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J. Biol. Chem., Vol. 281, Issue 11, 7657-7665, March 17, 2006

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The Catalytic Histidine Dyad of High Density Lipoprotein-associated Serum Paraoxonase-1 (PON1) Is Essential for PON1-mediated Inhibition of Low Density Lipoprotein Oxidation and Stimulation of Macrophage Cholesterol Efflux^*

Mira Rosenblat, Leonid Gaidukov, Olga Khersonsky, Jacob Vaya^¶, Roni Oren, Dan S. Tawfik, and Michael Aviram¹

From the Lipid Research Laboratory, Technion Faculty of Medicine, and the Rambam Medical Center, Rappaport Family Institute for Research in the Medical Sciences, Haifa 31096, Israel, the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel, and the ^¶Laboratory of Natural Medicinal Compounds, Migal-Galilee Technological Center, Kiryat-Shmona 11016, Israel

High density lipoprotein (HDL)-associated paraoxonase-1 (PON1) anti-atherogenic properties in macrophages, i.e. inhibition of cell-mediated oxidation of low density lipoprotein (LDL) and stimulation of cholesterol efflux, were studied using recombinant variants of PON1 and apoA-I expressed in Escherichia coli and reconstituted HDL (rHDL) particles composed of phosphatidylcholine/free cholesterol (PC/FC) and apoA-I. PON1 lactonase activity is stimulated by apoA-I by 7-fold relative to PC/FC particles. Wild-type (WT) PON1 bound to rHDL inhibited macrophage-mediated LDL oxidation and stimulated cholesterol efflux from the cells to 2.3- and 3.2-fold greater extents, respectively, compared with WT PON1 bound to PC/FC particles without apoA-I. We also tested PON1 catalytic histidine dyad mutants (H115Q and H134Q) that are properly folded and that bind HDL in a similar mode compared with WT PON1, but that 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 of the cells' 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 lipolactonase activity and propose a model in which PON1 acts as a lipolactonase to break down oxidized lipids and to generate LPC.

Received for publication, November 28, 2005 , and in revised form, January 10, 2006.

^* This work was supported by a grant from the Charles & M. R. Shapiro Foundation Endowed Biomedical Research Fund (to D. S. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Lipid Research Lab., Rambam Medical Center, Haifa 31096, Israel. Tel.: 972-4-854-2970; Fax: 972-4-854-2130; E-mail: aviram{at}tx.technion.ac.il.

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