Human ABCA1 BAC transgenic mice show increased high density lipoprotein cholesterol and ApoAI-dependent efflux stimulated by an internal promoter containing liver X receptor response elements in intron 1.
By using BAC transgenic mice, we have shown that increased human ABCA1 protein expression results in a significant increase in cholesterol efflux in different tissues and marked elevation in high density lipoprotein (HDL)-cholesterol levels associated with increases in apoAI and apoAII. Three novel ABCA1 transcripts containing three different transcription initiation sites that utilize sequences in intron 1 have been identified. In BAC transgenic mice there is an increased expression of ABCA1 protein, but the distribution of the ABCA1 product in different cells remains similar to wild type mice. An internal promoter in human intron 1 containing liver X response elements is functional in vivo and directly contributes to regulation of the human ABCA1 gene in multiple tissues and to raised HDL cholesterol, apoAI, and apoAII levels. A highly significant relationship between raised protein levels, increased efflux, and level of HDL elevation is evident. These data provide proof of the principle that increased human ABCA1 efflux activity is associated with an increase in HDL levels in vivo.
Singaraja
R R
RR
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics and Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Bocher
V
V
James
E R
ER
Clee
S M
SM
Zhang
L H
LH
Leavitt
B R
BR
Tan
B
B
Brooks-Wilson
A
A
Kwok
A
A
Bissada
N
N
Yang
Y Z
YZ
Liu
G
G
Tafuri
S R
SR
Fievet
C
C
Wellington
C L
CL
Staels
B
B
Hayden
M R
MR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism*; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D002784:Cholesterol