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Papers In Press, published online ahead of print January 10, 2006
Lipid Research Laboratory, Rambam Medical Center, Haifa 31096
Corresponding Author: aviram{at}tx.technion.ac.il
HDL-associated paraoxonase1 (PON1) anti-atherogenic properties in macrophages, i.e. inhibition of cell-mediated oxidation of LDL, and stimulation of cholesterol efflux were studied using, recombinant variants of PON1 and apolipoprotein A-I (apoA-I) expressed in E.coli, and reconstituted HDL (rHDL) particles composed of phosphatidylcholine / free cholesterol (PC/FC) and apoA-I. We have previously shown that, PON1’s lactonase activity is stimulated by apoA-I by ~7 fold relative to PC/FC particles. We now show that, wild type PON1, wt PON1 bound to rHDL, inhibits macrophage-mediated LDL oxidation and stimulates cholesterol efflux from the cells to a 2.3 and 3.2 fold greater extent than wt PON1 bound to PC/FC particles without apoA-I. We also tested PON1 mutants in the catalytic histidine dyad (His115Gln and His134Gln) that are properly folded, bind HDL in a mode similar to that of wt PON1, but exhibit almost no lactonase activity. These could not inhibit macrophage-mediated LDL oxidation, or stimulate rHDL-mediated cholesterol efflux from the cells. Furthermore, whereas HDL-bound wt PON1 induced the formation of lysophosphatidylcholine (LPC) in macrophages, the His dyad mutants did not, suggesting that the above anti-atherogenic properties of HDL-associated PON1 involve LPC release. Indeed, enrichment of macrophages with increasing concentrations of LPC resulted in inhibition in the cell's capability to oxidize LDL, and in stimulation of HDL-mediated cholesterol efflux from the macrophages, in an LPC dose–dependent manner. Thus, we provide the first direct indication that the anti-atherogenic properties of PON1 are related to its lipo-lactonase activity, and propose a model under which PON1 acts as a lipo-lactonase to break down oxidized lipids and generate LPC.
J. Biol. Chem, 10.1074/jbc.M512595200
Submitted on November 28, 2005
Revised on January 10, 2006
Accepted on January 10, 2006
The catalytic histidine dyad Of HDL-associated serum paraoxonase 1 (PON1) is essential for PON1 - mediated inhibition of LDL oxidation and stimulation of macrophage cholesterol efflux
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