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J. Biol. Chem., Vol. 281, Issue 44, 33053-33065, November 3, 2006

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ABCA1 Overexpression in the Liver of LDLr-KO Mice Leads to Accumulation of Pro-atherogenic Lipoproteins and Enhanced Atherosclerosis^*

Charles W. Joyce¹, Elke M. Wagner¹², Federica Basso, Marcelo J. Amar, Lita A. Freeman, Robert D. Shamburek, Catherine L. Knapper, Jafri Syed, Justina Wu, Boris L. Vaisman, Jamila Fruchart-Najib, Eric M. Billings^¶, Beverly Paigen^||, Alan T. Remaley, Silvia Santamarina-Fojo, and H. Bryan Brewer, Jr.^**

From the Molecular Disease Section and the ^¶Bioinformatics Core Facility, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, the Department d'Atherosclerose, Institut Pasteur, Lille cedex 59019, France, ^||The Jackson Laboratory, Bar Harbor, Maine 04509, and the ^**Cardiovascular Research Institute, Washington, D. C. 20010

The identification of ABCA1 as a key transporter responsible for cellular lipid efflux has led to considerable interest in defining its role in cholesterol metabolism and atherosclerosis. In this study, the effect of overexpressing ABCA1 in the liver of LDLr-KO mice was investigated. Compared with LDLr-KO mice, ABCA1-Tg x LDLr-KO (ABCA1-Tg) mice had significantly increased plasma cholesterol levels, mostly because of a 2.8-fold increase in cholesterol associated with a large pool of apoB-lipoproteins. ApoB synthesis was unchanged but the catabolism of ¹²⁵I-apoB-VLDL and -LDL were significantly delayed, accounting for the 1.35-fold increase in plasma apoB levels in ABCA1-Tg mice. We also found rapid in vivo transfer of free cholesterol from HDL to apoB-lipoproteins in ABCA1-Tg mice, associated with a significant 2.7-fold increase in the LCAT-derived cholesteryl linoleate content found primarily in apoB-lipoproteins. ABCA1-Tg mice had 1.4-fold increased hepatic cholesterol concentrations, leading to a compensatory 71% decrease in de novo hepatic cholesterol synthesis, as well as enhanced biliary cholesterol, and bile acid secretion. CAV-1, CYP2b10, and ABCG1 were significantly induced in ABCA1-overexpressing livers; however, no differences were observed in the hepatic expression of CYP71, CYP271, or ABCG5/G8 between ABCA1-Tg and control mice. As expected from the pro-atherogenic plasma lipid profile, aortic atherosclerosis was increased 10-fold in ABCA1-Tg mice. In summary, hepatic overexpression of ABCA1 in LDLr-KO mice leads to: 1) expansion of the pro-atherogenic apoB-lipoprotein cholesterol pool size via enhanced transfer of HDL-cholesterol to apoB-lipoproteins and delayed catabolism of cholesterol-enriched apoB-lipoproteins; 2) increased cholesterol concentration in the liver, resulting in up-regulated hepatobiliary sterol secretion; and 3) significantly enhanced aortic atherosclerotic lesions.

Received for publication, May 11, 2006 , and in revised form, August 21, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Both authors have contributed equally to this work.

² To whom correspondence should be addressed: NHLBI, National Institutes of Health, Bldg. 10, Rm. 7N105, Bethesda, MD 20892. Tel.: 301-496-5313; Fax: 301-402-0190; E-mail: ewagner{at}mail.nih.gov.

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