INHIBITION OF CHOLESTEROGENESIS DECREASES HEPATIC SECRETION OF APO-B-100 IN NORMOLIPIDEMIC SUBJECTS

We examined the effect of simvastatin, an inhibitor of 3-hydroxy-3-met hylglutaryl coenzyme A reductase, on the kinetics of very low-density lipoprotein apolipoprotein B-100 (VLDL apoB) in 13 normolipidemic men in a placebo-controlled crossover study. Simvastatin significantly dec reased the plasma concentrations of low-density Lipoprotein (LDL) chol esterol by 36%, triglycerides by 26%, mevalonic acid by 34%, and latho sterol by 32%. Hepatic secretion of VLDL apoB was measured using a pri med constant intravenous infusion of [1-C-13]leucine with monitoring o f isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional turnover rate was derived using a monoexponential function . Simvastatin decreased VLDL apoB pool size by 53% and the hepatic sec retion rate of VLDL apoB by 46% but did not significantly alter its fr actional catabolism. The change in hepatic VLDL apoB secretion was sig nificantly and independently correlated with changes in plasma mevalon ic acid and lathosterol concentrations and the lathosterol-to-choleste rol ratio. The data support the hypothesis that the rate or de novo ch olesterol synthesis directly regulates the hepatic secretion of VLDL a poB in normal subjects.