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Journal of Lipid Research, Vol. 50, 870-879, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1

Mira Rosenblat^*, Raymond Coleman, Srinivasa T. Reddy and Michael Aviram^1,*

^* Lipid Research Laboratory, Technion Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel
Department of Anatomy and Cell Biology, Technion Faculty of Medicine, Haifa, Israel
Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, University of California, Los Angeles, CA 90095-1679

Published, JLR Papers in Press, December 16, 2008.

¹ To whom correspondence should be addressed. e-mail: aviram{at}tx.technion.ac.il

This study questioned the role of paraoxonase 2 (PON2) in attenuation of macrophage lipids accumulation. Mouse peritoneal macrophages (MPMs) harvested from PON2-deficient mice versus control C57BL/6 mice, look like foam cells and were larger in size and filled with lipid droplets. Macrophage triglyceride (but not cholesterol) content, biosynthesis rate, and microsomal acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) activity (not mRNA and protein) in PON2-deficient versus control MPM were all significantly increased by 4.6-, 3.6-, and 4.4-fold, respectively. Similarly, microsomal DGAT1 activity and cellular triglyceride content were significantly decreased in human PON2-transfected cells as well as upon incubation of PON2-deficient MPM with recombinant PON2. In all the above experimental systems, PON2 also decreased macrophage oxidative state. Incubation of PON2-deficient MPM with the free radicals generator 2,2'-amidinopropane hydrochloride increased cellular oxidative stress and DGAT1 activity by 2.2- and 3.4-fold, respectively, whereas incubation of microsomes from PON2-deficient MPM with superoxide dismutase decreased DGAT1 activity by 40%. We thus conclude that PON2 attenuates macrophage triglyceride accumulation and foam cell formation via inhibition of microsomal DGAT1 activity, which appears to be sensitive to oxidative state.

Supplementary key words macrophages • triglycerides • oxidative stress

Abbreviations: AAPH, 2,2'-amidinopropane hydrochloride; DGAT1, acyl-CoA:diacylglycerol acyltransferase 1; hPON2, human paraoxonase 2; MPM, mouse peritoneal macrophage; oxLDL, oxidized low density lipoprotein; PON, paraoxonase; SOD, superoxide dismutase

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