The role of acyl-CoA: cholesterol acyltransferase in the metabolism of free cholesterol to cholesteryl esters or bile acids in primary cultures of rat hepatocytes.
Sandoz compound 58-035 has been shown to inhibit acyl-CoA: cholesterol acyltransferase activity in a variety of cell types. We have shown that it does not inhibit rat liver microsomal cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme of bile-acid synthesis, but it does inhibit acyl-CoA: cholesterol acyltransferase in both the microsomal fraction and in rat hepatocyte monolayers. To test the role of acyl-CoA: cholesterol acyltransferase in these cells, monolayers were incubated over 5 h in the presence and absence of 58-035 and in the presence of increasing amounts of mevalonic acid to provide a source of cholesterol. The addition of mevalonic acid increased the secretion of bile acids by the cells, and this was further increased by the addition of 58-035. The secretion of cholesteryl esters was conversely inhibited by the addition of 58-035. The results help define the role of acyl-CoA: cholesterol acyltransferase in determining the fate of intracellular cholesterol.
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006888:Hydroxycholesterols / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D017646:Organosilicon Compounds; D051381:Rats
D000577:Amides; D001647:Bile Acids and Salts; D002788:Cholesterol Esters; D006888:Hydroxycholesterols; D017646:Organosilicon Compounds; C007997:25-hydroxycholesterol; C040256:SAN 58035; D002784:Cholesterol; D004121:Dimethyl Sulfoxide