Role of acyl CoA:cholesterol acyltransferase in cholesterol absorption and its inhibition by 57-118 in the rabbit.

Esterification of cholesterol in rabbit small intestine mucosal microsomes by acyl CoA:cholesterol acyltransferase (ACAT, Ec 2.3.1.26) and mucosal cytosol by cholesterol esterase (EC 3.1.1.13) was studied. Compound 57-118. N-(1-oxo-9-octadecenyl)-DL-tryptophan(Z)ethyl ester, an inhibitor of cholesterol absorption, was found to inhibit in vitro ACAT in mucosal microsomes at concentrations of 2-20 nmol/0.5 ml incubation mixture, but had no effect on cholesterol esterase in the cytosol at similar concentrations. A kinetic analysis using a Lineweaver-Burk plot indicates that 57-118 acts as a competitive inhibitor of ACAT. An ex vivo study in the rabbit where 57-118 was given by gavage at a dose of 200 mg/kg also showed inhibition of ACAT but not of cholesterol esterase. High performance liquid chromatography determination of 57-118 in various subcellular fractions demonstrated the presence of this substance after oral administration in concentrations in mucosal microsomes equivalent to those required to show inhibition of ACAT in vitro. These data support the work of Norum et al. (1979, Eur. J. Clin. Invest. 9: 55-62) indicating mucosal ACAT plays a significant role in cholesterol absorption.