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Mechanism of ATP-binding Cassette Transporter A1-mediated Cellular Lipid Efflux to Apolipoprotein A-I and Formation of High Density Lipoprotein Particles
Open accessAbstract
The ATP-binding cassette transporter A1 (ABCA1) plays a critical role in the biogenesis of high density lipoprotein (HDL) particles and in mediating cellular cholesterol efflux. The mechanism by which ABCA1 achieves these effects is not established, despite extensive investigation. Here, we present a model that explains the essential features, especially the effects of ABCA1 activity in inducing apolipoprotein (apo) A-I binding to cells and the compositions of the discoidal HDL particles that are produced. The apo A-I/ABCA1 reaction scheme involves three steps. First, there is binding of a small regulatory pool of apo A-I to ABCA1, thereby enhancing net phospholipid translocation to the plasma membrane exofacial leaflet; this leads to unequal lateral packing densities in the two leaflets of the phospholipid bilayer. Second, the resultant membrane strain is relieved by bending and by creation of exovesiculated lipid domains. The formation of highly curved membrane surface promotes high affinity binding of apo A-I to these domains. Third, this pool of bound apo A-I spontaneously solubilizes the exovesiculated domain to create discoidal nascent HDL particles. These particles contain two, three, or four molecules of apo A-I and a complement of membrane phospholipid classes together with some cholesterol. A key feature of this mechanism is that membrane bending induced by ABCA1 lipid translocase activity creates the conditions required for nascent HDL assembly by apo A-I. Overall, this mechanism is consistent with the known properties of ABCA1 and apo A-I and reconciles many of the apparently discrepant findings in the literature.
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Citations
Cites
Intestinal ABCA1 directly contributes to HDL biogenesis in vivo
Brunham, L. R. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27352 · Cited by 519
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Self-citationThe cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity
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Molday, R. S., Garces, F. A., Scortecci, J. F., & Molday, L. L. (2022) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.101036 · Cited by 107
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Koldamova, R., Fitz, N. F., & Lefterov, I. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.02.010 · Cited by 102
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“They transfer excess cellular cholesterol onto lipid-poor lipoprotein particles containing apolipoprotein A1 (APOA-I) and apolipoprotein E (APOE) [23].”
BackgroundTang, W., Ma, W., Ding, H., Lin, M., Xiang, L., Lin, G., & Zhang, Z. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m082297 · Cited by 11
Apolipoprotein A-I directly interacts with extracellular domain 1 of human ABCA1
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Metadata
- Authors
- Vedhachalam, C., Duong, P. T., Nickel, M., Nguyen, D., Dhanasekaran, P., Saito, H., Rothblat, G. H., Lund-Katz, S., & Phillips, M. C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 282
- Issue
- 34
- Pages
- 25123-25130
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2025155898
- Cited by
- 337
- References
- 3
- FWCI
- 25.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
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