Intestinal absorption of cholesterol is mediated by a saturable, inhibitable transporter

Although the mechanism by which dietary cholesterol is absorbed from the in testine is poorly understood, it is generally accepted that cholesterol is absorbed from bile acid micelles in the jejunum. Once inside the enterocyte s, cholesterol is esterified by the action of acyl-coenzyme A:cholesterol a cyltransferase (ACAT), assembled into chylomicrons, and secreted into the l ymph. In this work, mechanistic aspects of cholesterol absorption were prob ed using compounds that block cholesterol absorption in hamsters. Sterol gl ycoside cholesterol absorption inhibitors, exemplified by L-166,143, (3 bet a,5 alpha,25R)-3-[(4 ",6 "-bis[2-fluoro-phenylcarbamoyl]-B-D-cellobiosyl)ox y]-spirostan-11-one, potently blocked absorption of radioactive cholesterol , and the potencies of several analogs correlated with their ability to low er plasma cholesterol. Each molecule of L-166,143 blocked the uptake of 500 molecules of cholesterol, rendering it unlikely that the inhibitor interac ts directly with the cholesterol or bile acid. Radiolabeled L-166,143 bound to the mucosa and binding was blocked by active, but not inactive, cholest erol absorption inhibitors. Subtle changes in the structure of sterol glyco sides yielded large changes in their ability to block both cholesterol abso rption and binding of radiolabeled L-166,143. Large species-to-species vari ation in potency was also observed. These lines of evidence support the int erpretation that dietary cholesterol is absorbed via a specific transporter found in the intestinal mucosa. (C) 2000 Elsevier Science B.V. All rights reserved.