Acyl coenzyme A:
cholesterol acyl
transferase and/or
cholesterol esterase may regulate the esterification and absorption of exogenous
cholesterol. To assess this, mucosal
acyl coenzyme A:
cholesterol acyl
transferase activity was inhibited selectively with three different drugs [
Sandoz #58-035, inhibitor 1; Lederle inhibitor 2 and inhibitor 3] and the effect upon the absorption of a [4-14C]
cholesterol meal was studied in the lymph
fistula rat. Compared to control rats, ACAT activity measured in mucosal homogenates from the
drug-treated rats was reduced 80-90%, 40%, and 30%, respectively, during the predicted time-frame for maximum mucosal esterification of
cholesterol (i.e., after
cholesterol is fed and before it appears in lymph). In contrast, [14C]
cholesterol absorption in the
drug-treated animals was unchanged from controls [5.7 +/- 1.2 (inhibitor 1) vs. 5.4 +/- 1.6 mumol/6 hr (control); 6.1 +/- 2.1 (inhibitor 2) and 5.2 +/- 1.5 (inhibitor 3) vs. 4.1 +/- 1.3 mumol/6 hr (control)]. Of the absorbed [14C]
cholesterol, approximately 75% was esterified in all groups.
Cholesterol esterase activity measured in the
drug-treated rats was unchanged compared to controls nor did the drugs inhibit this
enzyme in vitro. Under the conditions of this study, drugs causing substantial inhibition of
acyl coenzyme A:
cholesterol acyl
transferase activity had no effect on the absorption of exogenous
cholesterol.