title: Complete functional rescue of the ABCA1-/- mouse by human BAC transgenesis.
abstract: 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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Coutinho
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.forename: Martin
authors.initials: M
authors.lastname: Kang
authors.forename: David J
authors.initials: DJ
authors.lastname: Arenillas
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Bertram
authors.forename: Nagat
authors.initials: N
authors.lastname: Bissada
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
authors.forename: Catherine
authors.initials: C
authors.lastname: Fievet
authors.forename: Ann M
authors.initials: AM
authors.lastname: Joseph-George
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D015139:Blotting, Southern; D002784:Cholesterol / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000819:agonists; D004305:Dose-Response Relationship, Drug; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D057093:Orphan Nuclear Receptors; D010802:Phylogeny; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D012984:Software; D013045:Species Specificity; D014018:Tissue Distribution; D019076:Transgenes
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012313:RNA; D002784:Cholesterol