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

Atherosclerosis. 2005 Mar;179(1):69-77. doi: 10.1016/j.atherosclerosis.2004.10.028. Epub 2004 Dec 29.


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.

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Aryldialkylphosphatase / genetics*
  • Aryldialkylphosphatase / metabolism*
  • Biological Transport / physiology
  • CD36 Antigens
  • Cholesterol, HDL / metabolism*
  • Lysophosphatidylcholines / metabolism*
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Protein Binding / physiology
  • Receptors, Immunologic / metabolism
  • Receptors, Scavenger


  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • CD36 Antigens
  • Cholesterol, HDL
  • Lysophosphatidylcholines
  • Receptors, Immunologic
  • Receptors, Scavenger
  • Adenosine Triphosphate
  • Aryldialkylphosphatase