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Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis
Abstract
Objective— The ATP-binding cassette transporter, subfamily A, member 1 ( ABCA1 ) plays a key role in HDL cholesterol metabolism. However, the role of ABCA1 in modulating susceptibility to atherosclerosis is controversial. Methods and Results— We investigated the role of ABCA1 in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human ABCA1 -containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse Abca1 gene. ABCA1 overexpression in the atherosclerosis-susceptible Ldlr −/− background significantly reduced the development of atherosclerosis in both the presence and absence of mouse Abca1 . Next, we used mice with tissue-specific inactivation of Abca1 to dissect the discrete roles of Abca1 in different tissues on susceptibility to atherosclerosis. On the Apoe −/− background, mice lacking hepatic Abca1 had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of Abca1 on the Ldlr −/− background displayed no change in atherosclerotic lesion area. Conclusions— These data indicate that physiological expression of Abca1 modulates the susceptibility to atherosclerosis and establish hepatic Abca1 expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage Abca1 does not significantly modulate atherogenesis.
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“Cholesterol efflux from cells to apolipoprotein A-I (apoA-I) acceptors via the ATP-binding cassette transporters ABCA1 and ABCG1 is thought to be central in the antiatherogenic mechanism.”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE −/− Mice (2012) · cites this paper as [14]
In the citing paper
“Tissue-specific knockouts of the Abca1 locus were generated and revealed that liver and macrophage ABCA1 both play roles in preventing atherosclerosis.14”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE −/− Mice (2012) · cites this paper as [14]
In the citing paper
“This process seems to be essential for the formation of HDL particles because liver-and intestine-specific knockout mice for ABCA1 show strong reductions in HDL levels (45)(46)(47).”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [45]
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Greco, D. (2013) · DSpaceUnipr (University of Parma)
tissue-specific role of ATP binding cassette transporter A1 in atherogenesis
Bi, X. (2013) · WakeSpace (Wake Forest University)
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Metadata
- Authors
- Brunham, L. R., Singaraja, R. R., Duong, M., Timmins, J. M., Fievet, C., Bissada, N., Kang, M. H., Samra, A., Fruchart, J.-C., McManus, B., Staels, B., Parks, J. S., & Hayden, M. R.
- Affiliations
- Providence Health Care (CA)
- From the Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute (L.R.B., R.R.S., N.B., M.H.K., M.R.H.), University of British Columbia, Vancouver, Canada; the Department of Pathology/Section on Lipid Sciences (M.D., J.M.T., J.S.P.), Wake Forest University Health Sciences, Winston-Salem, NC; Institut Pasteur de Lille, Inserm U545 (C.F., J.C.F., B.S.), Université de Lille, France; and the iCAPTURE Centre (A.S., B.M.), St Paul’s Hospital/Providence Health Care, University of British Columbia, Vancouver, Canada.
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2009-04
- Volume
- 29
- Issue
- 4
- Pages
- 548-554
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2160940635
- Cited by
- 102
- References
- 37
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 7 · 2014: 11 · 2013: 10 · 2012: 9
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 49373, P01HL049373)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- ABCA1, atherosclerosis susceptibility, HDL cholesterol metabolism, tissue-specific gene deletion, Ldlr-deficient mice, ApoE-deficient mice, atheroprotection
- MeSH terms
- Animals, Apolipoproteins E, Dietary Fats, Disease Models, Animal, Humans, Cholesterol, HDL, Cholesterol, LDL, Liver, Mice, Transgenic, Phenotype, Receptors, LDL, Cholesterol, VLDL, Macrophages, Peritoneal, Mice, Knockout, ATP-Binding Cassette Transporters, Genetic Predisposition to Disease, Chromosomes, Artificial, Bacterial, Atherosclerosis, Mice, ATP Binding Cassette Transporter 1
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