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Pon1  -  paraoxonase 1

Mus musculus

Synonyms: A-esterase 1, Aromatic esterase 1, PON 1, Pon, Serum aryldialkylphosphatase 1, ...
 
 
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Disease relevance of Pon1

 

High impact information on Pon1

  • Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis [6].
  • 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 [6].
  • 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 chlorpyrifos [6].
  • PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs) [6].
  • 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 [7].
 

Chemical compound and disease context of Pon1

 

Biological context of Pon1

 

Anatomical context of Pon1

  • We have previously shown that paraoxonase 1 action on macrophages produced lysophosphatidylcholine (LPC) and significantly decreased cell-mediated LDL oxidation [13].
  • Consistent with these findings, the basal level of SAA was increased, whereas apoA-I and PON-1 decreased in primary hepatocytes from PPARalpha-deficient mice as compared with wild-type mice [14].
  • Mice having their bone marrow engrafted with HSCs expressing the PON1 transgene (PON1-Tg) driven by a macrophage-specific promoter were injected i.v. with saline (vehicle only) or with gadolinium chloride (GdCl(3)), an agent that rapidly causes Kupffer cell apoptosis [12].
  • The preferential association of PON1 with HDL is mediated in part by its signal peptide and by desorption from the plasma membrane of expressing cells by HDL or phospholipid [15].
  • Furthermore, we analyzed PON1-treated macrophages and PON1-transfected cells to demonstrate the contribution of PON1 to the attenuation of macrophage cholesterol and oxidized lipid accumulation and foam cell formation [16].
 

Associations of Pon1 with chemical compounds

  • We previously reported that hepatic Pon1 expression was decreased when C57BL/6J mice were fed a high-fat, high-cholesterol diet supplemented with cholic acid (CA) [11].
  • Compared with the more atherosclerosis-susceptible C57BL/6 mice, C3H/HeJ mice display resistance to dietary bile acid repression of hepatic PON1 mRNA and decreased high-density lipoprotein cholesterol [17].
  • In folic acid-treated animals, total cholesterol, mainly carried in very low-density and low-density lipoproteins, increased significantly, and homocysteine, HDL cholesterol, paraoxonase, and triglyceride levels did not change significantly [18].
  • The study measured plasma homocysteine, lipids, lipoproteins, low-density lipoprotein (LDL) oxidation, isoprostane, paraoxonase, and apolipoproteins, and aortic atherosclerotic areas [18].
  • Expressing human PON1 lowered the titer of autoantibodies against MDA-modified LDL, a proxy for oxidized LDL in mice [1].
 

Regulatory relationships of Pon1

  • Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration [19].
 

Other interactions of Pon1

  • Although the physiological roles of the PON family of proteins, PON1, PON2, and PON3, remain unknown, epidemiological, biochemical, and mouse genetic studies of PON1 suggest an anti-atherogenic function for paraoxonases [20].
  • Compared to Lcat (+/+) mice, HDL-cholesterol is reduced 94% and apoA-I, 90%, in Lcat (-/-) mice; this reduction in HDL is paralleled by a 71% decrease in PAF-AH activity and in a 58% decrease in PON activity [19].
  • Data showed no significant changes in HDL cholesterol, paraoxonase, apolipoprotein B or triglyceride levels [21].
  • Because cytokines stimulate the hepatic expression of inflammatory markers, we investigated their role in regulating SAA, apoA-I, and PON-1 expression [14].
  • The therapeutic potential of Kupffer cell expression of a transgene encoding paraoxonase-1 (PON1), whose plasma activity correlates with the protection from atherosclerosis, was examined in mice rendered atherosclerosis-susceptible through genetic deletion of the LDL receptor [12].
 

Analytical, diagnostic and therapeutic context of Pon1

References

  1. Human paraoxonase-1 overexpression inhibits atherosclerosis in a mouse model of metabolic syndrome. Mackness, B., Quarck, R., Verreth, W., Mackness, M., Holvoet, P. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  2. The role of paraoxonase (PON1) in the detoxication of organophosphates and its human polymorphism. Costa, L.G., Li, W.F., Richter, R.J., Shih, D.M., Lusis, A., Furlong, C.E. Chem. Biol. Interact. (1999) [Pubmed]
  3. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. Shih, D.M., Gu, L., Hama, S., Xia, Y.R., Navab, M., Fogelman, A.M., Lusis, A.J. J. Clin. Invest. (1996) [Pubmed]
  4. Expression of major HDL-associated antioxidant PON-1 is gender dependent and regulated during inflammation. bin Ali, A., Zhang, Q., Lim, Y.K., Fang, D., Retnam, L., Lim, S.K. Free Radic. Biol. Med. (2003) [Pubmed]
  5. Mouse liver paraoxonase-1 gene expression is downregulated in hyperhomocysteinemia. Janel, N., Robert, K., Chabert, C., Ledru, A., Gouédard, C., Barouki, R., Delabar, J.M., Chassé, J.F. Thromb. Haemost. (2004) [Pubmed]
  6. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. 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., Lusis, A.J. Nature (1998) [Pubmed]
  7. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. Aviram, M., Rosenblat, M., Bisgaier, C.L., Newton, R.S., Primo-Parmo, S.L., La Du, B.N. J. Clin. Invest. (1998) [Pubmed]
  8. Paraoxonase protects against chlorpyrifos toxicity in mice. Li, W.F., Furlong, C.E., Costa, L.G. Toxicol. Lett. (1995) [Pubmed]
  9. The effects of phenobarbital pretreatment on the metabolism and toxicity of paraoxon in the mouse. Vitarius, J.A., O'Shaughnessy, J.A., Sultatos, L.G. Pharmacol. Toxicol. (1995) [Pubmed]
  10. The genetic mapping and gene structure of mouse paraoxonase/arylesterase. Sorenson, R.C., Primo-Parmo, S.L., Camper, S.A., La Du, B.N. Genomics (1995) [Pubmed]
  11. A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids. Shih, D.M., Kast-Woelbern, H.R., Wong, J., Xia, Y.R., Edwards, P.A., Lusis, A.J. J. Lipid Res. (2006) [Pubmed]
  12. Facilitated replacement of Kupffer cells expressing a paraoxonase-1 transgene is essential for ameliorating atherosclerosis in mice. Bradshaw, G., Gutierrez, A., Miyake, J.H., Davis, K.R., Li, A.C., Glass, C.K., Curtiss, L.K., Davis, R.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Lysophosphatidylcholine (LPC) attenuates macrophage-mediated oxidation of LDL. Rosenblat, M., Oren, R., Aviram, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  14. Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes. Han, C.Y., Chiba, T., Campbell, J.S., Fausto, N., Chaisson, M., Orasanu, G., Plutzky, J., Chait, A. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  15. Paraoxonase, a cardioprotective enzyme: continuing issues. Getz, G.S., Reardon, C.A. Curr. Opin. Lipidol. (2004) [Pubmed]
  16. Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. Aviram, M., Rosenblat, M. Free Radic. Biol. Med. (2004) [Pubmed]
  17. Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4. Gutierrez, A., Ratliff, E.P., Andres, A.M., Huang, X., McKeehan, W.L., Davis, R.A. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  18. Folic acid supplementation delays atherosclerotic lesion development in apoE-deficient mice. Carnicer, R., A Navarro, M., Arbonés-Mainar, J.M., Acín, S., Guzmán, M.A., Surra, J.C., Arnal, C., de Las Heras, M., Blanco-Vaca, F., Osada, J. Life Sci. (2007) [Pubmed]
  19. Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration. Forte, T.M., Oda, M.N., Knoff, L., Frei, B., Suh, J., Harmony, J.A., Stuart, W.D., Rubin, E.M., Ng, D.S. J. Lipid Res. (1999) [Pubmed]
  20. Paraoxonase-2 Deficiency Aggravates Atherosclerosis in Mice Despite Lower Apolipoprotein-B-containing Lipoproteins: ANTI-ATHEROGENIC ROLE FOR PARAOXONASE-2. Ng, C.J., Bourquard, N., Grijalva, V., Hama, S., Shih, D.M., Navab, M., Fogelman, A.M., Lusis, A.J., Young, S., Reddy, S.T. J. Biol. Chem. (2006) [Pubmed]
  21. Hydroxytyrosol administration enhances atherosclerotic lesion development in apo e deficient mice. Acín, S., Navarro, M.A., Arbonés-Mainar, J.M., Guillén, N., Sarría, A.J., Carnicer, R., Surra, J.C., Orman, I., Segovia, J.C., Torre, R.d.e. .L., Covas, M.I., Fernández-Bolaños, J., Ruiz-Gutiérrez, V., Osada, J. J. Biochem. (2006) [Pubmed]
  22. Eucommia ulmoides Oliver Leaf Extract Increases Endogenous Antioxidant Activity in Type 2 Diabetic Mice. Park, S.A., Choi, M.S., Jung, U.J., Kim, M.J., Kim, D.J., Park, H.M., Park, Y.B., Lee, M.K. Journal of medicinal food (2006) [Pubmed]
  23. Oxidative stress is markedly elevated in lecithin:cholesterol acyltransferase-deficient mice and is paradoxically reversed in the apolipoprotein E knockout background in association with a reduction in atherosclerosis. Ng, D.S., Maguire, G.F., Wylie, J., Ravandi, A., Xuan, W., Ahmed, Z., Eskandarian, M., Kuksis, A., Connelly, P.W. J. Biol. Chem. (2002) [Pubmed]
 
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