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Journal of Lipid Research, Vol. 46, 2423-2431, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2

Ryan E. Temel, Richard G. Lee, Kathryn L. Kelley, Matthew A. Davis, Ramesh Shah, Janet K. Sawyer, Martha D. Wilson and Lawrence L. Rudel¹

Department of Pathology, Section on Lipid Sciences, Wake Forest University Health Sciences, Winston-Salem, NC

Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500232-JLR200

¹ To whom correspondence should be addressed. e-mail: lrudel{at}wfubmc.edu

The process of cholesterol absorption has yet to be completely defined at the molecular level. Because of its ability to esterify cholesterol for packaging into nascent chylomicrons, ACAT2 plays an important role in cholesterol absorption. However, it has been found that cholesterol absorption is not completely inhibited in ACAT2-deficient (ACAT2 KO) mice. Because ABCA1 mRNA expression was increased 3-fold in the small intestine of ACAT2 KO mice, we hypothesized that ABCA1-dependent cholesterol efflux sustains cholesterol absorption in the absence of ACAT2. To test this hypothesis, cholesterol absorption was measured in mice deficient in both ABCA1 and ACAT2 (DKO). Compared with wild-type, ABCA1 KO, or ACAT2 KO mice, DKO mice displayed the lowest level of cholesterol absorption. The concentrations of hepatic free and esterified cholesterol and gallbladder bile cholesterol were significantly reduced in DKO compared with wild-type and ABCA1 KO mice, although these measures of hepatic cholesterol metabolism were very similar in DKO and ACAT2 KO mice.

We conclude that ABCA1, especially in the absence of ACAT2, can have a significant effect on cholesterol absorption, although ACAT2 has a more substantial role in this process than ABCA1.

Abbreviations: apoB, apolipoprotein B; DKO, deficient in both ABCA1 and ACAT2; KO, -deficient; LXR, liver X receptor; NPC1L1, Niemann-Pick C1-like 1; SR-BI, scavenger receptor class B type I; TPC, plasma total cholesterol

Supplementary key words Niemann-Pick C1-like 1 • ATP-binding cassette transporter G5 • gallbladder bile • liver • plasma lipoproteins • ATP binding cassette transporter A1 • acyl-coenzyme A:cholesterol acyltransferase

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