SIMVASTATIN DECREASES THE HEPATIC SECRETION OF VERY-LOW-DENSITY LIPOPROTEIN APOLIPOPROTEIN B-100 IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA - PATHOPHYSIOLOGICAL AND THERAPEUTIC IMPLICATIONS

We studied six patients with heterozygous familial hypercholesterolaem ia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day(-1)), an inhibitor of 3-hydroxy-3-methyl-glutaryl-Coenzyme A. Simv astatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% (P=0002), triglycerides by 27% (P=005) and mevalonic acid (a measu re of in vivo cholesterol synthesis) by 20% (P=0002); high-density lip oprotein cholesterol increased by 17% (P=0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of 1-[C-13]-leucine with monitoring of the isotopic enrichment of apoB b y gas chromatography-mass spectrometry; fractional secretion rate (FSR ) was derived using a mono-exponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. ( 11.9 (SEM 3.5) pools day(-1) P= 0.10), 83% (51.4 (SEM 17.9) vs. (8.6 ( SEM 1.4), P=O .007 mg kg(-1) day(-1)) and 65% (234.2 (SEM 30.4) vs. 82 .6 (SEM 24.0)mg, P=0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL choles terol concentration (P=0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol. This effect does not appear to be directly rela ted to the inhibition of cholesterol synthesis and may be due to decre ased hepatic delivery of cholesterol esters via the LDL receptor-indep endent pathway, but these mechanisms require further investigation.