title: A target for cholesterol absorption inhibitors in the enterocyte brush border membrane.
abstract: Uptake of cholesterol by the intestinal absorptive epithelium can be selectively blocked by specific small molecules, like the sterol glycoside, L-166,143. Furthermore, (3)H-labeled L-166,143 administered orally to hamsters binds specifically to the intestinal mucosa, suggesting the existence of a cholesterol transporter. Using autoradiography, the binding site of (3)H-L-166,143 in the hamster small intestine was localized to the very apical aspect of the absorptive epithelial cells. Label was competed by non-radioactive L-166,143 and two structurally distinct cholesterol absorption inhibitors, suggesting a common site of action for these compounds. L-166,143 blocked uptake of (3)H-cholesterol into enterocytes in vivo, as demonstrated by autoradiography, suggesting that it inhibits a very early step of cholesterol absorption, incorporation into the brush border membrane. This conclusion was confirmed by studies in which intestinal brush borders were isolated from hamsters dosed with (3)H-cholesterol in the presence or absence of L-166,143. Uptake of (3)H-cholesterol into the membranes was substantially inhibited by the compound. In contrast, an inhibitor of acyl CoA:cholesterol acyltransferase, did not affect uptake of (3)H-cholesterol into the brush border membranes. These results strongly support the existence of a specific transporter that facilitates the movement of cholesterol from bile acid micelles into the brush border membranes of enterocytes.
authors.affiliation: Merck Research Laboratories, 126 E. Lincoln Ave., R80W-250, Rahway, NJ 07065, USA. patricia_detmers@merck.com
authors.forename: P A
authors.initials: PA
authors.lastname: Detmers
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: Hernandez
authors.forename: J
authors.initials: J
authors.lastname: Montenegro
authors.forename: J M
authors.initials: JM
authors.lastname: Lisnock
authors.forename: B
authors.initials: B
authors.lastname: Pikounis
authors.forename: M
authors.initials: M
authors.lastname: Steiner
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.forename: C
authors.initials: C
authors.lastname: Sparrow
authors.forename: Y S
authors.initials: YS
authors.lastname: Chao
authors.forename: S D
authors.initials: SD
authors.lastname: Wright
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001345:Autoradiography; D001647:Bile Acids and Salts / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000378:metabolism*; D006224:Cricetinae; D015536:Down-Regulation; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D012503:Saponins / Q000378:metabolism / Q000494:pharmacology*; D013150:Spirostans; D014316:Tritium
chemical_list: D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; C401968:L 165313; C401967:L 166143; D012503:Saponins; D013150:Spirostans; D014316:Tritium