Inhibition of cholesterogenesis decreases hepatic secretion of apoB-100 in normolipidemic subjects.
We examined the effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl 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 decreased the plasma concentrations of low-density lipoprotein (LDL) cholesterol by 36%, triglycerides by 26%, mevalonic acid by 34%, and lathosterol by 32%. Hepatic secretion of VLDL apoB was measured using a primed constant intravenous infusion of [1-13C]leucine with monitoring of 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 secretion rate of VLDL apoB by 46% but did not significantly alter its fractional catabolism. The change in hepatic VLDL apoB secretion was significantly and independently correlated with changes in plasma mevalonic acid and lathosterol concentrations and the lathosterol-to-cholesterol ratio. The data support the hypothesis that the rate of de novo cholesterol synthesis directly regulates the hepatic secretion of VLDL apoB in normal subjects.
Watts
G F
GF
Department of Medicine, University of Western Australia, Royal Perth Hospital, Perth, Australia.
Naoumova
R P
RP
Kelly
J M
JM
Riches
F M
FM
Croft
K D
KD
Thompson
G R
GR
D000328:Adult; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000378:metabolism; D002247:Carbon Isotopes; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007536:Isomerism; D007930:Leucine / Q000378:metabolism; D008074:Lipoproteins / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011897:Random Allocation; D012016:Reference Values; D012044:Regression Analysis; D019821:Simvastatin
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002247:Carbon Isotopes; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; C001521:lathosterol; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D007930:Leucine