© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Dietary Plant Stanol Esters Reduce VLDL Cholesterol Secretion and Bile Saturation in Apolipoprotein E*3-Leiden Transgenic Mice
From TNO Prevention and Health (O.L.V., H.v.d.B., E.C.M.d.W., W.v.D., L.M.H., H.M.G.P.), Leiden, and Nutrition and Toxicology Research Institute Maastricht (G.H., J.P., R.P.M.), Department of Human Biology, Maastricht University, Maastricht, the Netherlands.
Correspondence to Dr Ronald P. Mensink, Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands. E-mail r.mensink{at}hb.unimaas.nl
Abstract—Dietary
plant stanols lower serum cholesterol levels in humans and
in hyperlipidemic rodents, mainly by inhibition of the
intestinal cholesterol absorption. We used female
apolipoprotein E*3-Leiden transgenic mice to investigate the
consequences of this effect on serum lipid levels and hepatic lipid
metabolism. Five groups of 6 or 7 mice received for 9 weeks
a diet containing 0.25% cholesterol and 0.0%, 0.25%,
0.5%, 0.75%, or 1.0% (wt/wt) plant stanols (sitostanol 88%
[wt/wt], campestanol 10% [wt/wt]) esterified to fatty acids.
Compared with the control diet, plant stanol ester treatment
dose-dependently reduced serum cholesterol levels by 10%
to 33% (P<0.05), mainly in
very low density lipoproteins (VLDLs), intermediate density
lipoproteins, and low density lipoproteins. Furthermore, 1.0% of the
dietary plant stanols significantly decreased the liver contents of
cholesteryl esters (-62%), free cholesterol (-31%),
and triglycerides (-38%) but did not change the hepatic
VLDL-triglyceride and VLDL–apolipoprotein B
production rates. However, plant stanol ester feeding
significantly decreased the amounts of cholesteryl esters and free
cholesterol incorporated in nascent VLDLs by 72% and 30%,
respectively, resulting in a net 2-fold decreased VLDL
cholesterol output. Liver mRNA levels of low density
lipoprotein receptors, 3-hydroxy-3-methylglutaryl coenzyme A synthase,
cholesterol 7
-hydroxylase, and sterol 27-hydroxylase
were not changed by plant stanol ester feeding. Nevertheless, the serum
lathosterol-to-cholesterol ratio was significantly
increased by 23%, indicating that dietary plant stanol esters
increased whole-body cholesterol synthesis. Plant stanol
esters also significantly decreased the cholesterol
saturation index in bile by 55%. In conclusion, in apolipoprotein
E*3-Leiden transgenic mice, plant stanol ester feeding dose-dependently
lowered serum cholesterol levels as a result of a reduced
secretion of VLDL cholesterol. This was caused by a
decreased hepatic cholesterol content that also resulted in
a lowered biliary cholesterol output, indicative of a
reduced lithogenicity of bile in these
mice.
Key Words: plant sterols • sitostanol • apolipoprotein E*3-Leiden transgenic mice • lipoproteins • liver lipid metabolism
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