EFFECTS OF NB-598, A POTENT SQUALENE EPOXIDASE INHIBITOR, ON THE APICAL MEMBRANE UPTAKE OF CHOLESTEROL AND BASOLATERAL MEMBRANE SECRETION OF LIPIDS IN CACO-2 CELLS

Caco-2 cells grown on membrane filters were used as a model to study t he effects of NB-598, an inhibitor of squalene epoxidase, on cholester ol absorption from the intestinal epithelia. NB-598 (10 muM) inhibited the synthesis of sterol and sterol ester from C-14!acetate without a ffecting the synthesis of other lipids such as phospholipids (PL), fre e fatty acids (FFA) and triacylglycerol (TG). When labeled lipid was a pically loaded as a micellar lipid solution into Caco-2 cell cultures, NB-598 reduced basolaterally secreted radioactivity in cholesterol, c holesterol ester, PL and TG. Furthermore, NB-598 suppressed the basola teral secretion of apolipoprotein (apo) B. When microsomes prepared fr om control Caco-2 cells were incubated with 10 muM NB-598, acyl CoA:ch olesterol acyltransferase (ACAT) activity was inhibited slightly. Afte r incubating Caco-2 cells with 10 muM NB-598, a slight reduction in ce llular ACAT activity was also observed. These results suggest that sup pression of the secretion of particles containing apo B and reduction of cellular ACAT activity in the intestinal epithelia are part of the mechanism of the cholesterol-lowering effect of NB-598.