Abstract
Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos1,2,3. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs)4,5,6,7,8. To study the role of PON1 in vivo, we created PON1 -knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1 -knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1 -null mice were more susceptible to atherosclerosis than their wild-type littermates.
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Acknowledgements
This work was supported by an NIH grant (to A.J.L., A.M.F. and M.N.), an NIEHS grant (to C.E.F.) and an American Heart Association Grant-in-Aid awarded by Greater Los Angeles Affiliate (to D.M.S.). We thank H. Cheroutre and K. Williams of UCLA Transgenic Core Facility for blastocyst injections; W. R. Clark and K. M. Lyons for advice in gene targeting work; S. Charugundla for lipid assays; G. P. Hough for MCP-1 assay; and X.-P. Wang and Y.-S. Shi for aortic lesion analysis.
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Shih, D., Gu, L., Xia, YR. et al. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 394, 284–287 (1998). https://doi.org/10.1038/28406
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DOI: https://doi.org/10.1038/28406
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