Submitted on December 21, 2004
Revised on March 15, 2005
Accepted on March 15, 2005
Complete functional rescue of the ABCA1-/-mouse by human BAC transgenesis
Jonathan M. Coutinho, Roshni R. Singaraja, 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
Medical Genetics, Centre for Molec Med & Therap, University of British Columbia, Vancouver, BC V5Z 4H4
Corresponding Author: mrh{at}cmmt.ubc.ca
Humanized mouse models are useful tools to explore functional and regulatory differences between human and murine orthologous genes. We have combined a bioinformatics and an in vivo approach to assess functional and regulatory differences between the human and mouse ABCA1 gene. Computational analysis identified significant differences in potential regulatory sites between the human and mouse gene. The effect of these differences was assessed in vivo, using a BAC 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-/- mice. LXR 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 wildtype 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.
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