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
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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.
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Increased gene dosage of ABCA1 increases plasma HDL levels and protects from arteriosclerosis in animal models of hyperlipidemia.
“The reciprocal relationship also appears to be true in that increased gene dosage of ABCA1 increases plasma HDL levels and protects from arteriosclerosis in animal models of hyperlipidemia (48).”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [48]
The Results report significantly higher HDL-C in ABCA1 BAC transgenic mice than in control littermates, including when fed an atherogenic diet. The paper does not report an arteriosclerosis outcome or establish protection from arteriosclerosis in hyperlipidemic animal models; feeding an atherogenic diet does not by itself establish that protection. (LLM, conf=0.88)
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Research works printed but not linked: 18
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Self-citation
- Authors
- Singaraja, R. R., Bocher, V., James, E. R., Clee, S. M., Zhang, L.-H., Leavitt, B. R., Tan, B., Brooks-Wilson, A., Kwok, A., Bissada, N., Yang, Y.-Z., Liu, G., Tafuri, S. R., Fievet, C., Wellington, C. L., Staels, B., & Hayden, M. R.
- Affiliations
- University of British Columbia (CA)
- Université de Lille (FR)
- Pfizer (United States) (US)
- Corresponding author
- Hayden, Michael R.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-09
- Volume
- 276
- Issue
- 36
- Pages
- 33969-33979
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2157682988
- Cited by
- 194
- References
- 0
- Citations by year
- 2024: 1 · 2023: 2 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 1 · 2015: 3 · 2014: 6 · 2013: 3 · 2012: 7
- FWCI
- 24.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- ABCA1, HDL cholesterol, cholesterol efflux, apolipoprotein A-I, apolipoprotein A-II, intron 1, internal promoter, transcription start sites, BAC transgenic mice, gene expression regulation
- MeSH terms
- Liver X Receptors, Animals, Base Sequence, Cell Line, Cells, Cultured, Cholesterol, Cloning, Molecular, DNA-Binding Proteins, Humans, Immunohistochemistry, Introns, Lipids, Cholesterol, HDL, Liver, Macrophages, Mice, Transgenic, Models, Genetic, Molecular Sequence Data, Promoter Regions, Genetic, Receptors, Thyroid Hormone, RNA, Messenger, Transfection, Tumor Cells, Cultured, Transcriptional Activation, Apolipoprotein A-I, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, ATP-Binding Cassette Transporters, COS Cells, Reverse Transcriptase Polymerase Chain Reaction, Response Elements, Mice, Orphan Nuclear Receptors, ATP Binding Cassette Transporter 1
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