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Pathways by which reconstituted high-density lipoprotein mobilizes free cholesterol from whole body and from macrophages.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2010 Mar; Vol. 30 (3), pp. 526-32. Date of Electronic Publication: 2009 Dec 17. - Publication Year :
- 2010
-
Abstract
- Objective: Reconstituted high-density lipoprotein (rHDL) is of interest as a potential novel therapy for atherosclerosis because of its ability to promote free cholesterol (FC) mobilization after intravenous administration. We performed studies to identify the underlying molecular mechanisms by which rHDL promote FC mobilization from whole body in vivo and macrophages in vitro.<br />Methods and Results: Wild-type (WT), SR-BI knockout (KO), ABCA1 KO, and ABCG1 KO mice received either rHDL or phosphate-buffered saline intravenously. Blood was drawn before and at several time points after injection for apolipoprotein A-I, phosphatidylcholine, and FC measurement. In WT mice, serum FC peaked at 20 minutes and rapidly returned toward baseline levels by 24 hours. Unexpectedly, ABCA1 KO and ABCG1 KO mice did not differ from WT mice regarding the kinetics of FC mobilization. In contrast, in SR-BI KO mice the increase in FC level at 20 minutes was only 10% of that in control mice (P<0.01). Bone marrow-derived macrophages from WT, SR-BI O, ABCA1 KO, and ABCG1 KO mice were incubated in vitro with rHDL and cholesterol efflux was determined. Efflux from SR-BI KO and ABCA1 KO macrophages was not different from WT macrophages. In contrast, efflux from ABCG1 KO macrophages was approximately 50% lower as compared with WT macrophages (P<0.001).<br />Conclusions: The bulk mobilization of FC observed in circulation after rHDL administration is primarily mediated by SR-BI. However, cholesterol mobilization from macrophages to rHDL is primarily mediated by ABCG1.
- Subjects :
- ATP Binding Cassette Transporter 1
ATP Binding Cassette Transporter, Subfamily G, Member 1
ATP-Binding Cassette Transporters genetics
Animals
Cells, Cultured
Injections, Intravenous
Lipoproteins genetics
Lipoproteins, HDL administration & dosage
Macrophages cytology
Mice
Mice, Knockout
Models, Animal
Scavenger Receptors, Class B genetics
Signal Transduction physiology
ATP-Binding Cassette Transporters metabolism
Cholesterol metabolism
Lipoproteins metabolism
Lipoproteins, HDL pharmacology
Macrophages metabolism
Scavenger Receptors, Class B metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 30
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 20018934
- Full Text :
- https://doi.org/10.1161/ATVBAHA.109.196105