© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Cafestol Increases Serum Cholesterol Levels in Apolipoprotein E*3-Leiden Transgenic Mice by Suppression of Bile Acid Synthesis
From TNO Prevention and Health (S.M.P., M.C.J., V.E.H.D., L.M.H., H.M.G.P.), Gaubius Laboratory, Leiden; the Division of Nutrition and Epidemiology (B.d.R., M.V., L.A., M.B.K.), Wageningen Agricultural University, Wageningen; the Groningen Institute of Drug Studies (F.S.), Center for Digestive and Metabolic Diseases, Academic Hospital Groningen, Groningen; and the Wageningen Centre for Food Sciences (M.B.K.), Wageningen, The Netherlands.
Correspondence to Dr H.M.G. Princen, Gaubius Laboratory, TNO Prevention and Health, PO Box 2215, 2301 CE Leiden, The Netherlands. E-mail jmg.princen{at}pg.tno.nl
Abstract—Cafestol, a diterpene
present in unfiltered coffee, potently increases serum
cholesterol levels in humans. So far, no suitable animal
model has been found to study the biochemical background of this
effect. We determined the effect of cafestol on serum
cholesterol and triglycerides in different
mouse strains and subsequently studied its mechanism of action in
apolipoprotein (apo) E*3-Leiden transgenic mice. ApoE*3-Leiden,
heterozygous low density lipoprotein–receptor (LDLR+/-) knockout, or
wild-type (WT) C57BL/6 mice were fed a high- (0.05% wt/wt) or a low-
(0.01% wt/wt) cafestol diet or a placebo diet for 8 weeks.
Standardized to energy intake, these amounts are equal to 40, 8, or 0
cups of unfiltered coffee per 10 MJ per day in humans. In apoE*3-Leiden
mice, serum cholesterol was statistically significantly
increased by 33% on the low- and by 61% on the high-cafestol diet. In
LDLR+/- and WT mice, the increases were 20% and 24%, respectively,
on the low-cafestol diet and 55% and 46%, respectively, on the
high-cafestol diet. These increases were mainly due to a rise in very
low density lipoprotein (VLDL) and intermediate density lipoprotein
cholesterol in all 3 mouse strains. To investigate the
mechanism of this effect, apoE*3-Leiden mice were fed a high-cafestol
or a placebo diet for 3 weeks. Cafestol suppressed enzyme activity and
mRNA levels of cholesterol 7
-hydroxylase by 57% and
58%, respectively. mRNA levels of enzymes involved in the alternate
pathway of bile acid synthesis, ie, sterol 27-hydroxylase and oxysterol
7-hydroxylase, were reduced by 32% and 48%, respectively. The
total fecal bile acid output was decreased by 41%. Cafestol did not
affect hepatic free and esterified cholesterol, but it
decreased LDLR mRNA levels by 37%. The VLDL apoB and
triglyceride production rates, as measured after
Triton injection, were 2-fold decreased by cafestol, indicating that
the number of particles secreted had declined and that there was no
change in the amount of triglycerides present in the
VLDL particle during cafestol treatment. However, the VLDL particles
contained a 4-times higher amount of cholesteryl esters, resulting in a
net 2-fold increased secretion of cholesteryl esters. The decrease in
triglyceride production was the result of a
reduction in hepatic triglyceride content by 52%. In
conclusion, cafestol increases serum cholesterol levels in
apoE*3-Leiden mice by suppression of the major regulatory enzymes in
the bile acid synthesis pathways, leading to decreased LDLR mRNA levels
and increased secretion of hepatic cholesterol esters. We
suggest that suppression of bile acid synthesis may provide an
explanation for the cholesterol-raising effect of cafestol
in humans.
Key Words: bile acid synthesis • cholesterol 7-hydroxylase • sterol 27-hydroxylase • apolipoprotein E*3-Leiden mice • cafestol
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