J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on August 1, 2003

Papers In Press, published online ahead of print May 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300110-JLR200
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Submitted on March 11, 2003
Revised on April 30, 2003
Accepted on May 1, 2003

Alterations of plasma lipids in mice via adenovirual mediated hepatic overexpression of human ABCA1

Cheryl L. Wellington, Liam R. Brunham, Steven Zhou, Roshni R. Singaraja, Henk Visscher, Allison Gelfer, Colin Ross, Erick James, Guoquing Liu, Mary T. Huber, Yu-Zhou Yang, Robin J. Parks, Albert Groen, Jamila Fruchart-Najib, and Michael R. Hayden

Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia V6Z 4H4

Corresponding Author: mrh{at}cmmt.ubc.ca

ABCA1 is a lipid transporter that is essential for the generation of HDL. Although ABCA1 is expressed in several tissues, its particular abundance in the liver suggests that the liver may play a major role in HDL homeostasis. To determine the relationship between hepatic ABCA1 and plasma HDL-C levels, we treated mice with an adenovirus expressing human ABCA1 under the control of the CMV promoter. The livers of treated mice showed a dose-dependent increase in ABCA1 protein, ranging from 1.2-fold to 8.3-fold using doses from 5 x 108 - 1.5 x 109 pfu, with maximal expression observed on day 3 posttreatment. A selective increase in HDL-C levels occurred at day 3 in mice treated with 5 x 108 pfu Ad-ABCA1, but higher doses did not further elevate HDL-C levels. In contrast, TC, TG, PL, non-HDL-C and apoB levels all increased in a dose-dependent manner, suggesting that excessive overexpression of hepatic ABCA1 in the absence of its normal regulatory sequences altered total lipid homeostasis. A comparison of lipids in BAC transgenic mice, which express ABCA1 under the control of its endogenous regulatory sequences, with Ad-ABCA1-treated mice at comparable expression levels, showed that a greater specific increase in HDL-C occurred in BAC transgenic animals. Our results suggest that appropriate regulation of ABCA1 is critical for a selective increase in HDL-C levels.


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