ACAT inhibitors decrease secretion of cholesteryl esters and apolipoprotein B by perfused livers of African green monkeys

Abstract

To test the hypothesis that newly synthesized cholesteryl esters are required for hepatic lipoprotein assembly and secretion, isolated livers of African green monkeys were perfused with medium containing an ACAT inhibitor. Three ACAT inhibitors with different structural and chemical properties were used: CI-976 (Parke-Davis), CP-113818 (Pfizer), or PD-138142-15 (Parke-Davis). Each compound produced variable effects on secretion of lipids and apolipoproteins. A significant decrease in the secretion rates of cholesteryl ester and apoB was common to all three inhibitors, indicating that fewer lipoprotein particles were secreted during ACAT inhibition. Triacylglycerol secretion was decreased in the presence of CP-113818 and PD-138142-15 but no decrease in triacylglycerol secretion was observed with CI-976. Particles secreted in the presence of CI-976 were enriched in triacylglycerol relative to apoB. Effects on secretion of other apolipoproteins (apoA-I, apoA-II, and apoE) were variable. When all data were combined, the percent inhibition of cholesteryl ester secretion and apoB secretion in the presence of ACAT inhibitors was positively correlated (r = 0.84), whereas a similar relationship was not observed between triacylglycerol and apoB. While the results demonstrate some lack of specificity for these ACAT inhibitors, the complimentary results using the three different ACAT inhibitors suggest that secretion of cholesteryl ester and apoB are coordinately regulated. The data suggest that newly synthesized cholesteryl esters may participate in and promote the assembly and secretion of hepatic apoB-containing lipoproteins. The availability of triacylglycerol during lipoprotein assembly, while also important, would appear to serve a role separate from that of cholesteryl ester.