title: HDL particle size is a critical determinant of ABCA1-mediated macrophage cellular cholesterol export.
abstract: BACKGROUND
  High-density lipoprotein (HDL) is a heterogeneous population of particles. Differences in the capacities of HDL subfractions to remove cellular cholesterol may explain variable correlations between HDL-cholesterol and cardiovascular risk and inform future targets for HDL-related therapies. The ATP binding cassette transporter A1 (ABCA1) facilitates cholesterol efflux to lipid-free apolipoprotein A-I, but the majority of apolipoprotein A-I in the circulation is transported in a lipidated state and ABCA1-dependent efflux to individual HDL subfractions has not been systematically studied.
  
  
  OBJECTIVE
  Our aims were to determine which HDL particle subfractions are most efficient in mediating cellular cholesterol efflux from foam cell macrophages and to identify the cellular cholesterol transporters involved in this process.
  
  
  RESULTS
  We used reconstituted HDL particles of defined size and composition, isolated subfractions of human plasma HDL, cell lines stably expressing ABCA1 or ABCG1, and both mouse and human macrophages in which ABCA1 or ABCG1 expression was deleted. We show that ABCA1 is the major mediator of macrophage cholesterol efflux to HDL, demonstrating most marked efficiency with small, dense HDL subfractions (HDL3b and HDL3c). ABCG1 has a lesser role in cholesterol efflux and a negligible role in efflux to HDL3b and HDL3c subfractions.
  
  
  CONCLUSIONS
  Small, dense HDL subfractions are the most efficient mediators of cholesterol efflux, and ABCA1 mediates cholesterol efflux to small dense HDL and to lipid-free apolipoprotein A-I. HDL-directed therapies should target increasing the concentrations or the cholesterol efflux capacity of small, dense HDL species in vivo.
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Du
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Mi-Jurng
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Liming
authors.initials: L
authors.lastname: Hou
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Linda K
authors.initials: LK
authors.lastname: Curtiss
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: John R
authors.initials: JR
authors.lastname: Burnett
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Sian P
authors.initials: SP
authors.lastname: Cartland
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Quinn
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Maaike
authors.initials: M
authors.lastname: Kockx
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Anatol
authors.initials: A
authors.lastname: Kontush
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.).
authors.forename: Leonard
authors.initials: L
authors.lastname: Kritharides
authors.affiliation: From the Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia (X.-M.D., M.-J.K., L.H., S.P.C., C.M.Q., K.-A.R); INSERM, UMR_1166, Research Institute of Cardiovascular Disease, Metabolism and Nutrition, Pitié-Salpétrière University Hospital, Paris, France (W.L.G., M.J.C., A.K.); Université Pierre et Marie Curie-Paris 6, Paris, France (W.L.G., M.J.C., A.K.); Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (M.V.E.); Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA (L.K.C.); Department of Clinical Biochemistry, Royal Perth Hospital, Perth, Western Australia, Australia (J.R.B.); School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia (J.R.B.); Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia (M.K., L.K., W.J.); and Department of Cardiology, Concord Hospital, Sydney, New South Wales, Australia (L.K.). wendy.jessup@sydney.edu.au.
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000502:physiology; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D005487:Foam Cells / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008074:Lipoproteins / Q000172:deficiency / Q000502:physiology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D053439:Lipoproteins, HDL2 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010316:Particle Size; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013631:Tangier Disease / Q000201:enzymology / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D002784:Cholesterol; D008076:Cholesterol, HDL; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D053439:Lipoproteins, HDL2; D011993:Recombinant Fusion Proteins; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse
keywords: ATP binding cassette transporter 1; ATP-binding cassette transporters; cholesterol, HDL; cholesterol-efflux regulatory protein; foam cells; macrophages