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 the effects of NB-598, an inhibitor of squalene epoxidase, on cholesterol absorption from the intestinal epithelia. NB-598 (10 microM) inhibited the synthesis of sterol and sterol ester from [14C]acetate without affecting the synthesis of other lipids such as phospholipids (PL), free fatty acids (FFA) and triacylglycerol (TG). When labeled lipid was apically loaded as a micellar lipid solution into Caco-2 cell cultures, NB-598 reduced basolaterally secreted radioactivity in cholesterol, cholesterol ester, PL and TG. Furthermore, NB-598 suppressed the basolateral secretion of apolipoprotein (apo) B. When microsomes prepared from control Caco-2 cells were incubated with 10 microM NB-598, acyl CoA:cholesterol acyltransferase (ACAT) activity was inhibited slightly. After incubating Caco-2 cells with 10 microM NB-598, a slight reduction in cellular ACAT activity was also observed. These results suggest that suppression 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.
Horie
M
M
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
Iwasawa
Y
Y
Satoh
T
T
Shimizu
A
A
Nagata
Y
Y
Kamei
T
T
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism; D001596:Benzylamines / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008041:Linoleic Acids / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D053284:Polyunsaturated Alkamides; D019821:Simvastatin / Q000031:analogs & derivatives*; D050603:Squalene Monooxygenase; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D001596:Benzylamines; D002788:Cholesterol Esters; D008041:Linoleic Acids; D008055:Lipids; D009829:Oleic Acids; D053284:Polyunsaturated Alkamides; D013876:Thiophenes; D014316:Tritium; C066059:NB 598; D019301:Oleic Acid; D002784:Cholesterol; C063287:simvastatin acid; D008148:Lovastatin; D019821:Simvastatin; D010105:Oxygenases; D050603:Squalene Monooxygenase; D002785:Sterol O-Acyltransferase; C001757:N-(2-methylbenzyl)linoleamide