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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Apr 15, 1998; 101(8): 1581–1590.
PMCID: PMC508738

Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase.

Abstract

HDL levels are inversely related to the risk of developing atherosclerosis. In serum, paraoxonase (PON) is associated with HDL, and was shown to inhibit LDL oxidation. Whether PON also protects HDL from oxidation is unknown, and was determined in the present study. In humans, we found serum HDL PON activity and HDL susceptibility to oxidation to be inversely correlated (r2 = 0.77, n = 15). Supplementing human HDL with purified PON inhibited copper-induced HDL oxidation in a concentration-dependent manner. Adding PON to HDL prolonged the oxidation lag phase and reduced HDL peroxide and aldehyde formation by up to 95%. This inhibitory effect was most pronounced when PON was added before oxidation initiation. When purified PON was added to whole serum, essentially all of it became HDL-associated. The PON-enriched HDL was more resistant to copper ion-induced oxidation than was control HDL. Compared with control HDL, HDL from PON-treated serum showed a 66% prolongation in the lag phase of its oxidation, and up to a 40% reduction in peroxide and aldehyde content. In contrast, in the presence of various PON inhibitors, HDL oxidation induced by either copper ions or by a free radical generating system was markedly enhanced. As PON inhibited HDL oxidation, two major functions of HDL were assessed: macrophage cholesterol efflux, and LDL protection from oxidation. Compared with oxidized untreated HDL, oxidized PON-treated HDL caused a 45% increase in cellular cholesterol efflux from J-774 A.1 macrophages. Both HDL-associated PON and purified PON were potent inhibitors of LDL oxidation. Searching for a possible mechanism for PON-induced inhibition of HDL oxidation revealed PON (2 paraoxonase U/ml)-mediated hydrolysis of lipid peroxides (by 19%) and of cholesteryl linoleate hydroperoxides (by 90%) in oxidized HDL. HDL-associated PON, as well as purified PON, were also able to substantially hydrolyze (up to 25%) hydrogen peroxide (H2O2), a major reactive oxygen species produced under oxidative stress during atherogenesis. Finally, we analyzed serum PON activity in the atherosclerotic apolipoprotein E-deficient mice during aging and development of atherosclerotic lesions. With age, serum lipid peroxidation and lesion size increased, whereas serum PON activity decreased. We thus conclude that HDL-associated PON possesses peroxidase-like activity that can contribute to the protective effect of PON against lipoprotein oxidation. The presence of PON in HDL may thus be a major contributor to the antiatherogenicity of this lipoprotein.

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Selected References

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  • La Du BN, Adkins S, Kuo CL, Lipsig D. Studies on human serum paraoxonase/arylesterase. Chem Biol Interact. 1993 Jun;87(1-3):25–34. [PubMed]
  • La Du BN. Structural and functional diversity of paraoxonases. Nat Med. 1996 Nov;2(11):1186–1187. [PubMed]
  • Mackness MI, Mackness B, Durrington PN, Connelly PW, Hegele RA. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol. 1996 Apr;7(2):69–76. [PubMed]
  • Nevin DN, Zambon A, Furlong CE, Richter RJ, Humbert R, Hokanson JE, Brunzell JD. Paraoxonase genotypes, lipoprotein lipase activity, and HDL. Arterioscler Thromb Vasc Biol. 1996 Oct;16(10):1243–1249. [PubMed]
  • McElveen J, Mackness MI, Colley CM, Peard T, Warner S, Walker CH. Distribution of paraoxon hydrolytic activity in the serum of patients after myocardial infarction. Clin Chem. 1986 Apr;32(4):671–673. [PubMed]
  • Mackness MI, Harty D, Bhatnagar D, Winocour PH, Arrol S, Ishola M, Durrington PN. Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. Atherosclerosis. 1991 Feb;86(2-3):193–199. [PubMed]
  • Abbott CA, Mackness MI, Kumar S, Boulton AJ, Durrington PN. Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. Arterioscler Thromb Vasc Biol. 1995 Nov;15(11):1812–1818. [PubMed]
  • Banka CL. High density lipoprotein and lipoprotein oxidation. Curr Opin Lipidol. 1996 Jun;7(3):139–142. [PubMed]
  • Mackness MI, Durrington PN. HDL, its enzymes and its potential to influence lipid peroxidation. Atherosclerosis. 1995 Jun;115(2):243–253. [PubMed]
  • Mackness MI, Arrol S, Abbott C, Durrington PN. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis. 1993 Dec;104(1-2):129–135. [PubMed]
  • Mackness MI, Abbott C, Arrol S, Durrington PN. The role of high-density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J. 1993 Sep 15;294(Pt 3):829–834. [PMC free article] [PubMed]
  • Mackness MI, Arrol S, Durrington PN. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett. 1991 Jul 29;286(1-2):152–154. [PubMed]
  • Hayek T, Oiknine J, Dankner G, Brook JG, Aviram M. HDL apolipoprotein A-I attenuates oxidative modification of low density lipoprotein: studies in transgenic mice. Eur J Clin Chem Clin Biochem. 1995 Oct;33(10):721–725. [PubMed]
  • Navab M, Berliner JA, Watson AD, Hama SY, Territo MC, Lusis AJ, Shih DM, Van Lenten BJ, Frank JS, Demer LL, et al. The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol. 1996 Jul;16(7):831–842. [PubMed]
  • Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, Fogelman AM, Navab M. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 1995 Dec;96(6):2882–2891. [PMC free article] [PubMed]
  • Watson AD, Navab M, Hama SY, Sevanian A, Prescott SM, Stafforini DM, McIntyre TM, Du BN, Fogelman AM, Berliner JA. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest. 1995 Feb;95(2):774–782. [PMC free article] [PubMed]
  • Bowry VW, Stanley KK, Stocker R. High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10316–10320. [PMC free article] [PubMed]
  • Hahn M, Subbiah MT. Significant association of lipid peroxidation products with high density lipoproteins. Biochem Mol Biol Int. 1994 Jul;33(4):699–704. [PubMed]
  • Christison JK, Rye KA, Stocker R. Exchange of oxidized cholesteryl linoleate between LDL and HDL mediated by cholesteryl ester transfer protein. J Lipid Res. 1995 Sep;36(9):2017–2026. [PubMed]
  • Nagano Y, Arai H, Kita T. High density lipoprotein loses its effect to stimulate efflux of cholesterol from foam cells after oxidative modification. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6457–6461. [PMC free article] [PubMed]
  • Morel DW. Reduced cholesterol efflux to mildly oxidized high density lipoprotein. Biochem Biophys Res Commun. 1994 Apr 15;200(1):408–416. [PubMed]
  • Aviram M. Plasma lipoprotein separation by discontinuous density gradient ultracentrifugation in hyperlipoproteinemic patients. Biochem Med. 1983 Aug;30(1):111–118. [PubMed]
  • Esterbauer H, Striegl G, Puhl H, Rotheneder M. Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radic Res Commun. 1989;6(1):67–75. [PubMed]
  • Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302–310. [PubMed]
  • el-Saadani M, Esterbauer H, el-Sayed M, Goher M, Nassar AY, Jürgens G. A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent. J Lipid Res. 1989 Apr;30(4):627–630. [PubMed]
  • Vaya J, Belinky PA, Aviram M. Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic Biol Med. 1997;23(2):302–313. [PubMed]
  • Aviram M, Bierman EL, Oram JF. High density lipoprotein stimulates sterol translocation between intracellular and plasma membrane pools in human monocyte-derived macrophages. J Lipid Res. 1989 Jan;30(1):65–76. [PubMed]
  • Kuo CL, La Du BN. Comparison of purified human and rabbit serum paraoxonases. Drug Metab Dispos. 1995 Sep;23(9):935–944. [PubMed]
  • Gan KN, Smolen A, Eckerson HW, La Du BN. Purification of human serum paraoxonase/arylesterase. Evidence for one esterase catalyzing both activities. Drug Metab Dispos. 1991 Jan-Feb;19(1):100–106. [PubMed]
  • Eckerson HW, Romson J, Wyte C, La Du BN. The human serum paraoxonase polymorphism: identification of phenotypes by their response to salts. Am J Hum Genet. 1983 Mar;35(2):214–227. [PMC free article] [PubMed]
  • Kitchen BJ, Masters CJ, Winzor DJ. Effects of lipid removal on the molecular size and kinetic properties of bovine plasma arylesterase. Biochem J. 1973 Sep;135(1):93–99. [PMC free article] [PubMed]
  • Chen CH, Albers JJ. Characterization of proteoliposomes containing apoprotein A-I: a new substrate for the measurement of lecithin: cholesterol acyltransferase activity. J Lipid Res. 1982 Jul;23(5):680–691. [PubMed]
  • Aviram M, Maor I, Keidar S, Hayek T, Oiknine J, Bar-El Y, Adler Z, Kertzman V, Milo S. Lesioned low density lipoprotein in atherosclerotic apolipoprotein E-deficient transgenic mice and in humans is oxidized and aggregated. Biochem Biophys Res Commun. 1995 Nov 13;216(2):501–513. [PubMed]
  • Hayek T, Oiknine J, Brook JG, Aviram M. Increased plasma and lipoprotein lipid peroxidation in apo E-deficient mice. Biochem Biophys Res Commun. 1994 Jun 30;201(3):1567–1574. [PubMed]
  • Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P, Coleman R, Elis A, Aviram M. Reduced progression of atherosclerosis in apolipoprotein E-deficient mice following consumption of red wine, or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation. Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2744–2752. [PubMed]
  • Aviram M. Modified forms of low density lipoprotein and atherosclerosis. Atherosclerosis. 1993 Jan 4;98(1):1–9. [PubMed]
  • Garin MC, James RW, Dussoix P, Blanché H, Passa P, Froguel P, Ruiz J. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. J Clin Invest. 1997 Jan 1;99(1):62–66. [PMC free article] [PubMed]
  • Mackness MI, Arrol S, Mackness B, Durrington PN. Alloenzymes of paraoxonase and effectiveness of high-density lipoproteins in protecting low-density lipoprotein against lipid peroxidation. Lancet. 1997 Mar 22;349(9055):851–852. [PubMed]
  • Zhang SH, Reddick RL, Burkey B, Maeda N. Diet-induced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption. J Clin Invest. 1994 Sep;94(3):937–945. [PMC free article] [PubMed]
  • Reddick RL, Zhang SH, Maeda N. Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. Arterioscler Thromb. 1994 Jan;14(1):141–147. [PubMed]
  • Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb. 1994 Apr;14(4):605–616. [PubMed]
  • Palinski W, Hörkkö S, Miller E, Steinbrecher UP, Powell HC, Curtiss LK, Witztum JL. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest. 1996 Aug 1;98(3):800–814. [PMC free article] [PubMed]
  • Shih DM, Gu L, Hama S, Xia YR, Navab M, Fogelman AM, Lusis AJ. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest. 1996 Apr 1;97(7):1630–1639. [PMC free article] [PubMed]
  • Navab M, Hama-Levy S, Van Lenten BJ, Fonarow GC, Cardinez CJ, Castellani LW, Brennan ML, Lusis AJ, Fogelman AM, La Du BN. Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest. 1997 Apr 15;99(8):2005–2019. [PMC free article] [PubMed]
  • Lynch SM, Frei B. Mechanisms of copper- and iron-dependent oxidative modification of human low density lipoprotein. J Lipid Res. 1993 Oct;34(10):1745–1753. [PubMed]
  • Aviram M. Interaction of oxidized low density lipoprotein with macrophages in atherosclerosis, and the antiatherogenicity of antioxidants. Eur J Clin Chem Clin Biochem. 1996 Aug;34(8):599–608. [PubMed]
  • Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. [PubMed]
  • Jialal I, Grundy SM. Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein. J Lipid Res. 1992 Jun;33(6):899–906. [PubMed]
  • Parthasarathy S, Young SG, Witztum JL, Pittman RC, Steinberg D. Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest. 1986 Feb;77(2):641–644. [PMC free article] [PubMed]
  • de Whalley CV, Rankin SM, Hoult JR, Jessup W, Leake DS. Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages. Biochem Pharmacol. 1990 Jun 1;39(11):1743–1750. [PubMed]
  • Levy Y, Kaplan M, Ben-Amotz A, Aviram M. Effect of dietary supplementation of beta-carotene on human monocyte-macrophage-mediated oxidation of low density lipoprotein. Isr J Med Sci. 1996 Jun;32(6):473–478. [PubMed]
  • Fuhrman B, Lavy A, Aviram M. Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation. Am J Clin Nutr. 1995 Mar;61(3):549–554. [PubMed]
  • Fuhrman B, Buch S, Vaya J, Belinky PA, Coleman R, Hayek T, Aviram M. Licorice extract and its major polyphenol glabridin protect low-density lipoprotein against lipid peroxidation: in vitro and ex vivo studies in humans and in atherosclerotic apolipoprotein E-deficient mice. Am J Clin Nutr. 1997 Aug;66(2):267–275. [PubMed]
  • Mitchinson MJ, Ball RY, Carpenter KL, Enright JH. Macrophages and ceroid in human atherosclerosis. Eur Heart J. 1990 Aug;11 (Suppl E):116–121. [PubMed]
  • Gordon DJ, Knoke J, Probstfield JL, Superko R, Tyroler HA. High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial. Circulation. 1986 Dec;74(6):1217–1225. [PubMed]
  • Miller NE. Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis. Am Heart J. 1987 Feb;113(2 Pt 2):589–597. [PubMed]
  • Oram JF, Yokoyama S. Apolipoprotein-mediated removal of cellular cholesterol and phospholipids. J Lipid Res. 1996 Dec;37(12):2473–2491. [PubMed]
  • Reichl D, Miller NE. Pathophysiology of reverse cholesterol transport. Insights from inherited disorders of lipoprotein metabolism. Arteriosclerosis. 1989 Nov-Dec;9(6):785–797. [PubMed]
  • Sorenson RC, Primo-Parmo SL, Kuo CL, Adkins S, Lockridge O, La Du BN. Reconsideration of the catalytic center and mechanism of mammalian paraoxonase/arylesterase. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7187–7191. [PMC free article] [PubMed]
  • Hazen SL, Hsu FF, Duffin K, Heinecke JW. Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes converts low density lipoprotein cholesterol into a family of chlorinated sterols. J Biol Chem. 1996 Sep 20;271(38):23080–23088. [PubMed]
  • Wilkins GM, Leake DS. The effects of free radical scavengers on the oxidation of low-density lipoproteins by macrophages. Biochim Biophys Acta. 1994 Dec 8;1215(3):250–258. [PubMed]

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