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Journal of Lipid Research, Vol 37, 1-14, Copyright © 1996 by Lipid Research, Inc.
R Musanti, L Giorgini, PP Lovisolo, A Pirillo, A Chiari and G Ghiselli
There is evidence that the overproduction of apoB-100-containing
lipoproteins by the liver is the underlying event in some forms of
dyslipoproteinemia. This metabolic status is associated to an increased
risk of developing premature coronary artery disease CAD. The conclusions
from previous studies suggested that the availability to the hepatocytes of
cholesterol that is readily esterified is an important determinant for VLDL
and LDL secretion. In the present study, we set out to investigate the
effect of the specific stimulation and inhibition of the rate-limiting
enzyme of the cholesterol esterification, acyl-CoA:cholesterol
acyltransferase (ACAT, E.C. 2.3.1.26), on the lipid and on the apoB-100
secretion rate from a human hepatoma cell line (HepG2). When the specific
ACAT inhibitor FCE 27677 (10-5 M) was added to the cultures, a decrease of
the cellular cholesteryl ester content and at the same time a significant
reduction of the neutral lipids and of the apoB-100 secretion rate were
noticed. The stimulation of ACAT by 25-hydroxycholesterol (20 microgram/ml)
caused a 4-fold increase of the cellular cholesteryl ester content and a
2-fold increase of the lipoprotein secretion rate. FCE 27677 (10-5 M to
10-7 M) prevented the effects elicited by the oxysterol. On the contrary,
lovastatin (10-6 M) and gemfibrozil (10-6 M) had no effect. The analysis of
the lipid and of the apolipoprotein composition of the lipoproteins
secreted in the medium revealed that ACAT inhibition had the dual effect of
both decreasing the number of apoB-100-containing lipoproteins secreted as
well as their cholesteryl ester load. Altogether, these data support the
idea of a close relationship between ACAT activation, leading to increased
cholesteryl ester availability, and apoB-100-containing lipoprotein
secretion. It is speculated that ACAT inhibitors may prove useful for the
treatment of human dyslipoproteinemias caused by the hepatic overproduction
of apoB-100- containing lipoproteins.
ARTICLES
Inhibition of acyl-CoA: cholesterol acyltransferase decreases apolipoprotein B-100-containing lipoprotein secretion from HepG2 cells
Pharmacia Farmitalia Carlo Erba Research Institute, Cardiovascular Department, Milan, Italy.
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