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.