Regulation of Hepatic Paraoxonase-1 Expression

Serum paraoxonase-1 (PON1) is a member of the paraoxonases family (PON1, PON2, and PON3). PON1 is synthesized and secreted by the liver, and in circulation it is associated with HDL. PON1 has antioxidative properties, which are associated with the enzyme’s capability to decrease oxidative stress in atherosclerotic lesions and to attenuate atherosclerosis development. Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events and cardiovascular disease and is an independent risk factor for coronary artery disease. Therefore, pharmacological modulation of PON1 activity or PON1 gene expression could constitute a useful approach for preventing atherosclerosis. A primary determinant of serum PON1 levels is the availability of the enzyme for release by the liver, the principal site of PON1 production. Together with the enzyme secretion rate, enzymatic turnover, and protein stability, the level of PON1 gene expression is a major determinant of PON1 status. This paper summarizes recent progress in understanding the regulation of PON1 expression in hepatocytes.

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Longitudinal changes in serum paraoxonase-1 activity throughout normal pregnancy

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2006.156 ◽

2006 ◽

Vol 44 (7) ◽

Cited By ~ 10

Author(s):

Natàlia Ferré ◽

Jordi Camps ◽

Joan Fernández-Ballart ◽

Victoria Arija ◽

Michelle M. Murphy ◽

...

Keyword(s):

Vitamin C ◽

Normal Pregnancy ◽

Paraoxonase 1 ◽

Dietary Vitamin ◽

Pon1 Activity ◽

Longitudinal Changes ◽

Increased Risk ◽

Direct Association ◽

Vitamin C Supplementation ◽

Serum Paraoxonase

AbstractThe aim of this study was to investigate the longitudinal changes in serum paraoxonase-1 (PON1) activity from preconception throughout normal pregnancy and their relationships with maternal dietary vitamin C and E intake. The study was performed in 35 women (studied at preconception, at 8, 20 and 32weeks of pregnancy, and at labour). PON1 activity decreased significantly from 145.8 (109.8–198.8) U/L at preconception to 111.1 (85.3–179.9) U/L (p<0.01) at 32weeks and 100.4 (54.7–171.4) U/L (p<0.001) at labour. There was a direct association between vitamin C intake and PON1 at week 32 (p=0.018). We conclude that adequate vitamin C intake in pregnant women may merit consideration, since vitamin C supplementation has proved beneficial in the prevention of preeclampsia in women at increased risk of this condition.Clin Chem Lab Med 2006;44:880–2.

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The Effects of Anthocyanins and Their Microbial Metabolites on the Expression and Enzyme Activities of Paraoxonase 1, an Important Marker of HDL Function

Nutrients ◽

10.3390/nu11122872 ◽

2019 ◽

Vol 11 (12) ◽

pp. 2872

Author(s):

Hassan T. Aboufarrag ◽

Paul W. Needs ◽

Gerald Rimbach ◽

Paul A. Kroon

Keyword(s):

Gene Expression ◽

Enzyme Activities ◽

Molecular Mechanisms ◽

Oxidized Ldl ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Microbial Metabolites ◽

Hdl Function ◽

Pon1 Gene ◽

Gene Assay

High circulating HDL concentrations and measures of various HDL functions are inversely associated with cardiovascular disease (CVD) risk. Paraoxonase 1 (PON1) contributes to many of the athero-protective functions of HDL, such as promoting the reverse cholesterol transport process and reducing the levels of oxidized LDL. PON1 activities are influenced by several factors, the most important being diet and genetic polymorphisms. Reported data from randomized controlled trials have shown that anthocyanin consumption increased PON1 activity. However, the underlying molecular mechanisms by which anthocyanins increase PON1 activity are not understood. Therefore, the aim of this research was to investigate the ability of anthocyanins and their metabolites to increase PON1 gene expression and/or enzyme activities as potential mechanisms. The effect of the two predominant dietary anthocyanins and 18 of their recently identified microbial metabolites including their phase-II conjugates on PON1 gene expression was studied using a PON1-Huh7 stably-transfected cell line and reporter gene assay. The effects of these compounds on PON1 arylesterase and lactonase activities were investigated using two isoforms of the PON1 enzyme that are the phenotypes of the 192Q/R polymorphism. None of the compounds caused even modest changes in PON1 promoter activity (p ≥ 0.05). Further, none of the compounds at physiological concentrations caused any significant changes in the arylesterase or lactonase activity of either of the iso-enzymes. Cyanidin reduced the lactonase activity of the PON1-R192R enzyme at high concentrations (−22%, p < 0.001), but not at physiologically achievable concentrations. In conclusion, none of the data reported here support the notion that anthocyanins or their metabolites affect PON1 transactivation or enzyme activities.

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Reduced serum paraoxonase 1 (PON1) activity in patients with schizophrenia treated with olanzapine but not quetiapine

Neuropsychiatric Disease and Treatment ◽

10.2147/ndt.s52463 ◽

2013 ◽

pp. 1545 ◽

Cited By ~ 1

Author(s):

Yakup Albayrak ◽

Cüneyt Ünsal ◽

Neslihan Albayrak ◽

Murat Kuloglu ◽

Kenji Hashimoto

Keyword(s):

Paraoxonase 1 ◽

Pon1 Activity ◽

Serum Paraoxonase

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The association between PON1 gene polymorphisms (Q192R and L55M) and nephrotic syndrome in Iraqi children

Baghdad Journal of Biochemistry and Applied Biological Sciences ◽

10.47419/bjbabs.v2i03.55 ◽

2021 ◽

Vol 2 (03) ◽

pp. 118-130

Author(s):

Raghad Ali ◽

Rayah Baban ◽

Shatha Ali

Keyword(s):

Nephrotic Syndrome ◽

Lipid Profile ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Healthy Controls ◽

Coding Region ◽

Pon1 Gene ◽

Homozygous Genotype

Background: The role of paraoxonase 1 enzyme (PON1) and its single nucleotide polymorphisms (SNPs) in children with nephrotic syndrome (NS) has been reported previously in different ethnic and racial groups with divergent results. The human PON1 gene contains two coding region polymorphisms leading to two different PON1 isoforms. Objectives: The aim of the present study was to find out the association between the PON1 (Q192R and L55M) polymorphisms and their relation with serum PON1 activity as well as lipid profile tests (total cholesterol, TC; triglycerides, TG; high-density lipoprotein cholesterol, HDL-c; and low-density lipoprotein cholesterol, LDL-c) in children with NS. Methods: This study included a total of 80 participants (40 with NS in the age group of 2-14 years and 40 age and sex-matched healthy controls). The PON1 enzyme activity and lipid profile tests were measured in serum samples of all included participants. The PON1 genotype was determined by PCR-restriction enzyme fragment length polymorphism (PCR-RFLP) for both PON1 alleles (192 and 55) SNPs. Results: Our findings showed that the mean levels of lipid profile tests (TC, TG, LDL-c) were significantly increased in patients when compared with healthy controls (p<0.05), while the HDL-c concentration was significantly decreased in patients than that of controls. Also, the patients had significantly lower concentrations of PON1 when compared with the controls regardless of the genotype Q192R and L55M polymorphisms. Moreover, the homozygous RR genotype for PON1 SNP 192 and MM homozygous genotype for PON1 SNP 55 were significantly frequent in patients when compared with the controls. Conclusions: Our results support that the presence of the homozygous RR genotype for PON1 SNP 192 and MM homozygous genotype for PON1 SNP 55 were significantly higher in patients compared with the controls.

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Abstract 3132: Paraoxonase-1 Activity Is not Independently Related with the Risk of Future Coronary Artery Disease

Circulation ◽

10.1161/circ.118.suppl_18.s_1099 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Rakesh S Birjmohun ◽

Menno Vergeer ◽

Erik S Stroes ◽

Michael W Tanck ◽

Nicholas J Wareham ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Close Association ◽

Conditional Logistic Regression ◽

Hdl Cholesterol ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Q192r Polymorphism ◽

Artery Disease ◽

Cad Risk

Background Paraoxonase-1 (PON1) is a potent antioxidant enzyme bound to high-density lipoprotein (HDL). Its activity, but not its concentration, is controlled by the PON1 Q192R polymorphism. PON1 is considered to protect against atherogenesis, but it is unclear whether this relation is independent of its carrier, HDL. Objective To evaluate the predictive value of PON1 for coronary artery disease (CAD) we assessed PON1 activity and genotype (Q192R polymorphism) in a large cohort. Methods and results We performed a case-control study nested in the prospective EPIC-Norfolk cohort. Cases (n = 1138) were apparently healthy men and women aged 45–79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n=2237) were matched by age and sex. Serum PON1 activity was lower in cases vs. controls (59.9 ± 44.6 U/L vs. 63.4 ± 46.7 U/L, p=0.020) and correlated with HDL cholesterol (r= 0.16, p<0.0001). Whereas the PON1 Q192R polymorphism strongly controlled PON1 activity (QQ: 27 ± 9, QR: 87 ± 27 and RR 152 ± 44 U/L), it was not related to the risk of future CAD (Odds Ratio [OR] per R allele 0.98 [0.84–1.15], p=0.84). Using conditional logistic regression, quartiles of PON1 activity showed a modest inverse relation with CAD risk (OR for the highest vs. the lowest quartile 0.77 [0.63– 0.95], p=0.013; p for trend over quartiles 0.064). PON1 activity adjusted for Q192R genotype - a proxy for PON1 concentration -correlated better with HDL cholesterol (r=0.29, p<0.0001) and strongly predicted CAD risk (OR for the highest versus the lowest quartile 0.72 (0.58 – 0.91), p for trend over quartiles = 0.005). However, this relation was abolished after adjustment for HDL related parameters (HDL particle number, HDL cholesterol, HDL size and apolipoprotein A-I; OR for highest vs. lowest quartile 0.87 [0.66 –1.16], p for trend over quartiles = 0.13). Conclusion In the largest prospective study to date, we show that PON1 activity inversely relates to CAD risk, but not independently of HDL, presumably due to its close association with the HDL particle. Since the Q192R polymorphism profoundly affects lifelong PON1 activity, our inability to demonstrate a relation between the Q192R polymorphism and CAD risk suggests that PON1 activity is not a causal factor in atherogenesis.

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Association of PON1 gene polymorphisms and enzymatic activity with risk of coronary artery disease

Future Cardiology ◽

10.2217/fca-2020-0028 ◽

2021 ◽

Vol 17 (1) ◽

pp. 119-126

Author(s):

Charuta Godbole ◽

Saket Thaker ◽

Prafulla Kerkar ◽

Milind Nadkar ◽

Nithya Gogtay ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Enzymatic Activity ◽

Gene Polymorphisms ◽

Pon1 Activity ◽

Pon1 Gene ◽

Artery Disease ◽

Pon1 Polymorphisms ◽

Serum Pon1 Activity ◽

Control Study

Background: The present case–control study evaluated the association of PON1 gene polymorphisms and enzyme activity in the western Indian population. Materials & methods: Angiographically proven coronary artery disease (CAD) formed the cases. PON1 polymorphisms (Q192R, L55M) and enzymatic activity (paraoxonase) were assessed. Results: A total of 502 participants (251 per group) were studied. PON1 Q192R and L55M polymorphisms were not associated with the risk of CAD. Notably, a weak association was observed between Q192R polymorphisms and the risk of CAD. CAD patients had significantly lower PON1 enzymatic activity (U/L) as compared with the controls regardless of the genotype. Conclusion: Low serum PON1 activity was confirmed to be an independent predictor for the risk of CAD.

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PON1 gene polymorphisms in patients with chronic obstructive pulmonary disease

Journal of Clinical Pathology ◽

10.1136/jclinpath-2018-205194 ◽

2018 ◽

Vol 71 (11) ◽

pp. 963-970

Author(s):

Marija Grdić Rajković ◽

Sanja Popović-Grle ◽

Andrea Vukić Dugac ◽

Dunja Rogić ◽

Ivana Rako ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Operating Characteristic ◽

Fragment Length Polymorphism ◽

Characteristic Curve ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Pon1 Gene

AimsChronic obstructive pulmonary disease (COPD) is characterised with oxidative stress. Paraoxonase 1 (PON1) is an enzyme, coded by PON1 gene, with distinctive antiatherogenic and antioxidative roles. We aimed to investigate the frequencies of Q192R, L55M and −108C>T polymorphisms and association of those polymorphisms with paraoxonase and arylesterase activities in patients with COPD.MethodsPON1 genotype was determined by PCR–restriction fragment length polymorphism method. PON1 activity was measured by paraoxon and phenylacetate.ResultsOnly −108C>T polymorphism resulted in significantly different distribution of genotypes and alleles, with higher frequency of TT genotype and T allele in patients compared with control subjects. Moreover, T allele (OR 2.29 (95% CI 1.54 to 3.41); p<0.001) as well as TT genotype (OR 5.00 (95% CI 2.19 to 11.43); p<0.001) showed an association with the disease. −108C>T polymorphism was suggested as a significant diagnostic predictor for the disease (OR (95% CI) 2.65 (1.53 to 4.59), p=0.001), with an area under the receiver operating characteristic curve of 0.90 (95% CI 0.84 to 0.93) and with 83.90% of correctly classified cases.ConclusionsHigher frequency of TT genotype and T allele could contribute to the observed reduction of PON1 activity in patients with COPD. T allele and TT genotype are associated with COPD, and the PON1−108C>T polymorphism could be a potential predictor of the disease.

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Paraoxonase 1 Phenotype and Protein N-Homocysteinylation in Patients with Rheumatoid Arthritis: Implications for Cardiovascular Disease

Antioxidants ◽

10.3390/antiox9090899 ◽

2020 ◽

Vol 9 (9) ◽

pp. 899

Author(s):

Jolanta Parada-Turska ◽

Grażyna Wójcicka ◽

Jerzy Beltowski

Keyword(s):

Rheumatoid Arthritis ◽

Protein Concentration ◽

Serum Proteins ◽

Density Lipoprotein ◽

Cardiovascular Complications ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Phenyl Acetate ◽

Control Subjects ◽

Increased Risk

Paraoxonase 1 (PON1) is the high density lipoprotein-associated esterase which inhibits the development of atherosclerosis by metabolizing lipid peroxidation products as well as hydrolyzing proatherogenic metabolite of homocysteine (Hcy), Hcy thiolactone, which otherwise reacts with lysine groups of proteins, thus forming N-Hcy-protein in a process referred to as protein N-homocysteinylation. Rheumatoid arthritis (RA) is the chronic inflammatory autoimmune disease associated with increased risk of cardiovascular complications, but the underlying mechanisms are incompletely understood. We examined PON1 status and N-homocysteinylation of serum proteins in patients with RA. Blood was collected from 74 RA patients and 70 control subjects. PON1 activity was measured toward synthetic (paraoxon, phenyl acetate) and natural (Hcy thiolactone) substrates. PON1 protein concentration was measured by ELISA. Total Hcy as well as N-Hcy-protein were measured in serum as well. PON1 activity toward Hcy thiolactone was lower in RA patients than in control subjects which was accompanied by increased concentration of N-Hcy-protein despite normal total Hcy concentration. PON1 protein concentration was unchanged in the RA group, but the specific enzyme activity was reduced. When RA patients were categorized according to the DAS28-ESR score, PON1 concentration and enzymatic activity were lower whereas N-Hcy-protein was higher in those with high disease activity. PON1 activity and Hcy thiolactone were correlated with DAS28-ESR score and myeloperoxidase concentration. In conclusion, RA is associated with deficiency of PON1 activity and increased protein N-homocyseinylation which may contribute to accelerated development of cardiovascular diseases.

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