THE EFFECT OF ACYL COA - CHOLESTEROL ACYLTRANSFERASE INHIBITION ON THE UPTAKE, ESTERIFICATION AND SECRETION OF CHOLESTEROL BY THE HAMSTER SMALL-INTESTINE

Acyl CoA: cholesterol acyltransferase (ACAT) inhibitors are known to i nhibit cholesterol absorption and are under investigation to reduce hy percholesterolemia. These studies examine the effect of an ACAT inhibi tor 2-dimethyl-N-(2,4,6-trimethoxyphenyl)-dodecanamide (PD128042) on t he uptake, metabolism and secretion of cholesterol by the hamster inte stinal wall in a short-term model. Preliminary studies in this model i ndicated that the uptake of C-14-cholesterol and its subsequent esteri fication 2 hr postoral dosing occurs primarily in the duodenal and jej unal segments of the small intestine and most of the radiolabeled chol esterol and cholesteryl ester in the plasma was associated with chylom icrons. In both single- and multiple-dose studies, PD128042 (50 mg kg( -1) day(-1)) did not inhibit intestinal uptake of [C-14]-cholesterol b ut [C-14]-cholesteryl ester formation was inhibited. The free [C-14]-c holesterol appearing in plasma was not affected despite a large reduct ion in [C-14]- cholesteryl ester. In contrast, cholestyramine (1 g kg( -1) day(-1)) inhibited the uptake of the radiolabeled free cholesterol and the appearance of cholesteryl ester in the intestine and plasma. The effects of PD128042 on cholesterol and cholesteryl eater mass asso ciated with scraped intestinal mucosa were consistent with the effects observed with the use of the radiolabeled cholesterol. In addition, P D128042 did not affect the uptake of appearance of radiolabeled trigly ceride in the intestinal wall after oral gavage of H-3-trioleoylglycer ol. Taken together, the data suggest that ACAT inhibition reduces chol esterol absorption by limiting cholesteryl ester incorporation into ch ylomicrons and has no effect on the intestinal processing of free chol esterol to be secreted into plasma.