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Originally published In Press as doi:10.1074/jbc.M212377200 on January 27, 2003

J. Biol. Chem., Vol. 278, Issue 15, 13356-13366, April 11, 2003
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ABCA1 Is Essential for Efficient Basolateral Cholesterol Efflux during the Absorption of Dietary Cholesterol in Chickens*

Jacob D. MulliganDagger §, Matthew T. FlowersDagger ¶¶, Angie TebonDagger , J. James Bitgood||, Cheryl Wellington**, Michael R. Hayden**Dagger Dagger , and Alan D. AttieDagger §§

From the Departments of Dagger  Biochemistry, and || Animal Science, University of Wisconsin-Madison, Madison, Wisconsin 53706, ** Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia V65Z 4H4, Canada, and Dagger Dagger  Xenon Genetics, Burnaby, British Columbia V5G 4W8, Canada

The ATP-binding cassette transporter A1 (ABCA1) participates in the efflux of cholesterol from cells. It remains unclear whether ABCA1 functions to efflux cholesterol across the basolateral or apical membrane of the intestine. We used a chicken model of ABCA1 dysfunction, the Wisconsin hypoalpha mutant (WHAM) chicken, to address this issue. After an oral gavage of radioactive cholesterol, the percentage appearing in the bloodstream was reduced by 79% in the WHAM chicken along with a 97% reduction in the amount of tracer in high density lipoprotein. In contrast, the percentage of radioactive cholesterol absorbed from the lumen into the intestine was not affected by the ABCA1 mutation. Liver X receptor (LXR) agonists have been inferred to decrease cholesterol absorption through activation of ABCA1 expression. However, the LXR agonist T0901317 decreased cholesterol absorption equally in both wild type and WHAM chickens, indicating that the effect of LXR activation on cholesterol absorption is independent of ABCA1. The ABCA1 mutation resulted in accumulation of radioactive cholesterol ester in the intestine and the liver of the WHAM chicken (5.0- and 4.4-fold, respectively), whereas biliary lipid concentrations were unaltered by the WHAM mutation. In summary, ABCA1 regulates the efflux of cholesterol from the basolateral but not apical membrane in the intestine and the liver.

* This work was supported by National Institutes of Health (NIH) Grant HL56593 and Xenon Genetics, Inc.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by NIH Biology of Aging Training Grant T32-AG00213.

These two authors contributed equally to this work.

§§ To whom correspondence should be addressed: Dept. of Biochemistry, University of Wisconsin, 433 Babcock Dr., Madison, WI 53706-1544. Tel.: 608-262-1372; Fax: 608-263-9609.

¶¶ Supported by National Institutes of Health Molecular Biosciences Training Grant T32-GM07215-25.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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