Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2214-2225
© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Human Serum Paraoxonase/Arylesterase's Retained Hydrophobic N-Terminal Leader Sequence Associates With HDLs by Binding Phospholipids
Apolipoprotein A-I Stabilizes Activity
Abstract—In serum, human paraoxonase/arylesterase (PON1) is found exclusively associated with high density lipoprotein (HDL) and contributes to its antiatherogenic properties by inhibiting low density lipoprotein (LDL) oxidation. Difficulties in purifying PON1 from apolipoprotein A-I (apoA-I) suggested that PON1's association with HDL may occur through a direct binding between these 2 proteins. An unusual property of PON1 is that the mature protein retains its hydrophobic N-terminal signal sequence. By expressing in vitro a mutant PON1 with a cleavable N-terminus, we demonstrate that PON1 associates with lipoproteins through its N-terminus by binding phospholipids directly rather than binding apoA-I. Nonetheless, apoA-I stabilized arylesterase activity more than did phospholipid alone, apoA-II, or apoE. Consequently, we studied the role of apoA-I in PON1 expression and HDL association in mice genetically deficient in apoA-I. Though present in HDL fractions at decreased levels, PON1 arylesterase activity was less stable than in control mice. Furthermore, PON1 could be competitively removed from HDL by phospholipids, suggesting that PON1's retained N-terminal peptide allows transfer of the enzyme between phospholipid surfaces. Thus, our data suggest that PON1 is stabilized by apoA-I, and its binding to HDL and physiological distribution are dependent on the direct binding of the retained hydrophobic N-terminus to phospholipids optimally presented in association with apoA-I.
Key Words: atherogenesis • lipid peroxidation • HDL • LDL oxidation • paraoxonase
This article has been cited by other articles:
 |
|
 |
|
  C. Christoffersen, J. Ahnstrom, O. Axler, E. I. Christensen, B. Dahlback, and L. B. Nielsen The Signal Peptide Anchors Apolipoprotein M in Plasma Lipoproteins and Prevents Rapid Clearance of Apolipoprotein M from Plasma J. Biol. Chem., July 4, 2008; 283(27): 18765 - 18772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Moren, S. Deakin, M.-L. Liu, M.-R. Taskinen, and R. W. James HDL subfraction distribution of paraoxonase-1 and its relevance to enzyme activity and resistance to oxidative stress J. Lipid Res., June 1, 2008; 49(6): 1246 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Deakin, X. Moren, and R. W. James HDL Oxidation Compromises its Influence on Paraoxonase-1 Secretion and its Capacity to Modulate Enzyme Activity Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1146 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Thomas-Moya, M. Gianotti, A. M. Proenza, and I. Llado The age-related paraoxonase 1 response is altered by long-term caloric restriction in male and female rats J. Lipid Res., September 1, 2006; 47(9): 2042 - 2048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Christoffersen, L. B. Nielsen, O. Axler, A. Andersson, A. H. Johnsen, and B. Dahlback Isolation and characterization of human apolipoprotein M-containing lipoproteins J. Lipid Res., August 1, 2006; 47(8): 1833 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rosenblat, L. Gaidukov, O. Khersonsky, J. Vaya, R. Oren, D. S. Tawfik, and M. Aviram The Catalytic Histidine Dyad of High Density Lipoprotein-associated Serum Paraoxonase-1 (PON1) Is Essential for PON1-mediated Inhibition of Low Density Lipoprotein Oxidation and Stimulation of Macrophage Cholesterol Efflux J. Biol. Chem., March 17, 2006; 281(11): 7657 - 7665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-C. Blatter Garin, X. Moren, and R. W. James Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I J. Lipid Res., March 1, 2006; 47(3): 515 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Ferretti, T Bacchetti, F Principi, F Di Ludovico, B Viti, V A Angeleri, M Danni, and L Provinciali Increased levels of lipid hydroperoxides in plasma of patients with multiple sclerosis: a relationship with paraoxonase activity Multiple Sclerosis, December 1, 2005; 11(6): 677 - 682. [Abstract] [PDF]
|
|
|
|
|
|
D. I. Draganov, J. F. Teiber, A. Speelman, Y. Osawa, R. Sunahara, and B. N. La Du Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities J. Lipid Res., June 1, 2005; 46(6): 1239 - 1247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ferretti, T. Bacchetti, C. Moroni, S. Savino, A. Liuzzi, F. Balzola, and V. Bicchiega Paraoxonase Activity in High-Density Lipoproteins: A Comparison between Healthy and Obese Females J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1728 - 1733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Faber, O. Axler, B. Dahlback, and L. B. Nielsen Characterization of apoM in normal and genetically modified mice J. Lipid Res., July 1, 2004; 45(7): 1272 - 1278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Ferretti, T. Bacchetti, D. Busni, R. A. Rabini, and G. Curatola Protective Effect of Paraoxonase Activity in High-Density Lipoproteins against Erythrocyte Membranes Peroxidation: A Comparison between Healthy Subjects and Type 1 Diabetic Patients J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2957 - 2962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Connelly, G. F. Maguire, and D. I. Draganov Separation and quantitative recovery of mouse serum arylesterase and carboxylesterase activity J. Lipid Res., March 1, 2004; 45(3): 561 - 566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Delgado Alves, S. Kumar, and D. A. Isenberg Cross-reactivity between anti-cardiolipin, anti-high-density lipoprotein and anti-apolipoprotein A-I IgG antibodies in patients with systemic lupus erythematosus and primary antiphospholipid syndrome Rheumatology, July 1, 2003; 42(7): 893 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. G. Cabana, C. A. Reardon, N. Feng, S. Neath, J. Lukens, and G. S. Getz Serum paraoxonase: effect of the apolipoprotein composition of HDL and the acute phase response J. Lipid Res., April 1, 2003; 44(4): 780 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rosenblat, D. Draganov, C. E. Watson, C. L. Bisgaier, B. N. La Du, and M. Aviram Mouse Macrophage Paraoxonase 2 Activity Is Increased Whereas Cellular Paraoxonase 3 Activity Is Decreased Under Oxidative Stress Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 468 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Rozenberg, D. M. Shih, and M. Aviram Human Serum Paraoxonase 1 Decreases Macrophage Cholesterol Biosynthesis: Possible Role for Its Phospholipase-A2-Like Activity and Lysophosphatidylcholine Formation Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 461 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Parolini, G. Chiesa, Y. Zhu, T. Forte, S. Caligari, E. Gianazza, M. G. Sacco, C. R. Sirtori, and E. M. Rubin Targeted Replacement of Mouse Apolipoprotein A-I with Human ApoA-I or the Mutant ApoA-IMilano. EVIDENCE OF APOA-IM IMPAIRED HEPATIC SECRETION J. Biol. Chem., February 7, 2003; 278(7): 4740 - 4746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Josse, C. Ebel, D. Stroebel, A. Fontaine, F. Borges, A. Echalier, D. Baud, F. Renault, M. le Maire, E. Chabrieres, et al. Oligomeric States of the Detergent-solubilized Human Serum Paraoxonase (PON1) J. Biol. Chem., August 30, 2002; 277(36): 33386 - 33397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Desideri, M. C. Marinucci, G. Tomassoni, P. G. Masci, A. Santucci, and C. Ferri Vitamin E Supplementation Reduces Plasma Vascular Cell Adhesion Molecule-1 and von Willebrand Factor Levels and Increases Nitric Oxide Concentrations in Hypercholesterolemic Patients J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2940 - 2945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Ng, G. F. Maguire, J. Wylie, A. Ravandi, W. Xuan, Z. Ahmed, M. Eskandarian, A. Kuksis, and P. W. Connelly 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 J. Biol. Chem., March 29, 2002; 277(14): 11715 - 11720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Forte, G. Subbanagounder, J. A. Berliner, P. J. Blanche, A. O. Clermont, Z. Jia, M. N. Oda, R. M. Krauss, and J. K. Bielicki Altered activities of anti-atherogenic enzymes LCAT, paraoxonase, and platelet-activating factor acetylhydrolase in atherosclerosis-susceptible mice J. Lipid Res., March 1, 2002; 43(3): 477 - 485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Deakin, I. Leviev, M. Gomaraschi, L. Calabresi, G. Franceschini, and R. W. James Enzymatically Active Paraoxonase-1 Is Located at the External Membrane of Producing Cells and Released by a High Affinity, Saturable, Desorption Mechanism J. Biol. Chem., February 1, 2002; 277(6): 4301 - 4308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. W. Castellani and A. J. Lusis ApoA-II Versus ApoA-I: Two for One Is Not Always a Good Deal Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1870 - 1872. [Full Text] [PDF]
|
|
|
|
|
|
P. Holvoet, K. Peeters, S. Lund-Katz, A. Mertens, P. Verhamme, R. Quarck, D. Stengel, M. Lox, E. Deridder, H. Bernar, et al. Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1977 - 1983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Brushia, T. M. Forte, M. N. Oda, B. N. La Du, and J. K. Bielicki Baculovirus-mediated expression and purification of human serum paraoxonase 1A J. Lipid Res., June 1, 2001; 42(6): 951 - 958. [Abstract] [Full Text]
|
|
|
|
|
|
M. A. Deeg, E. L. Bierman, and M. C. Cheung GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex J. Lipid Res., March 1, 2001; 42(3): 442 - 451. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Billecke, D. Draganov, R. Counsell, P. Stetson, C. Watson, C. Hsu, and B. N. L. Du Human Serum Paraoxonase (pon1) Isozymes Q and R Hydrolyze Lactones and Cyclic Carbonate Esters Drug Metab. Dispos., November 1, 2000; 28(11): 1335 - 1342. [Abstract] [Full Text]
|
|
|
|
|
|
Bart De Geest, D. Stengel, M. Landeloos, M. Lox, L. Le Gat, D. Collen, P. Holvoet, and E. Ninio Effect of Overexpression of Human Apo A-I in C57BL/6 and C57BL/6 Apo E-Deficient Mice on 2 Lipoprotein-Associated Enzymes, Platelet-Activating Factor Acetylhydrolase and Paraoxonase : Comparison of Adenovirus-Mediated Human Apo A-I Gene Transfer and Human Apo A-I Transgenesis Arterioscler. Thromb. Vasc. Biol., October 1, 2000; 20 (10): e68 - e75. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Kudchodkar, A. G. Lacko, L. Dory, and T. V. Fungwe Dietary Fat Modulates Serum Paraoxonase 1 Activity in Rats J. Nutr., October 1, 2000; 130(10): 2427 - 2433. [Abstract] [Full Text]
|
|
|
|
|
|
C. C. Hedrick, K. Hassan, G. P. Hough, J. Yoo, S. Simzar, C. R. Quinto, S.-M. Kim, A. Dooley, S. Langi, S. Y. Hama, et al. Short-Term Feeding of Atherogenic Diet to Mice Results in Reduction of HDL and Paraoxonase That May Be Mediated by an Immune Mechanism Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1946 - 1952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. I. Draganov, P. L. Stetson, C. E. Watson, S. S. Billecke, and B. N. La Du Rabbit Serum Paraoxonase 3 (PON3) Is a High Density Lipoprotein-associated Lactonase and Protects Low Density Lipoprotein against Oxidation J. Biol. Chem., October 20, 2000; 275(43): 33435 - 33442. [Abstract] [Full Text] [PDF]
|
|