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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-0486
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1728-1733
Copyright © 2005 by The Endocrine Society

Paraoxonase Activity in High-Density Lipoproteins: A Comparison between Healthy and Obese Females

G. Ferretti, T. Bacchetti, C. Moroni, S. Savino, A. Liuzzi, F. Balzola and V. Bicchiega

Istituto di Biochimica, Facoltà di Medicina e Chirurgia, Università Politecnica delle Marche (G.F., T.B.), 60131 Ancona, Italy; and Laboratorio Sperimentale di Ricerche Nutrizionali-Istituto Auxologico Italiano, Ospedale San Giuseppe-Piancavallo 28920 (C.M., S.S., A.L., F.B., V.B.), Italy

Address all correspondence and requests for reprints to: Dr. Gianna Ferretti, Istituto di Biochimica, Facoltà di Medicina e Chirurgia, Università Politecnica delle Marche, Via Ranieri, 60131 Ancona, Italy. E-mail: g.ferretti{at}univpm.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Paraoxonase, an enzyme associated with high-density lipoprotein (HDL-PON), exerts a protective effect against oxidative damage of circulating cells and lipoproteins, modulates the susceptibility of HDL to atherogenic modifications such as glycation and homocysteinylation, and even exerts an antiinflammatory role. The aim of the present study was to investigate the relationship between lipoprotein oxidative stress and the activity of HDL-PON in healthy and obese subjects. Therefore, the activity of HDL-PON and the levels of lipid hydroperoxides in HDL and low-density lipoprotein (LDL) isolated from plasma of obese females (n = 12) and age-sex-matched controls (n = 31) were compared. Our results demonstrated for the first time that the activity of HDL-PON in obese subjects was significantly lower compared with that in controls (P < 0.001). Moreover, our results showed a significant increase in the levels of lipid hydroperoxides in HDL and LDL isolated from obese subjects (P < 0.001). The negative correlations established between HDL-PON activity and the levels of lipid hydroperoxides associated with HDL and LDL confirm the relationship between paraoxonase activity and lipid peroxidation of lipoproteins. Plasma levels of leptin correlated negatively with HDL-PON activity and positively with levels of lipid hydroperoxides in HDL and LDL of obese subjects, suggesting a relationship between leptin and oxidative damage of lipoproteins. In conclusion, our study demonstrated that the increase in oxidative stress in LDL and HDL of obese subjects is associated with a decrease in HDL-PON activity. The lower paraoxonase activity and the compositional changes in HDL and LDL could contribute to the greater risk of cardiovascular disease associated with obesity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SEVERAL STUDIES HAVE shown modifications of lipid and lipoprotein metabolism in obese subjects. Hypercholesterolemia, high levels of triglycerides (TG) and low density lipoproteins (LDL), and low levels of high density lipoproteins (HDL) are frequently observed in human obesity in both adult and pediatric patients (1, 2). Moreover, alterations of lipoprotein heterogeneity (3, 4, 5) and lipoprotein lipid and apoprotein composition have been demonstrated in obese subjects (5).

The modifications of lipoprotein levels and composition are probably related to the greater risk of cardiovascular disease associated with obesity (6). Moreover, several studies have demonstrated an increase in oxidative stress in obese subjects, with a higher susceptibility to lipid peroxidation of LDL isolated from obese subjects compared with healthy subjects (7, 8, 9, 10). It has been suggested that the increase in oxidative damage could be due to a decrease in antioxidant properties. In fact, low levels of ß-carotene and {alpha}-tocopherol have been observed in serum and LDL from obese patients (7, 10). Using animal models, it has been demonstrated that oxidation of LDL in obesity is associated with impaired HDL antioxidant defenses, such as decreased activity of the HDL-associated enzymes paraoxonase (HDL-PON) and lecithin:cholesterol acyltransferase (11).

HDL-PON is a calcium-dependent esterase able to hydrolyze oxidized phospholipids and thus protect lipoproteins (LDL and HDL) and membranes from oxidative modifications (12, 13, 14). The enzymatic activity of HDL-PON varies widely among healthy humans, and it has been suggested that subjects with low PON activity may have a greater risk of developing diseases in which oxidative damage and lipid peroxidation are involved compared with subjects with high PON activity (13). Moreover, previous studies have shown that the antioxidant properties of HDL and their susceptibility to atherogenic modifications induced in vitro, such as oxidation, glycation, and homocysteinylation, are related to HDL-PON activity (15, 16, 17).

The aim of this study was to investigate the relationship between lipoprotein oxidative stress and the activity of paraoxonase associated with HDL in healthy and obese subjects. Therefore, the activity of HDL-PON and the levels of lipid hydroperoxides in HDL and LDL isolated from plasma of obese subjects compared with HDL from age- and sex-matched controls have been studied.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Materials

PBS, potassium bromide, xylenol orange [o-cresolsulfonephthalein-3',3'-bis(methyliminodiacetic acid sodium salt)], ammonium iron (II) sulfate hexahydrate [Fe(NH4)2(SO4)2], sulfuric acid (H2SO4), butylated hydroxytoluene, Tris [(hydroxymethyl)aminomethane], sodium chloride (NaCl), magnesium chloride (MgCl2), calcium chloride (CaCl2), and paraoxon (dietyl-p-nitrophenyl phosphate) were purchased from Sigma-Aldrich Corp. (St. Louis, MO).

Subjects

Thirty-one healthy (31.5 ± 2.9 yr) and 12 obese (38.2 ± 3.6 yr) females were included in the study. Inclusion criteria for obese subjects were body mass index (BMI) greater than 25 kg/m2 and absence of endocrine, metabolic kidney disease, or medical problems other than obesity. The subjects were patients at the Italian Auxologic Institute. Control subjects included in the study were females with BMI less than 25 kg/m2 (Table 1Go). Plasma lipids levels in control and obese subjects are shown in Table 1Go. Controls and patients were not taking lipid-lowering drugs, angiotensin-converting enzyme inhibitors, antioxidants, or other medication that could affect lipid metabolism. Smokers were excluded from the study, because cigarette smoke has been shown to inhibit paraoxonase activity (18). Furthermore, subjects with a current or recent illness were excluded from the study, because modifications of PON activity were described in human patients during the acute phase response (19). Informed consent was obtained from each participating subject. The study was approved by the ethics committee of the Italian Auxologic Institute and was carried out in accordance with the principles of the Declaration of Helsinki as revised in 2000.


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  		TABLE 1. Clinical characteristics and plasma parameters in control and obese subjects

 
Isolation of human plasma HDL and LDL

Blood samples were obtained at 0800 h after overnight fasting from 31 control and 12 obese donors by venipuncture and were collected in heparin-containing Vacutainer tubes (Venoject, Terumo Europe NV, Leuven, Belgium).

Plasma was prepared by centrifugation at 3000 rpm for 20 min and thereafter used for the preparation of lipoproteins. HDL (density, 1.063–1.210 g/ml) and LDL (density, 1.025–1.063 g/ml) were isolated by single vertical spin density gradient ultracentrifugation for 1.30 h at 65,000 rpm (20) and dialyzed at 4 C for 24 h against 10 mM PBS, pH 7.4. Lipoproteins were used within 24 h after isolation. The protein concentrations of HDL and LDL were determined by the method of Lowry et al. (21), using serum albumin as standard. Total cholesterol, TG, and phospholipids in HDL from control and obese subjects were determined using commercial kits (Roche, Mannheim, Germany).

Evaluation of lipid peroxidation of HDL and LDL

The extent of lipid peroxidation in HDL and LDL isolated from plasma of 31 control (C-HDL and C-LDL) and 12 obese (O-HDL and O-LDL) females was evaluated by measuring the levels of lipid hydroperoxides by the ferrous oxidation xylenol orange assay, as previously described (22). Briefly, aliquots of HDL or LDL (100 µg) resuspended in 10 mM PBS were incubated at 37 C for 20 min with ferrous oxidation xylenol orange reagent (100 µM xylenol orange, 250 µM Fe2+, 25 mM H2SO4, and 4 mM butylated hydroxytoluene in 90% methanol). After 20 min of incubation at 37 C, samples were centrifuged at 3500 rpm for 15 min, and the absorbance of supernatant was evaluated at 560 nm. t-Butyl-hydroperoxide solution was used as the standard. The results are presented as nanomoles of lipid hydroperoxides for 100 µg protein of lipoproteins (nmol/100 µg).

HDL-PON activity assay

PON activity was assayed in HDL isolated from plasma of 31 control (C-HDL) and 12 obese females (O-HDL). An aliquot of HDL (100 µg) was resuspended in 5 mM Tris-HCl, pH 7.4, containing 0.15 M NaCl, 4 mM MgCl2, and 2 mM CaCl2. The reaction was initiated by adding the synthetic substrate paraoxon (dietyl-p-nitrophenyl phosphate; final concentration, 1 mM), and the increase in the absorbance was monitored at 412 nm. Enzyme activity was calculated from the rate of p-nitrophenol production (18 053 M/cm) and was expressed as units per milligram of HDL proteins; 1 U PON activity was defined as 1 nmol p-nitrophenol formed per minute under the above assay conditions (17, 18).

Statistics

All experiments using HDL or LDL from healthy and obese subjects (evaluation of enzymatic activity of paraoxonase and indexes of lipid peroxidation) were performed in duplicate and repeated three times. The results obtained in this study were shown as the mean ± SEM. For the comparison of normally distributed variables between groups, a t test was performed. For comparison of PON activity and lipid hydroperoxides, the nonparametric Mann-Whitney test was used. Differences were considered statistically significant at P < 0.05. Correlation coefficients were calculated by linear regression analysis. Multiple regression analysis was used to evaluate the correlations between HDL-PON and hydroperoxides, with leptin adjusted for BMI. P < 0.05 was considered statistically significant. (Microcal Origin 5.0 for Windows, OriginLab, Northampton, MA).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Blood biochemistry data

Table 1Go summarizes the biochemical data obtained from healthy and obese subjects. The mean serum TG level in obese patients was significantly higher than the control value (P < 0.001). Moreover, the levels of total cholesterol (TC) and LDL cholesterol (LDL-C) were significantly increased in obese subjects (P < 0.001), with an increase in LDL-C/HDL-C and TC/HDL-C ratios in obese subjects (P < 0.001). Thus, the obese subjects appeared to exhibit an atherogenic change in lipoprotein metabolism with respect to healthy subjects included in the study. The levels of leptin observed in plasma of obese subjects were significantly higher compared with controls (P < 0.001), in agreement with previous studies (23).

PON activity in HDL isolated from controls and obese subjects

The individual values of paraoxonase activity associated with HDL isolated from healthy subjects showed a large variability, in agreement with our previous studies (16, 17, 24). The HDL-PON activity values ranged from 118.3–990.6 U/mg; the mean value was 470.5 ± 53.1 U/mg (Fig. 1Go). Paraoxonase activity in HDL isolated from plasma of obese subjects ranged from 26.4–276.2 U/mg. The mean value (112.2 ± 23.2 U/mg) was about 4-fold lower than the control value (Fig. 1Go). The difference was significant (P < 0.001).



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  		FIG. 1. Values of paraoxonase activity in HDL isolated from plasma of control (C-HDL) and obese (O-HDL) subjects. Data are expressed as the mean ± SEM. *, P < 0.001 vs. PON activity in C-HDL.

 
A significant negative correlation was established between the HDL-PON activity and BMI in obese patients (r = –0.78; n = 12; P < 0.001), suggesting that subjects with higher BMI have a lower HDL-PON activity. Moreover, in our experimental conditions, HDL-PON activity in obese subjects was negatively correlated with the plasma levels of leptin (r = –0.90; n = 12; P < 0.001; Fig. 2Go). The above-mentioned correlations were significant after adjustment for BMI (P < 0.0001). No significant correlations were observed between HDL-PON activity and the levels of plasma lipids (TC, LDL-C, and HDL-C).



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  		FIG. 2. Correlation between the levels of HDL-PON activity and leptin in plasma of obese subjects (r = –0.90; P < 0.001; n = 12).

 
Levels of lipid hydroperoxides in HDL and LDL from controls and obese subjects

The levels of lipid hydroperoxides associated with HDL isolated from control subjects (C-HDL) ranged from 0.23–2.11 nmol/100 µg. In HDL from obese subjects (O-HDL) the levels of lipid hydroperoxides were between 1.70–6.05 nmol/100 µg. The mean levels of lipid hydroperoxides in healthy and obese subjects were 1.11 ± 0.099 and 3.9 ± 0.39 nmol/100 µg, respectively, and were significantly different (P < 0.001; Fig. 3Go).



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  		FIG. 3. Levels of lipid hydroperoxides in HDL ({square}) and LDL ({cjs2108}) isolated from plasma of control and obese subjects. Data are expressed as the mean ± SEM. *, P < 0.001 vs. lipid hydroperoxides in HDL from control subjects; **, P < 0.001 vs. levels of hydroperoxides in LDL from control subjects.

 
The analysis of the chemical composition of O-HDL showed significant changes with respect to C-HDL. A significant decrease in the percent content of proteins (50.6 ± 3.1% vs. 68.3 ± 2.4%; P < 0.001) and increases in TC (16.4 ± 0.8% vs. 7.5 ± 0.8%; P < 0.001) and TG (4.9 ± 0.2% vs. 2.5 ± 0.2%; P < 0.03) were observed in O-HDL compared with C-HDL. The levels of phospholipids were not significantly modified. The modifications in chemical composition reflect an increase in the cholesterol/protein ratio (0.324 ± 0.014 vs. 0.109 ± 0.016; P < 0.001) and in the TG/protein ratio in O-HDL compared with C-HDL (0.098 ± 0.001 vs. 0.036 ± 0.001; P < 0.001).

The levels of lipid hydroperoxides associated with LDL isolated from control subjects (C-LDL) ranged from 0.90–4.11 nmol/100 µg and from 2.64–10.6 nmol/100 µg in LDL from obese subjects (O-LDL). The mean levels were significantly different (6.2 ± 0.86 and 2.3 ± 0.75 nmol/100 µg protein, respectively; P < 0.001; Fig. 3Go).

A significant positive correlation was established between BMI and levels of lipid hydroperoxides associated with HDL (r = 0.89; n = 12; P < 0.001) or LDL (r = 0.76; n = 12; P < 0.006) from obese subjects.

Moreover, the levels of lipid hydroperoxides in HDL (r = 0.86; n = 12; P < 0.001) and LDL (r = 0.79; n = 12; P < 0.001) from obese subjects were positively correlated with the plasma levels of leptin.

Correlations

To investigate the relationship between HDL-PON activity and the susceptibility of HDL or LDL to oxidative stress, we studied the correlation between the enzyme activity and the levels of lipid hydroperoxides associated with lipoproteins in healthy and obese subjects. A negative correlation was found between the individual values of HDL-PON activity and the levels of lipid hydroperoxides associated with HDL from control (r = –0.94; n = 31; P < 0.001) and obese subjects (r = –0.96; n = 12; P < 0.001; Fig. 4Go). A negative correlation was also established between HDL-PON and levels of lipid hydroperoxides associated with LDL in the entire group of subjects (r = –0.75; n = 35; P < 0.001). These results demonstrate that lipoproteins in subjects with lower PON activity are more exposed to oxidative damage than those in subjects with higher PON activity.



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  		FIG. 4. A, Correlation between the levels of HDL-PON activity and lipid hydroperoxides in HDL from healthy subjects (r = –0.94; P < 0.001; n = 31). B, Correlation between the levels of HDL-PON activity and lipid hydroperoxides in HDL from obese subjects (r = –0.96; P < 0.001; n = 12).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Previous studies have shown modifications of the plasma levels of lipoproteins isolated from obese subjects and alterations in the activity of enzymes or proteins involved in lipoprotein metabolism, such as cholesteryl ester transfer protein (25), hepatic lipase (26), phospholipid transfer protein (27), and plasma lipoprotein lipase (26).

In the present study we demonstrated, for the first time, that the activity of the enzyme paraoxonase associated with HDL isolated from plasma of obese subjects (O-HDL) is significantly lower compared with that in healthy subjects (C-HDL). Moreover, our results showed modifications of lipid composition of O-HDL, with a decrease in the percent content of protein, an increase in the percent content of cholesterol and TG/protein and cholesterol/protein ratios. Higher levels of lipid hydroperoxides have been observed in HDL or LDL of obese subjects compared with controls. The compositional changes in HDL and the decrease in HDL-PON activity have been observed in obese subjects even in absence of modifications of HDL cholesterol. Other researchers have demonstrated that changes in PON activity may occur independently of modifications in HDL cholesterol (28).

The significant negative correlation found between HDL-PON activity and the levels of lipid hydroperoxides of HDL isolated from control and obese subjects demonstrates that subjects with lower PON activity are more exposed to oxidative damage than subjects with high PON activity, as shown in our previous studies in normolipemic and diabetic subjects (13, 24). Furthermore, a negative correlation has been established between HDL-PON activity and levels of lipid hydroperoxides associated with LDL. These results confirm the relationship between PON and its protective role against lipoprotein peroxidation, as demonstrated using PON purified from human plasma (14).

The significant correlations established between BMI of obese subjects and the levels of HDL lipid hydroperoxides (r = 0.89; n = 12; P < 0.001) or LDL lipid hydroperoxides (r = 0.76; n = 12; P < 0.006) confirm that obesity is associated with oxidative damage of lipoproteins, in agreement with previous studies (7, 8, 9, 10).

PON activity has been evaluated in several diseases associated with alterations of plasma lipid levels. Modifications of serum PON activity have been demonstrated in patients affected by diseases associated with alterations of lipoprotein metabolism, such as diabetes mellitus, familial hypercholesterolemia, and metabolic syndrome (24, 28, 29), even in the absence of alterations of PON genotypes.

Some hypotheses could be advanced to explain the decrease in PON activity associated with HDL from obese subjects compared with controls. Most plasma paraoxonase is bound to the surface of HDL. Sorenson et al. (30) have demonstrated that paraoxonase is a lipid-dependent enzyme; in fact, the conformation of paraoxonase within the hydrophobic environment of HDL is crucial for its activity. Phospholipids, especially those with long fatty acid chains, stabilize PON enzyme and are required for binding of PON at the lipoprotein surface (30). Furthermore, a preferential association between PON and apolipoprotein A-I and clusterin has been demonstrated, and it has been suggested that these apoproteins are also necessary for its stability and optimal activity (31).

Significant modifications of the chemical composition of HDL of obese subjects have been demonstrated in the present study. Lipid composition (percent content of lipids and/or products of lipid peroxidation) and lipid-apoprotein interactions modulate the structural organization and physico-chemical properties of lipoproteins (16, 32). Therefore, we suggest that the compositional modifications of HDL of obese subjects could affect the binding of paraoxonase to the surface of HDL, resulting in decreased enzyme activity.

The lower PON activity in HDL of obese patients could also be due to the presence of circulating inhibitors such as lipid peroxidation products. This hypothesis is supported by previous studies by Aviram et al. (33). Using purified PON, it has been demonstrated that oxidized LDL as well as oxidized palmitoyl arachidonoyl phosphatidylcholine, lysophosphatidylcholine, and oxidized cholesteryl arachidonate behave as inactivators of the enzyme activity (33).

In the present study plasma levels of leptin correlated positively with the levels of lipid hydroperoxides in LDL and HDL and negatively with PON activity in HDL of obese subjects. These results suggest a relationship between leptin and oxidative stress of lipoproteins in human obesity, in agreement with previous studies in vitro and in vivo. Leptin exerts atherogenic effects in cells in culture, and the molecular mechanisms involve the generation of free radicals (34, 35). Furthermore, using an animal model, Beltowsly et al. (36) demonstrated that hyperleptinemia induced by exogenous leptin administration markedly decreased plasma PON1 activity and induced oxidative stress. The relationship between leptin and oxidative damage has been confirmed recently by others (37, 38).

In conclusion, our study demonstrated a lower PON activity in HDL in obese patients and a relationship between HDL-PON and lipid hydroperoxides in HDL and LDL of control and obese subjects. An association between decreased HDL-associated paraoxonase activity and increased LDL oxidation and macrophage infiltration has been demonstrated in animal models (11).

These results confirm that obesity is associated with oxidative damage of lipoproteins, in agreement with previous studies. A higher susceptibility to lipid peroxidation of LDL related to a decrease in the level of antioxidant molecules such as ß-carotene and {alpha}-tocopherol has been previously observed in obese patients (7, 10).

Oxidative stress of lipoproteins is implicated in the development of coronary heart disease and atherosclerosis (39). In fact, oxidized HDL show impaired antiatherogenic activities, such as a decreased ability of HDL to promote the reverse cholesterol transport (40) and a decreased ability to protect lipoproteins and cell membranes from oxidative damage (15, 24, 33). Functional alterations of oxidized LDL have been widely demonstrated (41).

Whatever are the mechanisms involved in the modifications of lipid composition and paraoxonase activity in HDL of obese patients, the observed changes may play a role in the higher risk for atherosclerosis in the patients. This hypothesis is supported by previous studies suggesting that paraoxonase modulates the susceptibility of HDL to atherogenic modifications such as oxidation, glycation, and homocysteinylation (15, 16, 17, 33). Recent studies demonstrated that PON activity exerts an antiinflammatory action (42).

Watson et al. (14) suggested that the protective effect exerted by HDL against atherosclerosis may be dependent not on the absolute levels of HDL cholesterol in the blood, but, rather, on the abundance of HDL particles that contain protective enzymes (PON or platelet-activating factor-acetylhydrolase) relative to the concentration of oxidized LDL proximate to the arterial wall cells.


   Footnotes
 
First Published Online December 21, 2004

Abbreviations: BMI, Body mass index; -C, cholesterol; C-, control; HDL, high-density lipoprotein; HDL-PON, paraoxonase associated with HDL; LDL, low-density lipoprotein; O-, obese; TC, total cholesterol; TG, triglycerides.

Received March 31, 2004.

Accepted December 9, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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