title: Paraoxonase 1 (PON1) enhances HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter in association with increased HDL binding to the cells: a possible role for lysophosphatidylcholine.
abstract: We investigated the role of HDL-associated paraoxonase 1 (PON1) in HDL-mediated macrophage cholesterol efflux by using HDL derived from wild type mice (Control-HDL), from human PON1-transgenic mice (HDL-PON1Tg) or from PON1-knockout mice (HDL-PON1(0)). Cholesterol efflux from mouse peritoneal macrophages (MPM) or from J774 A.1 macrophage cell line by HDL-PON1Tg, was significantly increased (by 60%) compared to HDL-PON1(0). We demonstrated that this PON1 effect was associated with an increased HDL binding to the cells, as the binding of HDL-PON1Tg (or HDL-PON1(0) that was enriched with PON1) was increased by 50% compared to that of HDL-PON1(0). Using either a cAMP analogue, to increase ABCA1 receptor expression, or rabbit anti-mouse SR-BI specific antibody to block the SR-BI receptor, PON1 stimulation of HDL binding and of HDL-mediated macrophage cholesterol efflux, were both found to involve the ABCA1 transporter. Studies with PON1 specific inhibitors revealed that PON1 activity was required for its stimulation of HDL-mediated macrophage cholesterol efflux. Upon incubation of macrophages with Control-HDL or with HDL-PON1Tg, macrophage lysophosphatidylcholine (LPC) content was increased by 3.7- and 7.5-fold, respectively. Such an LPC enrichment of macrophages resulted in up to 60% increased HDL binding to the cells, and a 41% increased HDL-mediated cholesterol efflux. Similarly, macrophage loading with LPC (by either adding LPC, or PON1 or phospholipase A(2)) significantly increased apolipoprotein A-I (apoA-I) mediated cholesterol efflux by 104, 65 and 56%, respectively, in ABCA1 overexpressing macrophages. We conclude that HDL-associated PON1 may contribute to the attenuation of atherosclerosis development by its ability to act on macrophage phospholipids, to form LPC, in turn, stimulates HDL binding and HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter.
authors.affiliation: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa 31096, Israel.
authors.forename: Mira
authors.initials: M
authors.lastname: Rosenblat
authors.forename: Jacob
authors.initials: J
authors.lastname: Vaya
authors.forename: Diana
authors.initials: D
authors.lastname: Shih
authors.forename: Michael
authors.initials: M
authors.lastname: Aviram
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D018955:CD36 Antigens; D008076:Cholesterol, HDL / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D051116:Receptors, Scavenger
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D008244:Lysophosphatidylcholines; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D000255:Adenosine Triphosphate; D043303:Aryldialkylphosphatase