 39% reduction in low-density lipoprotein (LDL)-cholesterol. After discontinuing simvastatin, there were rebounds in plasma MVA and the L/C ratio to above basal levels but not in LDL cholesterol or apolipoprotein B (apoB), the latter continuing to decrease for a further 2 days. These results suggest that simvastatin rapidly down-regulates cholesterol synthesis, which is then up-regulated when the drug is withdrawn.