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(Circulation Research. 2007;100:1200.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Decreased Obesity and Atherosclerosis in Human Paraoxonase 3 Transgenic Mice

Diana M. Shih, Yu-Rong Xia, Xu-Ping Wang, Susanna S. Wang, Noam Bourquard, Alan M. Fogelman, Aldons J. Lusis, Srinivasa T. Reddy

From the Departments of Medicine (D.M.S., Y.-R.X., X.-P.W., S.S.W., A.M.F., A.J.L., S.T.R.); Molecular and Medical Pharmacology (N.B., S.T.R.); Microbiology, Immunology and Molecular Genetics (A.J.L.); and Human Genetics (A.J.L.), University of California, Los Angeles.

Correspondence to Diana M. Shih, Division of Cardiology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, BH-307 CHS, Los Angeles, CA 90095-1679. E-mail dshih{at}mednet.ucla.edu

Paraoxonase 3 (PON3) is a member of the PON family, which includes PON1, PON2, and PON3. Recently, PON3 was shown to prevent the oxidation of low-density lipoprotein in vitro. To test the role of PON3 in atherosclerosis and related traits, 2 independent lines of human PON3 transgenic (Tg) mice on the C57BL/6J (B6) background were constructed. Human PON3 mRNA was detected in various tissues, including liver, lung, kidney, brain, adipose, and aorta, of both lines of Tg mice. The human PON3 mRNA levels in the livers of PON3 Tg mice were 4- to 7-fold higher as compared with the endogenous mouse Pon3 mRNA levels. Human PON3 protein and activity were detected in the livers of Tg mice as well. No significant differences in plasma total, high-density lipoprotein, and very-low-density lipoprotein/low-density lipoprotein cholesterol and triglyceride and glucose levels were observed between the PON3 Tg and non-Tg mice. Interestingly, atherosclerotic lesion areas were significantly smaller in both lines of male PON3 Tg mice as compared with the male non-Tg littermates on B6 background fed an atherogenic diet. When bred onto the low-density lipoprotein receptor knockout mouse background, the male PON3 Tg mice also exhibited decreased atherosclerotic lesion areas and decreased expression of monocyte chemoattractant protein-1 in the aorta as compared with the male non-Tg littermates. In addition, decreased adiposity and lower circulating leptin levels were observed in both lines of male PON3 Tg mice as compared with the male non-Tg mice. In an F2 cross, adipose Pon3 mRNA levels inversely correlated with adiposity and related traits. Our study demonstrates that elevated PON3 expression significantly decreases atherosclerotic lesion formation and adiposity in male mice. PON3 may play an important role in protection against obesity and atherosclerosis.

Key Words: atherosclerosis • obesity • genetics

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