Inhibition of cholesterogenesis decreases hepatic secretion of
apolipoprotein b-100 in normolipidaemic subjects.
Watts, Gf, Rp Naoumova, Jm Kelly, Fm Riches, Kd Croft, and Gr
Thompson.
Department of Medicine, University of Western Australia, Royal
Perth Hospital, Perth Western Australia; Lipoprotein Team, MRC
Clinical Sciences Centre, Royal Postgraduate Medical School,
Hammersmith Hospital, London, UK
APStracts 4:0105E, 1997.
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
normolipidaemic men in a placebo-controlled, cross-over study.
Simvastatin significantly decreased the plasma concentrations of 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 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 lathosterol:cholesterol ratio. The data supports the hypothesis
that the rate of de novo cholesterol synthesis directly regulates the
hepatic secretion of VLDL apoB in normal subjects.
Received 9 January 1997; accepted in final form 18 April 1997.
APS Manuscript Number E11-7.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 13 May 1997