Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I

Garin, Marie-Claude Blatter; Moren, Xenia; James, Richard

doi:10.1194/jlr.m500281-jlr200

Cited by 95 publications

(38 citation statements)

References 26 publications

(33 reference statements)

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“…We also found a positive correlation between PONase/HTase activities and HDL levels, which is consistent with the literature 44) . As shown in epidemiological studies, elevated cholesterol, LDL and triglyceride levels and low HDL levels constitute risk factors for atherosclerotic heart disease; however, in atherosclerotic lesions, oxidatively modified HDL is also found 45) .…”

Section: Discussionsupporting

confidence: 81%

Serum PON-1 Activity but not Q192R Polymorphism is Related to the Extent of Atherosclerosis

Bayrak

Tokgözoğlu

et al. 2012

JAT

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Aim: Paraoxonase-1 (PON1) is an antioxidant enzyme located in high density lipoprotein (HDL). PON1 was defined as a protective factor against atherosclerosis. The aim of this study was to investigate the possible relationship between serum paraoxonase (PONase), homocysteine thiolactonase (HTase) activities and PON1 Q192R polymorphism, and the extent and severity of atherosclerosis. Methods: Blood specimens were collected from 142 individuals who had no coronary artery lesions angiographically (control group) and 128 individuals who had angiographically documented coronary artery disease of several degrees (patient group). The extent and severity of arterial lesions were evaluated by the Gensini scoring system. PONase and HTase activities were measured in serum using a spectrophotometric method. PON1 Q192R polymorphism was evaluated using PCR-RFLP after DNA isolation from blood. Results: Serum PONase and HTase activities were significantly lower in the patient group than in healthy controls (135.7 56.0 U/mL vs 153.8 62.0 U/mL, p 0.05; 36.0 6.1 U/mL vs 43.0 4.04 U/mL, p 0.01; respectively). In the patient group, there was a negative correlation between PONase, HTase activities and the Gensini score (r 0.168, p 0.039; r 0.164, p 0.006, respectively). In both groups, there was no significant difference in the distribution of PON1 Q192R polymorphism. In the patient group, the distribution of Gensini scores according to genotypes was not significant. Conclusion: It has been concluded that serum PONase and HTase activities might be a more relevant marker than PON1 genotype in evaluating the extent and severity of atherosclerosis.

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Section: Discussionsupporting

confidence: 81%

Serum PON-1 Activity but not Q192R Polymorphism is Related to the Extent of Atherosclerosis

Bayrak

Tokgözoğlu

et al. 2012

JAT

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“…IVB). This observation might be related to the positive correlation between serum PON1 and HDL levels (40,41). Therefore, increased PON1 levels seem to shift the binding equilibrium and increase the levels of tightly HDL-bound PON1, thus increasing PON1's stability and lactonase activity.…”

Section: Discussionmentioning

confidence: 99%

The development of human sera tests for HDL-bound serum PON1 and its lipolactonase activity

Gaidukov

Tawfik

2007

Journal of Lipid Research

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Serum paraoxonase (PON1) is a lipolactonase that associates with HDL-apolipoprotein A-I (HDL-apoA-I) and thereby plays a role in the prevention of atherosclerosis. Current sera tests make use of promiscuous substrates and provide no indications regarding HDL-PON1 complex formation. We developed new enzymatic tests that detect total PON1 levels, irrespective of HDL status and R/Q polymorphism, as well as the degree of catalytic stimulation and increased stability that follow PON1's tight binding to HDLapoA-I. The tests are based on measuring total PON1 levels with a fluorogenic phosphotriester, measuring the lipolactonase activity with a chromogenic lactone, and assaying the enzyme's chelator-mediated inactivation rate. The latter two are affected by tight HDL binding and thereby derive the levels of the serum PON1-HDL complex. We demonstrate these new tests with a group of healthy individuals (n 5 54) and show that the levels of PON1-HDL vary by a factor of 12. Whereas the traditionally applied paraoxonase and arylesterase tests weakly reflect PON1-HDL levels (R 5 0.64), the lipolactonase test provides better correlation (R 5 0.80). These new tests indicate the levels and activity of PON1 in a physiologically relevant context as well as the levels and quality of the HDL particles with which the enzyme is associated. Serum paraoxonase (PON1) is a HDL-associated enzyme playing an important role in organophosphate detoxification and the prevention of atherosclerosis (1, 2). HDLbound PON1 inhibits LDL oxidation (3-5) and stimulates cholesterol efflux from macrophages (6, 7). PON1 knockout mice are highly susceptible to atherosclerosis (8, 9). Accordingly, serum PON1 levels seem to be inversely related to the level of cardiovascular disease, although this correlation is weak (10-12). PON1 hydrolyzes a broad range of substrates and has been traditionally described as paraoxonase/arylesterase (2). However, it recently became apparent that PON1 is in fact a lactonase with lipophilic lactones constituting its primary substrates (13,14). Impairing the lactonase activity of PON1, through mutations of its catalytic dyad (15), diminishes PON1's ability to prevent LDL oxidation and stimulate macrophage cholesterol efflux, indicating that the antiatherogenic functions of PON1 are likely to be mediated by its lipolactonase activity (16).PON1 is synthesized in the liver and secreted into the blood, where it associates with HDL complexes carrying apolipoprotein A-I (apoA-I) (17). The structural model of PON1 indicated that the HDL surface lies in close proximity to PON1's active site, thus providing an optimal environment for the enzyme's interaction with its lipophilic substrates (18). Indeed, it has been shown that PON1 binds HDL-apoA-I particles with nanomolar affinity (19). HDLapoA-I binding stabilizes the enzyme and selectively stimulates its lipolactonase activity (19).The impact of PON1 on atherosclerotic disease and resistance to organophosphate toxicity led to intensive investigations of its natural polymorphism...

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“…Two nonsynonymous variants (i.e., amino acid substitutions) have been the main targets of investigation, resulting in some association signals ( 111,112 ). SR-BI has been the focus of numerous investigators, because it was shown to infl uence HDL-C concentrations and the susceptibility to CAD in animal studies ( 14 ).…”

Section: Linkage and Candidate-gene Studies For Analyzing Polygenic Hmentioning

confidence: 99%

Genetic causes of high and low serum HDL-cholesterol

Weissglas‐Volkov

Pajukanta

2010

Journal of Lipid Research

180

132

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Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I

Cited by 95 publications

References 26 publications

Serum PON-1 Activity but not Q192R Polymorphism is Related to the Extent of Atherosclerosis

Serum PON-1 Activity but not Q192R Polymorphism is Related to the Extent of Atherosclerosis

The development of human sera tests for HDL-bound serum PON1 and its lipolactonase activity

Genetic causes of high and low serum HDL-cholesterol

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