PON1
Serum paraoxonase/arylesterase 1 (EC 3.1.1.2) (EC 3.1.1.81) (EC 3.1.8.1) (PON 1) (Aromatic esterase 1) (A-esterase 1) (K-45) (Serum aryldialkylphosphatase 1) [PON]
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Aging is defined as the accumulation of progressive organ dysfunction. There is much evidence linking the involvement of oxidative stress in the pathogenesis of aging. With increasing age, susceptibility to the development of diseases related to lipid peroxidation and tissue injury increases, due to chronic inflammatory processes, and production of reactive oxygen species (ROS) and free radicals. The paraoxonase (PON) gene family is composed of three members ([i]PON1[/i], [i]PON2[/i], [i]PON3[/i]) that share considerable structural homology and are located adjacently on chromosome 7 in humans. The most studied member product is PON1, a protein associated with high-density lipoprotein with paraoxonase/esterase activity. Nevertheless, all the three proteins prevent oxidative stress. The major aim of this review is to highlight the importance of the role of PON enzymes in the aging process, and in the development of the main diseases present in the elderly: cardiovascular disease, diabetes mellitus, neurodegenerative diseases, and cancer.
Keywords
- PON
- aging
- atherosclerosis
- cancer
- diabetes
- heart disease
- lipid peroxidation
- lipids
- neurodegenerative diseases
- paraoxonase
Pharmacological interventions to increase the concentration of high-density lipoprotein (HDL) have led to disappointing results and have contributed to the emergence of the concept of HDL functionality. The anti-atherogenic activity of HDLs can be explained by their functionality or quality. The capacity of HDLs to maintain cellular cholesterol homeostasis and to transport cholesterol from peripheral cells to the liver for elimination is one of their principal anti-atherogenic activities. However, HDLs possess several other attributes that contribute to their protective effect against cardiovascular diseases. HDL functionality is regulated by various proteins and lipids making up HDL particles. However, several studies investigated the role of paraoxonase 1 (PON1) and suggest a significant role of this protein in the regulation of the functionality of HDLs. Moreover, research on PON1 attracted much interest following several studies indicating that it is involved in cardiovascular protection. However, the mechanisms by which PON1 exerts these effects remain to be elucidated.
MeSH Terms
- Age Factors
- Aging
- Animals
- Aryldialkylphosphatase
- Cardiovascular Diseases
- Cholesterol Ester Transfer Proteins
- Cholesterol, HDL
- Humans
- Phosphatidylcholine-Sterol O-Acyltransferase
- Signal Transduction
Keywords
- HDL functionality
- PON1
- aging
- cholesterol efflux
- efflux de cholestérol
- fonctionnalité des HDL
- vieillissement
Reverse cholesterol transport (RCT), which is intimately linked to high-density lipoproteins (HDLs), plays a key role in cholesterol homeostasis and the prevention of atherosclerosis. The goal of the present study was to investigate the effect of aging and advanced glycation end products (AGEs) on RCT as well as on other factors that may affect the antiatherogenic property of HDLs. The transfer of macrophage-derived cholesterol to the plasma and liver and then to the feces for elimination was significantly lower in aged mice than in young mice. Chronic injection of d -galactose (D-gal) or AGEs also significantly reduced RCT (65.3% reduction in [ H]cholesterol levels in the plasma of D-gal-treated mice after 48 h compared with control mice, P < 0.01). The injection of both D-gal and aminoguanidine hydrochloride increased [ H]cholesterol levels in the plasma, although the levels were lower than those of control mice. The in vitro incubation of HDLs with dicarbonyl compounds increased the carbonyl and conjugated diene content of HDLs and significantly reduced PON1 paraoxonase activity (87.4% lower than control HDLs, P < 0.0001). Treating J774A.1 macrophages with glycated fetal bovine serum increased carbonyl formation (39.5% increase, P < 0.003) and reduced ABCA1 protein expression and the capacity of macrophages to liberate cholesterol (69.1% decrease, P < 0.0001). Our results showed, for the first time, that RCT is altered with aging and that AGEs contribute significantly to this alteration.
MeSH Terms
- ATP Binding Cassette Transporter 1
- Animals
- Cell Line
- Cholesterol
- Gene Expression Regulation
- Glycation End Products, Advanced
- Lipoproteins, HDL
- Macrophages
- Male
- Mice
- Mice, Inbred C57BL
Keywords
- HDL
- advanced glycation end products
- aging
- produit finaux de glycation avancée
- reverse cholesterol transport
- transport inverse du cholestérol
- vieillissement
BACKGROUND The present study was performed to identify the association of PON1 rs662 polymorphism with serum lipid levels and human longevity in the Bama Zhuang population. MATERIAL AND METHODS PON1 genotypes were determined by Taqman SNP Genotyping Assays in 110 long-lived inhabitants (longevity group, aged 90-110 years), 110 healthy inhabitants in Bama County (control 1 group, aged 43-82 years) and 110 healthy inhabitants in Nandan County (control 2 group, aged 28-82 years) without family history of longevity. RESULTS BMI (body mass index) and TG (serum total triglyceride) level were lower in the longevity group than in the two control groups, while the contents of serum LDL-c (low-density lipoprotein cholesterol) and HDL-c (high-density lipoprotein cholesterol) and the levels of SBP (systolic blood pressure) and DBP (diastolic blood pressure) in the longevity group were higher than in the two control groups (p<0.01). Significant differences in the frequencies of three genotypes (GG, AG, and AA) were observed between the longevity group and control 2 group (χ²=15.190, p=0.001). The minor allele frequency (MAF) of rs662 was significantly higher in the longevity group than in the two control groups. The levels of HDL-c in the longevity group were different among the three genotypes (p<0.05). The levels of TG for GG and GG AG genotypes were significantly different, while the levels of TC (total cholesterol) and HDL-c for AG and GG AG genotypes were significantly different among the three groups (p<0.05). Serum lipid parameters were correlated with several environmental factors, including age, gender, DBP, SBP, and BMI. The association of PON1 rs662 polymorphism and serum lipid levels was different among the three groups. CONCLUSIONS PON1 polymorphism might be one of the genetic factors of longevity in the Bama Zhuang population. The PON1 rs662 SNP (single nucleotide polymorphism) was associated with serum HDL-c levels in the longevity group.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Alleles
- Aryldialkylphosphatase
- Asian Continental Ancestry Group
- Case-Control Studies
- Ethnic Groups
- Female
- Gene Frequency
- Genotype
- Humans
- Linkage Disequilibrium
- Lipids
- Longevity
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
The aim of this study was to compare serum lipid profiles and ovarian gene expression between aged and younger female mice fed a control or a high-fat diet for 2 months. For this 16 female mice (C57BL/6) of 4 months (Young, n = 8) or 13 months (Old, n = 8) of age were used. The females were divided into four groups: (i) young females fed a normal diet; (ii) young females fed a high-fat diet; (iii) old females fed a normal diet; and (iv) old females fed a high-fat diet. Food intake was reduced (P < 0.05) in mice fed with a high-fat (2.9 ± 0.1 g) diet in comparison with control mice (3.9 ± 0.1 g). Body weight was higher for old females on the high-fat diet (35.1 ± 0.3 g) than for young females on the same diet (23.3 ± 0.4 g; P < 0.05). PON1 activity was lower in the high-fat than control diet group (114.3 ± 5.8 vs. 78.1 ± 6.0 kU/L, respectively) and was higher in older than younger females (85.9 ± 6.4 vs. 106.5 ± 5.3; P < 0.05, respectively). Females fed a high-fat diet had lower expression of Igf1 mRNA (P = 0.04). There was an interaction between age and diet for the expression of Gdf9 and Survivin, with lower expression in older females in both diets and young females that received the high-fat diet (P < 0.05). Concluding, the high-fat diet reduced the expression of ovarian Igf1 mRNA, and Gdf9 and Survivin mRNA in younger females, which can indicate lower fertility rates. High-density lipoprotein concentration and PON1 activity were higher in aged female mice.
MeSH Terms
- Aging
- Animals
- Aryldialkylphosphatase
- Cholesterol
- Diet, High-Fat
- Eating
- Female
- Gene Expression Regulation
- Growth Differentiation Factor 9
- Inhibitor of Apoptosis Proteins
- Insulin-Like Growth Factor I
- Lipids
- Mice, Inbred C57BL
- Ovary
- Repressor Proteins
- Survivin
Keywords
- AMH
- FOXO3a
- IGF-1
- SIRT1
Genetic mutations in the paraoxonase 1 (PON1) encoding gene have been considered to affect mortality and of these the functional promoter region polymorphisms Q192R and L55M are among the most widely studied. The aim of this study was to determine whether the Q192R and L55M polymorphisms of PON1 can increase susceptibility to longevity. A meta-analysis was performed to obtain a comprehensive estimation of the association between Q192R and L55M and longevity in long-lived individuals (LLIs) aged 80 years or more. A search was carried out in the PubMed database (from January 2001 to May 2014) to obtain data on the role of PON1 polymorphisms in longevity and a pooled odds ratio (OR) with a 95% confidence interval (CI) was used to assess the associations. The meta-analysis was based on 9 studies of PON1 Q192R and 5 studies of PON1 L55M that covered a total of 5086 LLIs and 4494 controls. Overall, significantly increased risks were not observed for either Q192R or L55M. The results of the statistical calculations were as follows: R vs. Q (additive model): OR = 1.080, 95% CI = 0.989-1.179, p = 0.088 and RR RQ vs. QQ (dominant model): OR = 1.099, 95% CI = 0.975-1.240, p = 0.124; M vs. L (additive model): OR = 0.946, 95% CI = 0.862-1.039, p = 0.245 and MM ML vs. LL (dominant model): OR = 0.951, 95% CI = 0.836-1.081, p = 0.442 for Q192R and L55M, respectively. The results did not change with an age cut-off among the LLIs of ≥ 93 years. No evidence that the Q192R and L55M polymorphisms of PON1 impacted on the probability of reaching extreme ages was found although this cannot be completely ruled out; however, the possibility of population-specific effects due to the influence of and interaction between different genes or environmental factors could not be ruled out.
MeSH Terms
- Age Distribution
- Aged
- Aged, 80 and over
- Aging
- Aryldialkylphosphatase
- Female
- Humans
- Longevity
- Male
- Middle Aged
- Mutation
- Polymorphism, Single Nucleotide
- Sex Distribution
Keywords
- Aged, 80 and over
- Aging genetics
- Alleles
- Genotype
- Humans
There is much evidence linking the involvement of oxidative stress in the pathogenesis of aging. Paraoxonase 1 (PON1) is an HDL-associated antioxidant enzyme that inhibits the oxidative modification of low-density lipoproteins (LDL). We have investigated the changes in plasma PON1 activity, LDL oxidation, radical scavenging activity and lipid peroxidation in D-galactose-induced aging rat model and also compared the results with 24-month naturally aged rats. Arylesterase activity of PON1, susceptibility of LDL for oxidation, plasma radical scavenging activity and plasma thiobarbituric acid reactive substances (TBARS) were measured in normal control rats (4-months-old control rats subjected to D-galactose-induced experimental aging, and 24-month-old naturally aged rats). There was a significant decrease in plasma PON1 arylesterase activity in both subcutaneous D-galactose-treated groups and 24-month-old aged rats (P < 0.05, for each). TBARS, an oxidative stress marker, was seen to increase in the experimental groups (P < 0.01). In both subcutaneous galactose-treated and naturally aged rats, there was a significant rise in plasma LDL oxidation (P < 0.05, for each). However, radical scavenging activity was decreased significantly (P < 0.01) in both groups, as compared to control. The D-galactose-induced rat model of aging mimics the naturally aged rat with reference to PON1 arylesterase activity and susceptibility to LDL oxidation. The results emphasize the importance of PON1 with respect to aging and its association with redox balance of the body.
MeSH Terms
- Aging
- Animals
- Aryldialkylphosphatase
- Biomarkers
- Galactose
- Lipid Peroxidation
- Lipoproteins, LDL
- Male
- Models, Animal
- Oxidation-Reduction
- Oxidative Stress
- Rats
- Rats, Wistar
- Thiobarbituric Acid Reactive Substances
Paraoxonase 1 (PON1) is associated with HDL and modulates the antioxidant and anti-inflammatory role of HDL. The goals of the present study were to investigate the effect of ageing and the role of PON1 on the anti-inflammatory activity of HDL, and to determine whether extra-virgin olive oil (EVOO) consumption could improve the atheroprotective activity of HDL. HDL and PON1 were isolated from the plasma of ten young (Y-HDL and Y-PON1) and ten elderly (E-HDL and E-PON1) healthy volunteers before and after 12 weeks of EVOO consumption. Inflammation was assessed by measuring intracellular adhesion molecule 1 (ICAM-1) expression. THP-1 (human acute monocytic leukaemia cell line) monocyte chemotaxis was measured using a Boyden chamber. Oxidative damage to HDL was assessed by measuring conjugated diene formation and changes in electrophoretic migration. Y-HDL had more anti-inflammatory activity than E-HDL. The conjugated diene content and the electrophoretic mobility of E-HDL were higher than those of Y-HDL. Y-PON1 had significant anti-inflammatory activity, reducing ICAM-1 expression by 32·64 (SD 2·63)%, while E-PON1 had no significant effect. THP-1 chemotaxis measurements confirmed the ICAM-1 expression results. The 12 weeks of EVOO consumption significantly increased the anti-inflammatory activities of both HDL and PON1. The anti-inflammatory activity of HDL was modulated by PON1 and was lower in the elderly volunteers. EVOO consumption increased the anti-inflammatory effect of HDL and reduced the age-related decrease in anti-atherogenic activity.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Anti-Inflammatory Agents
- Antioxidants
- Aryldialkylphosphatase
- Chemotaxis
- Diet
- Dietary Fats
- Female
- Humans
- Inflammation
- Intercellular Adhesion Molecule-1
- Lipoproteins, HDL
- Male
- Metabolic Diseases
- Monocytes
- Olea
- Olive Oil
- Oxidative Stress
- Plant Oils
- Young Adult
Early detection of inflammation in neonatal calves allows early intervention, which may reduce mortality. Paraoxonase-1 (PON1) is a negative acute phase protein in humans. The aims of this study were to investigate age-related variability in serum PON1 activity and its clinical usefulness in neonatal calves. In healthy calves (n=9), PON1 activity increased with age from 2 to 21 days of age. There was no significant increase in PON1 activity in healthy calves from days 21 to 120 (n=15), but PON1 activity was significantly higher in adult cattle (n=45). In sick calves, serum PON1 was significantly lower in calves <7 days of age with diarrhoea (n=8) and in calves >28- to 120-days-old with respiratory disease (n=8) in comparison with age matched controls (n=20 and n=15, respectively). These results support the role of PON1 as a negative acute phase protein in cattle.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Aryldialkylphosphatase
- Cattle
- Cattle Diseases
- Gene Expression Regulation, Developmental
- Gene Expression Regulation, Enzymologic
Keywords
- Acute phase protein
- Age
- Calves
- Paraoxonase-1
Oxidative stress is thought to play a major role in the development of several age-dependent diseases. Proteins are major targets for oxidative attack. Protein hydroperoxides are formed by hydroxyl and singlet oxygen attack on protein, forming relatively stable hydroperoxides on histidine, tyrosine and tryptophan residues. This study investigated the levels of plasma protein hydroperoxides and antioxidant potential of plasma during aging in humans. We correlated the protein hydroperoxide formation with plasma antioxidant potential, paraoxonase 1 (PON1) arylesterase activity and plasma total thiols. The protein hydroperoxides and antioxidant potential were measured in plasma of human subjects aged between 20 and 81 years of both genders. Increase in plasma protein hydroperoxides and decrease in plasma antioxidant potential were observed as function of human age. This study provides strong correlation between plasma protein hydroperoxides formation and decrease in plasma antioxidant potential during aging. PON1 arylesterase activity and plasma total thiols levels were also found to show significant correlation with increasing levels of plasma protein hydroperoxides during aging. The plasma protein hydroperoxides provide a reliable marker of long-term redox balance and degree of oxidative stress during aging process.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antioxidants
- Aryldialkylphosphatase
- Biomarkers
- Blood Proteins
- Carboxylic Ester Hydrolases
- Female
- Humans
- Hydrogen Peroxide
- Male
- Middle Aged
- Oxidation-Reduction
- Oxidative Stress
- Sulfhydryl Compounds
Considering the beneficial effects of physical activity on health and disease in older people, the aim of the present study was to investigate the changes in reactive oxygen metabolites and paraoxonase 1 (PON1) activity during an intervention period on increased physical activity among older people. Serum diacron reactive oxygen metabolites (d-ROMs), PON1 activity and cardiometabolic variables were measured in 43 asymptomatic Japanese volunteers (18 men/25 women, mean age 68.9 years) in the pre- and post-phase of a 6-month intervention program aiming at a mild but sustained increase in physical activity. While the d-ROMs and PON1 activity levels were not significantly altered after the intervention, there was an inverse correlation between percentage changes of d-ROMs and PON1 activity during this intervention period. Multiple regression analysis revealed their significant and inverse correlation as independent of percentage changes of the other cardiometabolic variables (β=-0.3, P < 0.05). The inverse d-ROMs-PON1 relationship may indicate the value of concurrent measurement of these two components of oxidation-antioxidation balance when studying the effects of physical activity in an older population. Further studies are necessary to confirm the observed relationship.
MeSH Terms
- Aged
- Aging
- Aryldialkylphosphatase
- Exercise Test
- Female
- Follow-Up Studies
- Humans
- Japan
- Male
- Metabolic Syndrome
- Motor Activity
- Reactive Oxygen Species
- Spectrophotometry