Alternate transcripts expressed in response to diet reflect tissue-specific regulation of ABCA1.
ABCA1 is essential for the transport of lipids across plasma membranes and for the maintenance of plasma HDL-cholesterol levels. The transcriptional regulation of ABCA1 is complex and is currently poorly understood. We previously generated human ABCA1 bacterial artificial chromosome transgenic mice that expressed RNA and protein, which allowed us to identify three alternate ABCA1 transcripts. Each transcript arises from different exon 1 sequences (exon1b, exon1c, and exon1d) that are spliced directly into exon 2, which contains the ATG site, and all generate full-length protein. We have now determined the tissue-specific expression of each of these transcripts in humans and mice and have shown that their patterns of expression are similar. Exon1d transcript is predominantly expressed in liver and macrophages and is preferentially increased in the liver in response to a high-fat diet. The exon1b transcript is expressed predominantly in liver, testis, and macrophages, but it is only upregulated in macrophages in response to a high-fat diet. The exon1c transcript is ubiquitously expressed and is upregulated in the brain, stomach, and other tissues in mice on a high-fat diet. Our data indicate that specific transcripts in different tissues play key roles in alterations of ABCA1-mediated changes in HDL levels and atherosclerosis in response to environmental stimuli.
Singaraja
Roshni R
RR
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
James
Erick R
ER
Crim
Jennifer
J
Visscher
Henk
H
Chatterjee
Alu
A
Hayden
Michael R
MR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D022202:Chromosomes, Artificial, Bacterial; D004036:Diet, Atherogenic; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D013154:Spleen / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D014018:Tissue Distribution; D014158:Transcription, Genetic
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters