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Journal of Lipid Research, Vol. 46, 1113-1123, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Complete functional rescue of the ABCA1^–/– mouse by human BAC transgenesis

Jonathan M. Coutinho^1,*, Roshni R. Singaraja^1,*, Martin Kang^*, David J. Arenillas^*, Lisa N. Bertram^*, Nagat Bissada^*, Bart Staels, Jean-Charles Fruchart, Catherine Fievet, Ann M. Joseph-George, Wyeth W. Wasserman^* and Michael R. Hayden^2,*

^* Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada
Institut Pasteur de Lille,, U545 Institut National de la Santé et de la Recherche Médicale, Lille Cedex, France
Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M400506-JLR200

¹ J. M. Coutinho and R. R. Singaraja contributed equally to this work.

² To whom correspondence should be addressed. e-mail: mrh{at}cmmt.ubc.ca

Humanized mouse models are useful tools to explore the functional and regulatory differences between human and murine orthologous genes. We have combined a bioinformatics approach and an in vivo approach to assess the functional and regulatory differences between the human and mouse ABCA1 genes. Computational analysis identified significant differences in potential regulatory sites between the human and mouse genes. The effect of these differences was assessed in vivo, using a bacterial artificial chromosome transgenic humanized ABCA1 mouse model that expresses the human gene in the absence of mouse ABCA1. Humanized mice expressed human ABCA1 protein at levels similar to wild-type mice and fully compensated for cholesterol efflux activity and lipid levels seen in ABCA1-deficient mice. Liver X receptor agonist administration resulted in significant increases in HDL values associated with parallel increases in the hepatic ABCA1 protein and mRNA levels in the humanized ABCA1 mice, as seen in the wild-type animals.

Our studies indicate that despite differences in potential regulatory regions, the human ABCA1 gene is able to functionally fully compensate for the mouse gene. Our humanized ABCA1 mice can serve as a useful model system for functional analysis of the human ABCA1 gene in vivo and can be used for the generation of potential new therapeutics that target HDL metabolism.

Abbreviations: apoB, apolipoprotein B; BAC, bacterial artificial chromosome; CETP, cholesteryl ester transfer protein; CYP7A1, cholesterol 7-hydroxylase; FISH, fluorescent in situ hybridization; HDL-C, high density lipoprotein cholesterol; LXR, liver X receptor; PPAR, peroxisome proliferator-activated receptor ; RCT, reverse cholesterol transport; RXR, retinoid X receptor; TFBS, transcription factor binding site

Supplementary key words ATP binding cassette type A1 • humanized mouse • bacterial artificial chromosome • phylogenetic footprinting • liver X receptor • transcription factor binding site

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