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Journal of Lipid Research, Vol. 50, 2235-2244, November 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Influence of class B scavenger receptors on cholesterol flux across the brush border membrane and intestinal absorption

David V. Nguyen^*, Victor A. Drover, Martin Knopfel, Padmaja Dhanasekaran^*, Helmut Hauser and Michael C. Phillips^1,*

^* Gastroenterology, Hepatology, and Nutrition Division, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318
Departments of Biochemistry and Medicine, Medical College of Wisconsin, Milwaukee, WI 53226
Lipideon Biotechnology, ETH Zurich, 8093 Zurich, Switzerland

¹ To whom correspondence should be addressed. e-mail: phillipsmi{at}email.chop.edu

To learn more about how the step of cholesterol uptake into the brush border membrane (BBM) of enterocytes influences overall cholesterol absorption, we measured cholesterol absorption 4 and 24 h after administration of an intragastric bolus of radioactive cholesterol in mice with scavenger receptor class B, type 1 (SR-BI) and/or cluster determinant 36 (CD36) deleted. The cholesterol absorption efficiency is unaltered by deletion of either one or both of the receptors. In vitro determinations of the cholesterol uptake specific activity of the BBM from the mice reveal that the scavenger receptors facilitate cholesterol uptake into the proximal BBM. It follows that cholesterol uptake into the BBM is not normally rate-limiting for the cholesterol absorption process in vivo; a subsequent step, such as NPC1L1-mediated transfer from the BBM into the interior of the enterocyte, is rate-limiting. The absorption of dietary cholesterol after 4 h in mice lacking SR-BI and/or CD36 and fed a high-fat/high-cholesterol diet is delayed to more distal regions of the small intestine. This effect probably arises because ATP binding cassette half transporters G5 and G8-mediated back flux of cholesterol from the BBM to the lumen of the small intestine limits absorption and causes the local cholesterol uptake facilitated by SR-BI and CD36 to become rate-limiting under this dietary condition.

Supplementary key words dietary cholesterol • enterocytes • scavenger receptor class B, type 1 • cluster determinant 36 • Niemann Pick C1-Like 1 • ATP binding cassette half transporters G5 and G8

Abbreviations: ABCG5/G8, ATP binding cassette half transporters G5 and G8; ACAT-2, acylCoA:cholesterol-acyltransferase-2; BBM, brush border membrane; BBMV, brush border membrane vesicle; BSM, mixed bile salt micelle; CD36, cluster determinant 36; HFHC, high-fat/high-cholesterol diet; NPC1L1, Niemann Pick C1-Like 1; SR-BI, scavenger receptor class B, type 1; SUV, small unilamellar vesicle; WT, wild type

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