Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2003 Oct 15;375(Pt 2):275–285. doi: 10.1042/BJ20030663

Beneficial effect of oleoylated lipids on paraoxonase 1: protection against oxidative inactivation and stabilization.

Su Duy Nguyen 1, Dai-Eun Sok 1
PMCID: PMC1223694  PMID: 12871208

Abstract

The effect of lipids on PON1 (paraoxonase 1), one of antioxidant proteins in high-density lipoprotein, was investigated in respect to inhibition, protection against oxidative inactivation, and stabilization. When the effect of lipids on the PON1 activity was examined, a remarkable inhibition was expressed by polyenoic fatty acids (C18:2-C20:5). Linoleic acid, the most potent ( K(i), 3.8 microM), showed competitive inhibition. Next, various lipids were examined for prevention against the inactivation of PON1 by ascorbate/Cu2+, which caused a remarkable (>or =90%) inactivation of PON1. Compared with saturated fatty acids (C6-C18), exhibiting a modest protection (9-40%), monoenoic acids (C16:1-C20:1) showed a greater maximal protective effect (Emax, 70-82%), with oleic acid being the most effective (EC50, 2.7 microM). In contrast, polyenoic acids showed no protection. Noteworthy, linoleic acid prohibited the protective action of oleic acid non-competitively. In the structure-activity relationship, a negatively charged group seems to be required for the protective action. Consistent with this, dioleoylphosphatidylglycerol, negatively charged, was more protective than dioleoylphosphatidylcholine. These data, together with requirement of Ca2+ (EC50, 0.6 microM) for the protective action, may support the existence of a specific site responsible for the protective action. A similar protective action of lipids was also observed in the inactivation of PON1 by ascorbate/Fe2+, peroxides or p -hydroxymercuribenzoate. Separately, PON1 was stabilized by oleic acid or oleoylated phospholipids, in combination with Ca2+, but not linoleic acid. These results suggest that in contrast to an adverse action of linoleic acid, monoenoic acids or their phospholipid derivatives play a beneficial role in protecting PON1 from oxidative inactivation as well as in stabilizing PON1.

Full Text

The Full Text of this article is available as a PDF (195.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmed Z., Ravandi A., Maguire G. F., Emili A., Draganov D., La Du B. N., Kuksis A., Connelly P. W. Apolipoprotein A-I promotes the formation of phosphatidylcholine core aldehydes that are hydrolyzed by paraoxonase (PON-1) during high density lipoprotein oxidation with a peroxynitrite donor. J Biol Chem. 2001 Apr 24;276(27):24473–24481. doi: 10.1074/jbc.M010459200. [DOI] [PubMed] [Google Scholar]
  2. Ahmed Z., Ravandi A., Maguire G. F., Emili A., Draganov D., La Du B. N., Kuksis A., Connelly P. W. Apolipoprotein A-I promotes the formation of phosphatidylcholine core aldehydes that are hydrolyzed by paraoxonase (PON-1) during high density lipoprotein oxidation with a peroxynitrite donor. J Biol Chem. 2001 Apr 24;276(27):24473–24481. doi: 10.1074/jbc.M010459200. [DOI] [PubMed] [Google Scholar]
  3. Ahmed Zakaria, Ravandi Amir, Maguire Graham F., Emili Andrew, Draganov Dragomir, La Du Bert N., Kuksis Arnis, Connelly Philip W. Multiple substrates for paraoxonase-1 during oxidation of phosphatidylcholine by peroxynitrite. Biochem Biophys Res Commun. 2002 Jan 11;290(1):391–396. doi: 10.1006/bbrc.2001.6150. [DOI] [PubMed] [Google Scholar]
  4. Aviram M., Billecke S., Sorenson R., Bisgaier C., Newton R., Rosenblat M., Erogul J., Hsu C., Dunlop C., La Du B. Paraoxonase active site required for protection against LDL oxidation involves its free sulfhydryl group and is different from that required for its arylesterase/paraoxonase activities: selective action of human paraoxonase allozymes Q and R. Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1617–1624. doi: 10.1161/01.atv.18.10.1617. [DOI] [PubMed] [Google Scholar]
  5. Aviram M., Hardak E., Vaya J., Mahmood S., Milo S., Hoffman A., Billicke S., Draganov D., Rosenblat M. Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities. Circulation. 2000 May 30;101(21):2510–2517. doi: 10.1161/01.cir.101.21.2510. [DOI] [PubMed] [Google Scholar]
  6. Aviram M., Rosenblat M., Billecke S., Erogul J., Sorenson R., Bisgaier C. L., Newton R. S., La Du B. Human serum paraoxonase (PON 1) is inactivated by oxidized low density lipoprotein and preserved by antioxidants. Free Radic Biol Med. 1999 Apr;26(7-8):892–904. doi: 10.1016/s0891-5849(98)00272-x. [DOI] [PubMed] [Google Scholar]
  7. Aviram M., Rosenblat M., Bisgaier C. L., Newton R. S., Primo-Parmo S. L., La Du B. N. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest. 1998 Apr 15;101(8):1581–1590. doi: 10.1172/JCI1649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Berliner J. A., Navab M., Fogelman A. M., Frank J. S., Demer L. L., Edwards P. A., Watson A. D., Lusis A. J. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995 May 1;91(9):2488–2496. doi: 10.1161/01.cir.91.9.2488. [DOI] [PubMed] [Google Scholar]
  9. Bub Achim, Barth Stephan, Watzl Bernhard, Briviba Karlis, Herbert Birgit Maria, Lührmann Petra Maria, Neuhäuser-Berthold Monika, Rechkemmer Gerhard. Paraoxonase 1 Q192R (PON1-192) polymorphism is associated with reduced lipid peroxidation in R-allele-carrier but not in QQ homozygous elderly subjects on a tomato-rich diet. Eur J Nutr. 2002 Dec;41(6):237–243. doi: 10.1007/s00394-002-0389-8. [DOI] [PubMed] [Google Scholar]
  10. Davies H. G., Richter R. J., Keifer M., Broomfield C. A., Sowalla J., Furlong C. E. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet. 1996 Nov;14(3):334–336. doi: 10.1038/ng1196-334. [DOI] [PubMed] [Google Scholar]
  11. Doorn J. A., Sorenson R. C., Billecke S. S., Hsu C., La Du B. N. Evidence that several conserved histidine residues are required for hydrolytic activity of human paraoxonase/arylesterase. Chem Biol Interact. 1999 May 14;119-120:235–241. doi: 10.1016/s0009-2797(99)00032-0. [DOI] [PubMed] [Google Scholar]
  12. Eckerson H. W., Wyte C. M., La Du B. N. The human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet. 1983 Nov;35(6):1126–1138. [PMC free article] [PubMed] [Google Scholar]
  13. Ferguson E., Parthasarathy S., Joseph J., Kalyanaraman B. Generation and initial characterization of a novel polyclonal antibody directed against homocysteine thiolactone-modified low density lipoprotein. J Lipid Res. 1998 Apr;39(4):925–933. [PubMed] [Google Scholar]
  14. Ferretti G., Bacchetti T., Marchionni C., Caldarelli L., Curatola G. Effect of glycation of high density lipoproteins on their physicochemical properties and on paraoxonase activity. Acta Diabetol. 2001 Dec;38(4):163–169. doi: 10.1007/s592-001-8074-z. [DOI] [PubMed] [Google Scholar]
  15. Fuhrman Bianca, Aviram Michael. Preservation of paraoxonase activity by wine flavonoids: possible role in protection of LDL from lipid peroxidation. Ann N Y Acad Sci. 2002 May;957:321–324. doi: 10.1111/j.1749-6632.2002.tb02933.x. [DOI] [PubMed] [Google Scholar]
  16. Furlong Clement E., Cole Toby B., Jarvik Gail P., Costa Lucio G. Pharmacogenomic considerations of the paraoxonase polymorphisms. Pharmacogenomics. 2002 May;3(3):341–348. doi: 10.1517/14622416.3.3.341. [DOI] [PubMed] [Google Scholar]
  17. Gan K. N., Smolen A., Eckerson H. W., La Du B. N. Purification of human serum paraoxonase/arylesterase. Evidence for one esterase catalyzing both activities. Drug Metab Dispos. 1991 Jan-Feb;19(1):100–106. [PubMed] [Google Scholar]
  18. Garavito R. M., Ferguson-Miller S. Detergents as tools in membrane biochemistry. J Biol Chem. 2001 Jun 29;276(35):32403–32406. doi: 10.1074/jbc.R100031200. [DOI] [PubMed] [Google Scholar]
  19. Halliwell B., Gutteridge J. M., Aruoma O. I. The deoxyribose method: a simple "test-tube" assay for determination of rate constants for reactions of hydroxyl radicals. Anal Biochem. 1987 Aug 15;165(1):215–219. doi: 10.1016/0003-2697(87)90222-3. [DOI] [PubMed] [Google Scholar]
  20. Huber-Wunderlich M., Glockshuber R. A single dipeptide sequence modulates the redox properties of a whole enzyme family. Fold Des. 1998;3(3):161–171. doi: 10.1016/S1359-0278(98)00024-8. [DOI] [PubMed] [Google Scholar]
  21. Jakubowski H. Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. J Biol Chem. 2000 Feb 11;275(6):3957–3962. doi: 10.1074/jbc.275.6.3957. [DOI] [PubMed] [Google Scholar]
  22. Jakubowski H., Zhang L., Bardeguez A., Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res. 2000 Jul 7;87(1):45–51. doi: 10.1161/01.res.87.1.45. [DOI] [PubMed] [Google Scholar]
  23. Jaouad Leila, Milochevitch Christelle, Khalil Abdelouahed. PON1 paraoxonase activity is reduced during HDL oxidation and is an indicator of HDL antioxidant capacity. Free Radic Res. 2003 Jan;37(1):77–83. doi: 10.1080/1071576021000036614. [DOI] [PubMed] [Google Scholar]
  24. Jarvik Gail P., Tsai Nancey Trevanian, McKinstry Laura A., Wani Roohi, Brophy Victoria H., Richter Rebecca J., Schellenberg Gerard D., Heagerty Patrick J., Hatsukami Thomas S., Furlong Clement E. Vitamin C and E intake is associated with increased paraoxonase activity. Arterioscler Thromb Vasc Biol. 2002 Aug 1;22(8):1329–1333. doi: 10.1161/01.atv.0000027101.40323.3a. [DOI] [PubMed] [Google Scholar]
  25. Jessup Wendy, Wilson Paul, Gaus Katharina, Kritharides Len. Oxidized lipoproteins and macrophages. Vascul Pharmacol. 2002 Apr;38(4):239–248. doi: 10.1016/s1537-1891(02)00174-x. [DOI] [PubMed] [Google Scholar]
  26. Josse D., Lockridge O., Xie W., Bartels C. F., Schopfer L. M., Masson P. The active site of human paraoxonase (PON1). J Appl Toxicol. 2001 Dec;21 (Suppl 1):S7–11. doi: 10.1002/jat.789. [DOI] [PubMed] [Google Scholar]
  27. Josse D., Xie W., Renault F., Rochu D., Schopfer L. M., Masson P., Lockridge O. Identification of residues essential for human paraoxonase (PON1) arylesterase/organophosphatase activities. Biochemistry. 1999 Mar 2;38(9):2816–2825. doi: 10.1021/bi982281h. [DOI] [PubMed] [Google Scholar]
  28. Kudchodkar B. J., Lacko A. G., Dory L., Fungwe T. V. Dietary fat modulates serum paraoxonase 1 activity in rats. J Nutr. 2000 Oct;130(10):2427–2433. doi: 10.1093/jn/130.10.2427. [DOI] [PubMed] [Google Scholar]
  29. Kuo C. L., La Du B. N. Calcium binding by human and rabbit serum paraoxonases. Structural stability and enzymatic activity. Drug Metab Dispos. 1998 Jul;26(7):653–660. [PubMed] [Google Scholar]
  30. Kuo C. L., La Du B. N. Comparison of purified human and rabbit serum paraoxonases. Drug Metab Dispos. 1995 Sep;23(9):935–944. [PubMed] [Google Scholar]
  31. La Du B. N., Adkins S., Kuo C. L., Lipsig D. Studies on human serum paraoxonase/arylesterase. Chem Biol Interact. 1993 Jun;87(1-3):25–34. doi: 10.1016/0009-2797(93)90022-q. [DOI] [PubMed] [Google Scholar]
  32. La Du B. N. Structural and functional diversity of paraoxonases. Nat Med. 1996 Nov;2(11):1186–1187. doi: 10.1038/nm1196-1186. [DOI] [PubMed] [Google Scholar]
  33. Mackness B., Davies G. K., Turkie W., Lee E., Roberts D. H., Hill E., Roberts C., Durrington P. N., Mackness M. I. Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype? Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1451–1457. doi: 10.1161/hq0901.094247. [DOI] [PubMed] [Google Scholar]
  34. Mackness Bharti, Durrington Paul N., Mackness Michael I. The paraoxonase gene family and coronary heart disease. Curr Opin Lipidol. 2002 Aug;13(4):357–362. doi: 10.1097/00041433-200208000-00002. [DOI] [PubMed] [Google Scholar]
  35. Mackness M. I., Mackness B., Durrington P. N., Connelly P. W., Hegele R. A. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol. 1996 Apr;7(2):69–76. doi: 10.1097/00041433-199604000-00004. [DOI] [PubMed] [Google Scholar]
  36. Marathe Gopal K., Zimmerman Guy A., McIntyre Thomas M. Platelet-activating factor acetylhydrolase, and not paraoxonase-1, is the oxidized phospholipid hydrolase of high density lipoprotein particles. J Biol Chem. 2002 Dec 3;278(6):3937–3947. doi: 10.1074/jbc.M211126200. [DOI] [PubMed] [Google Scholar]
  37. Murakami K., Chan S. Y., Routtenberg A. Protein kinase C activation by cis-fatty acid in the absence of Ca2+ and phospholipids. J Biol Chem. 1986 Nov 25;261(33):15424–15429. [PubMed] [Google Scholar]
  38. Nicolosi R. J., Wilson T. A., Rogers E. J., Kritchevsky D. Effects of specific fatty acids (8:0, 14:0, cis-18:1, trans-18:1) on plasma lipoproteins, early atherogenic potential, and LDL oxidative properties in the hamster. J Lipid Res. 1998 Oct;39(10):1972–1980. [PubMed] [Google Scholar]
  39. Nicolosi Robert J., Wilson Thomas A., Handelman Garry, Foxall Thomas, Keaney John F., Vita Joseph A. Decreased aortic early atherosclerosis in hypercholesterolemic hamsters fed oleic acid-rich TriSun oil compared to linoleic acid-rich sunflower oil. J Nutr Biochem. 2002 Jul;13(7):392–402. doi: 10.1016/s0955-2863(02)00202-4. [DOI] [PubMed] [Google Scholar]
  40. Rozenberg Orit, Rosenblat Mira, Coleman Raymond, Shih Diana M., Aviram Michael. Paraoxonase (PON1) deficiency is associated with increased macrophage oxidative stress: studies in PON1-knockout mice. Free Radic Biol Med. 2003 Mar 15;34(6):774–784. doi: 10.1016/s0891-5849(02)01429-6. [DOI] [PubMed] [Google Scholar]
  41. Ruiz J., Blanché H., James R. W., Garin M. C., Vaisse C., Charpentier G., Cohen N., Morabia A., Passa P., Froguel P. Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet. 1995 Sep 30;346(8979):869–872. doi: 10.1016/s0140-6736(95)92709-3. [DOI] [PubMed] [Google Scholar]
  42. Shih D. M., Gu L., Hama S., Xia Y. R., Navab M., Fogelman A. M., Lusis A. J. 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. doi: 10.1172/JCI118589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Shih D. M., Gu L., Xia Y. R., Navab M., Li W. F., Hama S., Castellani L. W., Furlong C. E., Costa L. G., Fogelman A. M. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature. 1998 Jul 16;394(6690):284–287. doi: 10.1038/28406. [DOI] [PubMed] [Google Scholar]
  44. Skinner J., Sinclair C., Romeo C., Armstrong D., Charbonneau H., Rossie S. Purification of a fatty acid-stimulated protein-serine/threonine phosphatase from bovine brain and its identification as a homolog of protein phosphatase 5. J Biol Chem. 1997 Sep 5;272(36):22464–22471. doi: 10.1074/jbc.272.36.22464. [DOI] [PubMed] [Google Scholar]
  45. Sok D. E. Ascorbate-induced oxidative inactivation of Zn2+-glycerophosphocholine cholinephosphodiesterase. J Neurochem. 1998 Mar;70(3):1167–1174. doi: 10.1046/j.1471-4159.1998.70031167.x. [DOI] [PubMed] [Google Scholar]
  46. Sorenson R. C., Bisgaier C. L., Aviram M., Hsu C., Billecke S., La Du B. N. Human serum Paraoxonase/Arylesterase's retained hydrophobic N-terminal leader sequence associates with HDLs by binding phospholipids : apolipoprotein A-I stabilizes activity. Arterioscler Thromb Vasc Biol. 1999 Sep;19(9):2214–2225. doi: 10.1161/01.atv.19.9.2214. [DOI] [PubMed] [Google Scholar]
  47. Sorenson R. C., Primo-Parmo S. L., Kuo C. L., Adkins S., Lockridge O., La Du B. N. 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. doi: 10.1073/pnas.92.16.7187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Stadtman E. R., Oliver C. N. Metal-catalyzed oxidation of proteins. Physiological consequences. J Biol Chem. 1991 Feb 5;266(4):2005–2008. [PubMed] [Google Scholar]
  49. Tomás M., Sentí M., Elosua R., Vila J., Sala J., Masià R., Marrugat J. Interaction between the Gln-Arg 192 variants of the paraoxonase gene and oleic acid intake as a determinant of high-density lipoprotein cholesterol and paraoxonase activity. Eur J Pharmacol. 2001 Dec 7;432(2-3):121–128. doi: 10.1016/s0014-2999(01)01482-0. [DOI] [PubMed] [Google Scholar]
  50. Tomás M., Sentí M., García-Faria F., Vila J., Torrents A., Covas M., Marrugat J. Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):2113–2119. doi: 10.1161/01.atv.20.9.2113. [DOI] [PubMed] [Google Scholar]
  51. Watson A. D., Berliner J. A., Hama S. Y., La Du B. N., Faull K. F., Fogelman A. M., 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. doi: 10.1172/JCI118359. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES