[Show abstract][Hide abstract] ABSTRACT: Paraoxonase-1 (PON1) is an HDL-associated lipolactonase capable of preventing LDL and cell membrane oxidation and is therefore considered to be atheroprotective. PON1 contributes to the antioxidative function of HDL and reductions in HDL-PON1 activity, prevalent in a wide variety of diseases with an inflammatory component, and is believed to lead to dysfunctional HDL, which can promote inflammation and atherosclerosis. However, PON1 is multifunctional and may contribute to other HDL functions such as in innate immunity, preventing infection by quorum-sensing Gram-negative bacteria by destroying acyl lactone mediators of quorum sensing. In this chapter we explore the role of PON1 in atherosclerosis and other inflammatory diseases, its role in determining the toxicity of certain pesticides, prevention of bacterial infection, putative new roles for PON1 in cancer development, the noninflammatory removal of toxic membrane products of apoptosis, and the promotion of healthy aging.
[Show abstract][Hide abstract] ABSTRACT: Paraoxonase 1 (PON1) protects against the development of atherosclerosis by hydrolysing damaging lipid peroxides formed in low-density lipoprotein (LDL) and cell membranes. The effect of migration on PON1 activity is unknown. We have investigated the effect of migration on serum PON1 activity by comparing an Indian Gujarati community who had migrated to Sandwell (West Midlands, UK) with people still living in their villages of origin around the town of Navsari (Gujarat, NorthWest India) and determined biochemical and nutritional parameters which may correlate with PON1 activity. PON1 activity was almost double in men and women living in Sandwell compared to those in Navsari. In the Spearman's Rank correlation analysis, PON1 activity was significantly negatively correlated with fasting glucose and C-reactive protein, and positively with fasting non-esterified fatty acids, homeostasis model assessment (HOMA)-insulin sensitivity, and high-density lipoprotein (HDL) in rural Indian men, positively with HDL and apolipoprotein A1 (apo A1) in migrant Indian men, negatively with HOMA-cell activity and apo A1. It was positively correlated with HDL cholesterol, mean LDL particle diameter, and oxidised-LDL (ox-LDL) in rural Indian women and positively with HDL cholesterol, apo A1, and ox-LDL in migrant Indian women. Multivariate analysis with PON1 as the dependent variable indicated significant relationships with migrant status and HDL cholesterol only (both p<0.001). In conclusion, in the South Asian populations studied here, PON1 activity significantly correlated with measures of insulin sensitivity and the metabolic syndrome; however, by far the strongest determinant of PON1 activity was migration, or at least environmental and dietary changes which accompany migration. We also found an as yet unexplained lack of gender difference in HDL cholesterol, which requires further investigation.
[Show abstract][Hide abstract] ABSTRACT: To investigate the relationships between serum paraoxonase-1 (PON1), insulin resistance, and metabolic syndrome (MetS) in childhood obesity.
We studied 110 obese children and 36 non-obese children with a similar gender and age distribution. We measured serum PON1 activity against 5-thiobutyl butyrolactone (TBBLase) and against paraoxon (paraoxonase). PON1 concentration was measured separately as were the levels of several standard metabolic variables. The homeostasis model assessment (HOMA) index was calculated as an estimate of insulin resistance.
TBBLase was significantly decreased in obese children (P=0.008), while paraoxonase activity and PON1 concentrations showed non-significant trends towards decrease and increase, respectively (P=0.054 and P=0.060). TBBLase and paraoxonase specific activities were significantly decreased (P=0.004 and P=0.018, respectively). TBBLase specific activity was inversely associated with BMI, percentage body fat, insulin, HOMA, triglycerides, and C-reactive protein, and directly associated with HDL-cholesterol. Paraoxonase specific activity showed similar associations with BMI, percentage fat, HDL-cholesterol, and C-reactive protein. Obese children with MetS had lower TBBLase activities than obese children without MetS (P=0.018). Linear regression analyses showed that TBBLase was independently associated with HDL-cholesterol, BMI, percentage body fat and PON155 polymorphism, but paraoxonase activity was associated only with PON1192 polymorphism.
Our results suggest that PON1 may play a role in the onset and development of metabolic alterations in childhood obesity leading to diabetes and cardiovascular disease later in life. However, being derived from statistical association study, this finding cannot be seen as showing cause-effect.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To investigate the relationships between the levels of the antioxidant enzyme paraoxonase-1 (PON1) and corneal endothelial alterations in patients with chronic obstructive pulmonary disease (COPD) undergoing cataract surgery.
We studied 172 patients with cataract attending our ophthalmology clinic. Based on spirometric analysis, they were segregated into two groups, 110 (64%) with COPD and 62 (36%) without COPD. Corneal endothelial cell morphology was examined by widefield noncontact specular microscopy, which allows measurements of endothelial cell density (ECD), hexagonality, and endothelial cell size coefficient of variation (ECCV). Corneal thickness was measured by noncontact pachimetry. PON1 and plasma TNFα concentrations were analyzed by ELISA. Serum PON1 activity was analyzed by spectrophotometry.
Patients with COPD had significant decreases in ECD, hexagonality, and corneal thickness, and a significant increase in ECCV. They also had significant decreases in serum PON1 activity but not in PON1 concentration. Serum PON1 activity showed a significant direct association with ECD, and an inverse association with corneal thickness.
Results of the present study suggest that PON1 may be involved in the pathophysiology of corneal endothelial alterations in patients with COPD.
[Show abstract][Hide abstract] ABSTRACT: We studied the influence of PON1 on metabolic alterations induced by oxidized LDL when incubated with endothelial cells. HUVEC cells were incubated with native LDL, oxidized LDL, oxidized LDL plus HDL from wild type mice, and oxidized LDL plus HDL from PON1-deficient mice. Results showed alterations in carbohydrate and phospholipid metabolism and increased apoptosis in cells incubated with oxidized LDL. These changes were partially prevented by wild type mouse HDL, but the effects were less effective with HDL from PON1-deficient mice. Our results suggest that PON1 may play a significant role in endothelial cell survival by protecting cells from alterations in the respiratory chain induced by oxidized LDL. These results extend current knowledge on the protective role of HDL and PON1 against oxidation and apoptosis in endothelial cells.
Full-text · Article · May 2013 · Mediators of Inflammation
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Paraoxonase-1 (PON1) is a Ca(2+) dependent, high-density lipoprotein-associated lactonase which is capable of retarding/inhibiting low-density lipoprotein (LDL) oxidation. LDL oxidation is believed to be central to the initiation and progression of atherosclerosis, therefore, PON1 is considered to be atheroprotective.
Relevant literature on PON1 was identified in PubMed. Here, we discuss the background to research on PON1 in atherosclerosis, the evidence for and against PON1 being atheroprotective, potential mechanisms of this atheroprotection and current knowledge on human PON1 regulation.
Although current knowledge on PON1 indicates it to be atheroprotective, further clinical and basic studies are warranted to show that PON1 is causally linked to atherosclerosis, how it is atheroprotective and how it is regulated in vivo in humans.
[Show abstract][Hide abstract] ABSTRACT: Hereditary hemochromatosis (HH) is characterized by accumulation of iron, oxidative stress, inflammation and fibrogenesis in liver tissue. In this setting, research on the protection afforded by intracellular antioxidants is of clinical relevance. Paraoxonase1 (PON1) is an enzyme that degrades lipid peroxides. This study investigates the alterations in serum PON1 status, PON1 gene polymorphisms and PON1 hepatic expression in patients with HH. We performed a case-control study in 77 patients with HH (80.5% men, 22 to 70 years of age) and 408 healthy individuals (43.1% men, 26 to 74 years of age). Serum PON1 activities against different substrates and PON1192 and PON155 polymorphisms were analyzed. PON1 protein expression was investigated in 20 liver biopsies. HH patients had significantly lower serum PON1 activity, which was inversely correlated with ferritin (marker of iron stores) and serum 8isoprostane plasma concentrations (index of oxidative stress). PON1 protein expression in liver tissue was higher in patients, and showed stronger staining in hepatocytes surrounding the areas of inflammation. Our study provides preliminary evidence that PON1 may play a role in protecting against iron-induced oxidative stress in HH.
Full-text · Article · Mar 2013 · The Journal of Lipid Research
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress is a determinant of liver steatosis and the progression to more severe forms of disease. The present study investigated the effect of paraoxonase-1 (PON1) deficiency on histological alterations and hepatic metabolism in mice fed a high-fat high-cholesterol diet. We performed non-targeted metabolomics on liver tissues from 8 male PON1-deficient mice and 8 wild-type animals fed a high-fat, high-cholesterol diet for 22 weeks. We also measured 8-oxo-20-deoxyguanosine, reduced and oxidized glutathione, malondialdehyde, 8-isoprostanes and protein carbonyl concentrations. Results indicated lipid droplets in 14.5% of the hepatocytes of wild-type mice and in 83.3% of the PON1-deficient animals (P < 0.001). The metabolomic assay included 322 biochemical compounds, 169 of which were significantly decreased and 16 increased in PON1-deficient mice. There were significant increases in lipid peroxide concentrations and oxidative stress markers. We also found decreased glycolysis and the Krebs cycle. The urea cycle was decreased, and the pyrimidine cycle had a significant increase in orotate. The pathways of triglyceride and phospholipid synthesis were significantly increased. We conclude that PON1 deficiency is associated with oxidative stress and metabolic alterations leading to steatosis in the livers of mice receiving a high-fat high-cholesterol diet.
Full-text · Article · Feb 2013 · Journal of Proteome Research
[Show abstract][Hide abstract] ABSTRACT: Serum paraoxonase-1 (PON1) retards the oxidation of low-density lipoprotein and cell membranes and is atheroprotective. Polymorphisms in the promoter region of the PON1 gene have been shown to affect serum PON1 levels and have been related to the presence of coronary heart disease (CHD) in some studies. However, contradictory results have been reported with regard to promoter region polymorphisms and CHD presence; therefore we have re-examined the effects of the C-108T and G-909C promoter polymorphisms on PON1 levels and the presence of CHD in a large case-control study.
Paraoxonase-1 activity, concentration and the C-108T and G-909C polymorphisms were measured in 417 people with CHD and 282 healthy controls, in a case control study.
Paraoxonase-1 activity and concentration were significantly lower in the CHD population compared to controls regardless of their C-108T and G-909C genotype (p < 0.001). Paraoxonase-1 activity was significantly different in the C-108T genotypes in both the control and CHD groups in the order TT < TC < CC (p < 0.01). Paraoxonase-1 concentration was significantly different in the CHD group only in the G-909C genotype in the order GG > GC > CC (p < 0.01). Haplotype analysis revealed no consistent patterns of PON1 activity in the CHD population; however, in the controls PON1 activity differed between haplotypes GGCC > GGTC > GGTT (p < 0.05) and GCCC > GCTC > GCTT (p < 0.02). Neither promoter polymorphism was associated with CHD presence.
Paraoxonase-1 status was significantly lower in people with CHD and was affected by the promoter region polymorphisms.
Full-text · Article · Feb 2013 · Archives of Medical Science
[Show abstract][Hide abstract] ABSTRACT: There is considerable interest in the research of molecules modulating the acute inflammatory response in patients with sepsis. Paraoxonases (PON) are antioxidant and anti-inflammatory enzymes that inhibit the production of the monocyte chemoattractant protein-1 (MCP-1). This preliminary study investigated changes in PON status and MCP-1 concentrations in critically ill patients with severe sepsis treated in an ICU and their relationship with the evolution of disease.
This was a longitudinal, prospective and observational study on 15 patients with sepsis, studied at baseline and on days 1, 2, 5, 7 and 10 of their stay in the ICU. In all the patients we measured serum PON1 and PON3 concentrations, PON1 paraoxonase and lactonase activities, serum MCP-1 concentrations, and several standard biochemical and haematological parameters.
MCP-1 concentration significantly decreased with the resolution of sepsis, and this decrease was especially important during the first 5 days of hospitalisation. PON1 and PON3 tended to decrease during the first 5 days in ICU and significantly increased in days 7 and 10. Linear regression analysis showed significant and direct correlations among serum MCP-1 concentration and lactate levels at baseline. At the end of stay, PON1 paraoxonase and lactonase activities were significantly correlated with organ system function measurements.
We observed an inverse pattern between changes in MCP-1, and PON1 and PON3 levels in patients with sepsis, this was related to the resolution of their infection after receiving treatment in an ICU.
Full-text · Article · Oct 2012 · Clinical Chemistry and Laboratory Medicine
[Show abstract][Hide abstract] ABSTRACT: To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM).
589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study.
PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found.
[Show abstract][Hide abstract] ABSTRACT: High-density lipoprotein (HDL) is protective against atherosclerosis development. Other than its central role in reverse cholesterol transport, HDL exhibits several other mechanisms by which it is protective. These include antioxidative, anti-inflammatory and antiapoptopic activities and the normalisation of vascular function. In light of the current view that oxidative modification of low-density lipoprotein (LDL) is essential for the initiation and progression of atherosclerosis, the antioxidative properties of HDL may be an important protective mechanism. HDL can retard the oxidation of LDL and limit its atherogenicity. Several proteins are present on HDL and the evidence that some of them metabolise lipid peroxidation products of phospholipids, cholesteryl esters and triglycerides associated with LDL and vascular cell membranes are discussed in this review.
Full-text · Article · Jun 2012 · Panminerva medica
[Show abstract][Hide abstract] ABSTRACT: The inhibition of low-density lipoprotein (LDL) oxidation by high-density lipoprotein (HDL) is a major antiatherogenic property of this lipoprotein. This activity is due, in part, to HDL associated proteins. However, whether these proteins interact in the antioxidant activity of HDL is unknown. LDL was incubated with apolipoprotein A1 (apo A1), lecithin:cholesterol acyltransferase (LCAT), and paraoxonase-1 (PON1) alone or in combination, in the presence or absence of HDL under oxidizing conditions. LDL lipid peroxide concentrations were determined. Apo A1, LCAT, and PON1 all inhibit LDL oxidation in the absence of HDL and enhance the ability of HDL to inhibit LDL oxidation. Their effect was additive rather than synergistic; the combination of these proteins significantly enhanced the length of time LDL was protected from oxidation. This seemed to be due to the ability of PON1 to prevent the oxidative inactivation of LCAT. Apo A1, LCAT, and PON1 can all contribute to the antioxidant activity of HDL in vitro. The combination of apo A1, LCAT, and PON1 prolongs the time that HDL can prevent LDL oxidation, due, at least in part, to the prevention LCAT inactivation.
Full-text · Article · Feb 2012 · International Union of Biochemistry and Molecular Biology Life
[Show abstract][Hide abstract] ABSTRACT: We investigated the influence of the HIV infection on serum paraoxonase-3 (PON3) concentration and assessed the relationships with lipoprotein-associated abnormalities, immunological response, and accelerated atherosclerosis. We studied 207 HIV-infected patients and 385 healthy volunteers. Serum PON3 was determined by in-house ELISA, and PON3 distribution in lipoproteins was investigated by fast-performance liquid chromatography (FPLC). Polymorphisms of the PON3 promoter were analyzed by the Iplex Gold MassArray(TM) method. PON3 concentrations were increased (about three times) in HIV-infected patients with respect to controls (P < 0.001) and were inversely correlated with oxidized LDL levels (P = 0.038). Long-term use of nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy was associated with a decrease of PON3 concentrations. In a multivariate linear regression analysis, these relationships were still strong when the main confounding covariates were considered. PON3 was mainly found in HDL in HIV-infected patients, but a substantial amount of the protein was detected in LDL particles. This study reports for the first time an important increase in serum PON3 concentrations in HIV-infected patients that is associated with their oxidative status and their treatment with NNRTI. Long-term, prospective studies are needed to confirm the possible influence of this enzyme on the course of this disease and its possible utility as an analytical biomarker.
Full-text · Article · Jan 2012 · The Journal of Lipid Research
[Show abstract][Hide abstract] ABSTRACT: There are no data on the relationship between serum paraoxonase-3 (PON3) concentration and atherosclerosis in humans. Our aim was to investigate possible associations, using recently developed methods, in patients with peripheral artery disease (PAD) or coronary artery disease (CAD).
We studied 118 PAD and 72 CAD patients and 175 healthy volunteers. Serum PON3 was determined by in-house ELISA using polyclonal antibodies generated against a synthetic peptide with a sequence specific to PON3. Polymorphisms of the PON3 promoter were analysed by the Iplex Gold MassArray™ method.
There was a significant increase in serum PON3 concentration in both groups of patients with respect to the control group. In PAD patients, we observed significant positive correlations between PON3, insulin levels and HOMA index. These associations were not observed in CAD. There were significant positive associations between serum PON3 and β-2-microglobulin, CCL2 and high-sensitivity C-reactive protein in CAD patients, but not in PAD. We did not find any significant differences in PON3 gene promoter polymorphisms and their haplotypes between patients and controls, indicating that associations were not genetically determined.
In both atherosclerotic phenotypes, serum PON3 concentration was increased, but this was associated with decreased insulin sensitivity in PAD and with inflammation in CAD.
[Show abstract][Hide abstract] ABSTRACT: Therapeutic strategies to increase high-density lipoprotein (HDL) to treat or prevent vascular disease include the use of cholesteryl-ester transfer protein (CETP) inhibitors. Here, we show, to the best of our knowledge for the first time, that addition of CETP to HDL enhances the ability of HDL to inhibit low-density lipoprotein oxidation by ∼ 30% for total HDL and HDL(2) (both P < 0.05) and 75% for HDL(3) (P < 0.01). Therefore, CETP inhibition may be detrimental to the antiatherosclerotic properties of HDL, and these findings may partly explain the failure of the CETP inhibitor, torcetrapib, treatment to retard vascular disease despite large increases in HDL, in addition to its "off target" toxicity, a property which appears not to be shared by other members of this class of CETP inhibitor currently under clinical trial. Further, detailed studies are urgently required.
Full-text · Article · Sep 2011 · International Union of Biochemistry and Molecular Biology Life
[Show abstract][Hide abstract] ABSTRACT: To investigate the effects of dilution on high-density lipoprotein (HDL) associated paraoxonase-1 (PON1) activity.
HDL was prepared by ultracentrifugation, diluted with TRIS buffer pH 8.2 (0-128 fold) and assayed spectrophotometrically for PON1 activity using paraoxon and phenyl acetate.
HDL-PON1 activity increased progressively with dilution to over 200% of the undiluted activity by 128 fold dilution (P<0.001). Conversely HDL size decreased.
These results indicate the urgent need to standardise conditions for measuring PON1 activity.
Full-text · Article · Aug 2011 · Clinical biochemistry