DEMONSTRATION OF A DIRECT EFFECT ON HEPATIC ACYL COA-CHOLESTEROL ACYLTRANSFERASE (ACAT) ACTIVITY BY AN ORALLY-ADMINISTERED ENZYME-INHIBITOR IN THE HAMSTER

Orally active inhibitors of acyl CoA:cholesterol acyl transferase (ACA T), such as Lederle CL277082 (LE), are known to reduce plasma and hepa tic cholesteryl ester levels, although the mechanisms are not well und erstood. Several groups have reported the inhibition of cholesterol ab sorption upon oral ACAT inhibitor administration. In this study, we us ed 7-day dietary and drug treatments of hamsters to examine the possib le effects of LE on hepatic ACAT. ACAT assays were performed using liv er homogenates in the absence and presence of a saturating level of ex ogenously added cholesterol. LE (100 mg/kg/day) treatment of chow or 0 .5% cholesterol-fed animals caused reductions in ACAT activity without additional cholesterol as compared with non-treated animals. When a s aturating level of cholesterol was added to the assays, reductions in ACAT activity upon LE treatment of chow- or cholesterol-fed animals we re also observed. Treatment of cholesterol-fed animals with cholestyra mine in the diet reduced ACAT activity in the absence of added cholest erol. However, ACAT activities similar to those of non-treated animals were observed at a saturating level of cholesterol. This latter effec t demonstrates that inhibition of cholesterol absorption reduces chole sterol delivery to the liver but does not reduce cholesterol esterifyi ng capacity since cholestyramine is not absorbed and has no direct eff ect on the liver. The decreased ACAT activity in homogenates from LE-t reated animals could also be mimicked in a dose-dependent manner by th e addition of exogenous LE to liver homogenates from non-treated anima ls. These results indicate that hepatic ACAT activity is regulated by the availability of free cholesterol, and that orally administered LE has a direct effect on hepatic ACAT activity in the liver. In addition , the data are consistent with LE activity in the liver as being respo nsible, in part, for the reduced hepatic and plasma cholesteryl esters in treated animals.