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Article

Dietary Fat Modulates Serum Paraoxonase 1 Activity in Rats^{1 ,2}

Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107-2699 and ^* Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202

³To whom correspondence should be addressed.

	ABSTRACT

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We examined the effects of dietary fats with specific fatty acid compositions, on serum paraoxonase (PON1) activity in rats. Male adult Sprague-Dawley rats were divided randomly into four dietary groups. One group received the control diet [AIN 93M with soybean oil (5 g/100 g diet)], whereas the remaining three groups received the modified control diet supplemented with (15 g/100 g diet) triolein, tripalmitin or fish oil, respectively. After 20 d, blood was obtained after overnight food deprivation and PON1 activity was determined. Serum lipids and lipid components of lipoproteins were also determined. Serum PON1 activity [µmol/(L·min)] was significantly (P < 0.05) higher in triolein (98 ± 6) and lower in fish oil (41 ± 4), compared with tripalmitin-fed rats (63 ± 11). Serum PON1 activity in tripalmitin-fed rats was comparable to that of controls (67 ± 9). Serum PON1 activity correlated significantly with serum lecithin:cholesterol acyltransferase (LCAT) activity (r = 0.77, P < 0.001) and was transported in blood principally in association with the denser subfraction of HDL, very high density lipoprotein (VHDL; d > 1.15 kg/L). Serum PON1 activity correlated strongly with serum lipids as well as lipids of VLDL, HDL and its subfractions. Multiple linear regression analysis, however, showed a significant relationship of serum PON1 activity, principally with the phospholipids of VHDL (r = 0.47, P < 0.002). These data suggest that the modulation of serum PON1 activity by dietary fat may be mediated via the effect of the specific fatty acids on the synthesis and secretion of VHDL, the subfraction of HDL that transports the majority of PON1 in the blood.

KEY WORDS: • paraoxonase 1 • dietary fat • lipoproteins • rats

	INTRODUCTION

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Increased plasma levels of HDL offer protection against atherosclerosis and coronary heart disease (Gordon et al. 1981 , Tall 1990 ). HDL have been proposed to act in concert with the enzyme lecithin:cholesterol acyltransferase (LCAT)⁵ to remove excess cholesterol from arterial tissue and thus prevent atherosclerosis (Fielding and Fielding 1995 , Glomset 1979 ). Several lines of evidence suggest that oxidative modification of plasma LDL plays a major role in the pathogenesis of atherosclerosis (Fogelman et al. 1980 , Steinberg et al. 1989 ) and that HDL protect LDL from oxidation (Banka 1996 , Parthasarthy et al.1990 ). Although the mechanism of this protection is not clear, increasing attention is being focused on the potential antioxidant activity of serum enzymes associated with HDL. One of these enzymes, paraoxonase (PON1, aryldialkyl phosphatase, EC 3.1.8.1.) has been postulated to play an important role in protecting LDL and HDL from oxidation, thus preventing atherosclerosis (Aviram et al. 1998 , Mackness et al. 1991 , Watson et al. 1995 )

Serum PON1 is a calcium-dependent esterase, which detoxifies organophosphorous poisons (Furlong et al. 1993 , La Du et al. 1993 , Shih et al.1998 ) and lipid peroxides (Aviram et al. 1998 , Mackness et al. 1991 , Watson et al. 1995 ). It is a member of a multigene family with two other PON- like genes, designated PON2 and PON3, which show extensive sequence similarity with the serum PON1 gene. PON (or a related protein) is widely distributed in many human and mouse tissues, including the liver, brain, lung, heart, kidneys, small intestine and aorta (Ozols 1999 , Primo-Parma et al. 1996 ). Whether these tissues contribute to the PON1 activity found in the blood is not known at present. Because serum PON1 activity correlates well with hepatic PON1 mRNA levels, serum PON1 activity is believed to reflect primarily the expression of hepatic PON1 (Mackness et al.1996 , Shih et al. 1996 ).

At present, very little is known about the regulation of the expression (synthesis, secretion and degradation) of PON1. Although polymorphism accounts for a large degree of variation in enzyme activities in humans, a number of studies suggest that endocrine, diet or other environmental factors influence PON1 activity by as yet unknown mechanism(s) (Leview et al. 1997 , Mackness et al.1996 , Ruiz et al. 1995 ). Decreased levels of serum PON1 activity have been found in several chronic diseases, including insulin-dependent and noninsulin-dependent diabetes (Ikeda et al. 1998 , Mackness et al. 1991 , McElveen et al.1986 ). Those studies showed that enzyme mass in diabetics was similar to that in age-matched controls, whereas the enzyme activity was decreased significantly, suggesting the presence of a circulating inhibitor or an alteration of the enzyme-substrate interaction (Abbott et al. 1995 ). Serum PON1 levels are low in hypoalphalipoproteinemia (James et al. 1998 ) and in some studies, positive correlations between PON1 and the levels of serum cholesterol, triglycerides, HDL cholesterol and apolipoprotein A1 (apo-A1) have been observed (Hegele et al. 1995 , Nevin et al.1996 , Saha et al.1991 ). La Du et al. (1993) showed that apo-A1 is not a cofactor, but that the type and composition of phospholipids play a role in modulating PON1 activity in vitro.

Studies by Shih et al. (1996) suggested that genetic factors may also regulate serum PON1 activity. They showed that feeding a high fat, high cholesterol diet reduced serum PON1 activity in C57BL/6J, atherosclerosis-susceptible mice, but not in atherosclerosis-resistant C3H/HeJ mice. These changes are reflected in the levels of hepatic PON1 mRNA levels. Profiling of normal mouse plasma PON1 suggested that the enzyme was associated with larger HDL particles, but when mice were fed an atherogenic diet, PON1 activity shifted to smaller, lipid-poor HDL particles in the atherosclerosis-susceptible but not in the atherosclerosis-resistant mice.

In this study, we examined the effects of dietary fat on the activity and distribution of serum PON1 in Sprague-Dawley rats. In addition, we explored the relationship of PON1 with serum and lipoprotein lipids and with serum LCAT, another enzyme associated with serum HDL.

	MATERIALS AND METHODS

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Materials.

Semipurified diets (AIN 93M or modifications of it) were obtained from Dyets (Bethlehem, PA). Purified fats (triolein and tripalmitin) used to modify the diets were donated by ABITEC (Columbus, OH). Purified menhaden fish oil (RBU 648) was donated by Zapata Protein (USA), (Reedville, VA). All other chemicals were obtained from Sigma Chemical (St. Louis, MO).

Animals and diets.

Male Sprague-Dawley (Harlan Sprague Dawley, Indianapolis, IN) rats, weighing 200 g were used in this study. They were housed in groups of 4/cage in suspended stainless steel cages (40 x 24 x 18 cm), in a temperature-controlled room (20–23°C) with a 12-h light:dark cycle. All rats were fed a pelleted commercial nonpurified diet (Purina Rodent Chow, #500, TMI Nutrition, St. Louis, MO) for 1 wk after arrival. They were then assigned randomly to the experimental, semipurified powdered diets (n = 8/group). One group received the control diet (AIN-93M, Reeves et al.1993 ); the remaining three groups were fed the control diet without the fat, but supplemented (15 g/100 g diet) with triolein (>95% oleic acid, maximum peroxide value 0.84 meq/kg), tripalmitin (>95% palmitic acid, maximum peroxide value 0.48 meq/kg) or purified fish oil (menhaden, maximum peroxide value 10 meq/kg), respectively. The compositions of the purified, isocaloric diets are given in Table 1 . Additions to the control diet were made at the expense of sucrose and fat. Diets were prepared weekly by mechanical mixing and stored in a refrigerator (4°C) until used. Rats were given uninterrupted access to food and distilled water during the experimental period. Food intake was measured daily and rats were weighed at weekly intervals.

Isolation of serum lipoproteins.

Serum lipoproteins were isolated within 24 h of obtaining the serum. Aliquots of plasma were adjusted to a density of 1.3 kg/L using KBr and CaCl₂ (1 mmol/L). Plasma was then layered sequentially under NaCl-KBr salt solutions, and the lipoprotein fractions were separated by density gradient ultracentrifugation, essentially as described previously (Kudchodkar et al. 1988 , Terpstra et al. 1981 ). The following six fractions of different volumes and densities were collected for the determination of cholesterol, triglycerides, phospholipids and PON activity: fraction 1, d < 1.008 kg/L (VLDL, 2 mL); fraction 2, d = 1.008–1.059 kg/L (LDL, 4 mL); fraction 3, d = 1.059–1.086 kg/L (HDL₂, 1 mL); fraction 4, d = 1.086–1.152 kg/L (HDL₃, 1 mL); fraction 5, d = 1.152–1.179 kg/L [very high density lipoprotein (VHDL₁), 1 mL]; fraction 6, d = 1.179–1.23 kg/L (VHDL₂, 1 mL). The separation of subfractions is arbitrarily based on the density of the isolated fraction. The cholesterol values of fractions 3–6 agreed with high precision (>95%) with total HDL cholesterol values obtained by a CDC certified pathology laboratory. These fractions were therefore considered as subfractions of HDL. The lipoprotein fractions were stored at 4°C before analysis.

Determination of serum PON1 activity.

PON1 activity in the lipoprotein fractions was determined within 2 h after obtaining the lipoprotein fractions. Serum PON1 activity was determined by an adaptation of the spectrophotometric method of Furlong et al. (1989) to the microtiter plate assay method. Aliquots (10 µL) of diluted (1:5) serum or the lipoprotein fractions were placed in microtiter plate wells in triplicate; the reaction was initiated by adding 190 µL of the substrate (1.2 mmol/L paraoxon in 0.26 mmol/L Tris-HCl, pH 8.5, 25 mmol/L CaCl₂ and 0.5 mol/L NaCl). After mixing, the plate was read immediately at 405 nm to establish 0 time values. Readings were repeated at 2-min interval for 10 min. Nonenzymatic hydrolysis of paraoxon was subtracted from the total rate of hydrolysis. The enzyme activity was calculated from the linear portion of the plot (A₄₀₅/time) using the molar extinction coefficient for p-nitrophenol [17,100 (mol/L)^-1 · cm^-1]. One unit (U) of paraoxonase1 activity equals 1 µmol/(L · min) of p-nitrophenol released.

Determination of serum and lipoprotein lipids.

Total cholesterol (CHOL), triglycerides (TG) and phospholipids (PL) in serum and individual lipoprotein fractions were determined using enzymatic reagents (CHOL and TG, DMA, Arlington, TX; PL, Wako Pure Chemicals, Richmond, VA). The methods were adapted to microtiter plate assay method essentially as described by Shireman and Durieux (1993) . After appropriate dilutions, aliquots of serum or the lipoprotein fraction were placed in microtiter plate wells in triplicate and the total volume was adjusted to 50 µL using PBS; 150 µL of the desired reagent was added and after mixing, the plate was incubated at 37°C for 35 min. After cooling, the absorbance was read at 490 nm in a microtiter plate reader (Bio Rad, Richmond, CA). The concentration was calculated using calibration curves constructed with diluted standards. The performance of the assay was monitored routinely by analyzing control plasma in both the normal and abnormal cholesterol and triglycerides ranges.

Statistical analysis.

Values reported in the text and in tables represent means ± SD. One-way ANOVA followed by Bonferroni/Dunn tests was performed to determine whether any significant differences occurred among dietary groups fed 15 g fat/100 g diet. The control group was not included in the ANOVA. Correlational analyses were performed using a linear regression procedure. Where appropriate, multiple regression analysis was performed to determine independent relationships among the variables. A probability 0.05 was accepted as significant. All analyses were performed using the StatView 4.5 statistical software (Abacus Concepts, Berkley, CA).

	RESULTS

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Body weights and serum lipids.

Final body weights of rats fed tripalmitin were significantly lower than those of rats fed the triolein and fish oil diets as well as rats fed the control diet, likely due to the lower amount of food consumed by these rats. The relative liver weights, however, did not differ among the groups (Table 2 ).

Serum cholesterol and phospholipid distribution among lipoproteins.

The cholesterol concentration of all four lipoproteins was significantly lower in rats fed the fish oil diet compared with those fed the triolein and tripalmitin diets (Table 3 ). In rats fed the fish oil diet, the PL concentration of all four fractions was significantly lower than in those fed triolein. However, compared with rats fed tripalmitin, the PL concentration of VLDL and HDL in rats fed fish oil was significantly lower, whereas that of LDL and VHDL did not differ.

Serum PON1 activity and its distribution among lipoproteins.

Serum PON1 activity was significantly higher (P < 0.05) in rats fed triolein and lower in those fed fish oil compared with rats fed tripalmitin. Serum PON1 activity in rats fed the tripalmitin diet appeared similar to that of control rats (Fig. 1 ).

View larger version (25K): [in this window] [in a new window]   Figure 1. Serum paraoxonase 1 (PON1)activity in rats fed diets with different types of triglycerides. Serum PON1 activity was determined as described in Materials and Methods. Values are means ± SD, n = 8. Only rats fed 15 g fat/100 g diet are compared. Controls consumed 5 g fat/100 g diet. Means with no common letter differ significantly, P 0.05.

Because serum PON1 correlated significantly with all lipids in serum and lipoprotein fractions, multiple regression analysis was performed to determine independent relationships among the variables. Among serum lipids, PON1 correlated only with PL (r = 0.45, P < 0.002); among the lipoprotein fractions, the relationship was predominantly with the phospholipids of VHDL (r = 0.47, P < 0.002). Serum PON1 activity also correlated directly (r = 0.77, P < 0.0001) with serum LCAT activity, as determined by the exogenous substrate method (Fig. 2 ). A significant direct correlation was also observed between VLDL-TG and VHDL-PL (r = 0.61, P < 0.0003, Fig. 3 ).

View larger version (22K): [in this window] [in a new window]   Figure 2. Relationship between serum paraoxonase 1 and lecithin:cholesterol acyltransferase (LCAT) activities in rats (n = 32) fed the control diet and diets with different types of triglycerides. LCAT activity was measured by the exogenous substrate method.

View larger version (24K): [in this window] [in a new window]   Figure 3. Relationship between serum VLDL triglycerides and very high density lipoprotein (VHDL) phospholipids in rats (n = 32) fed the control diet and different types of triglycerides. The positive relationship between VLDL-triglycerides and VHDL-phospholipids indicates a metabolic relationship between these serum lipoproteins.

	DISCUSSION

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In blood, PON1 circulates in association with HDL (Kelso et al. 1984 , Mackness et al.1985 ). Our results are consistent with these observations. Our results further suggest that the bulk (80–85%) of PON1 activity is associated with the highest density subfraction, VHDL, which constitutes 10–12% of total HDL, on the basis of the cholesterol content. Surprisingly, little PON1 activity was detected in HDL₂. Approximately 10% of the activity was found associated with the lipoprotein-deficient serum. Previous studies have shown that HDL-associated LCAT, platelet-activating factor acetyl hydrolase and lipid transfer proteins are also associated predominantly with VHDL (Lacko et al. 1974 , Tselepis et al. 1995 ); as such, they may explain the observed relationship between PON1 and LCAT. Dietary fat did not significantly alter the distribution of PON1 among the lipoprotein fractions.

A number of studies in humans have revealed strong associations between serum PON1 activity and serum lipids, especially with serum TG and HDL cholesterol levels (Hegele et al. 1995 , Nevin et al. 1996 , Saha et al. 1991 ). Our data also show strong correlations between serum PON1 and serum and lipoprotein lipids. Multiple regression analyses, however, suggest that when all serum lipids were taken into account, serum PL was the only independent predictor of serum PON1 activity. Among all lipoprotein lipid components, only the phospholipids of VHDL were strongly related to serum PON1. There was no relationship between VLDL lipids and serum PON1 activity. These data suggest that the relationship of PON1 to VLDL lipids is a consequence of a metabolic relationship of VLDL and VHDL, the major carrier of PON1 in blood.

Serum HDL is highly heterogeneous with respect to particle size, lipid and apoprotein composition and function (Navab et al. 1998 , Nichols et al. 1981 , Tall 1990 ). Serum HDL originates from synthesis and secretion by the liver and via the catabolism of circulating VLDL (Eisenberg 1984 , Tall 1990 ). Nevin et al. (1996) suggested previously that plasma PON1 mass may depend on the number of carrier HDL particles. Similarly, Blatter-Garin et al. (1994) concluded that the differences in concentration of serum PON1 between the healthy subjects from Geneva and Manchester were largely a function of differences in apo-A1 concentrations between the two populations. They also suggested that the HDL particle number may be an important determinant of serum PON1 levels. Although our data are consistent with these suggestions, they also indicate that the availability of specific subfractions of HDL (VHDL) secreted by liver and not those generated during the catabolism of VLDL may modulate the transport of PON1 in blood. Smaller HDL particles formed during the catabolism of VLDL in plasma are converted to HDL₂ through the action of plasma LCAT (Eisenberg 1984 , Tall 1990 ). Failure to find any PON1 or LCAT in HDL₂ fractions suggests that VHDL, which transport PON1 and LCAT in the circulation, may not be converted to the larger HDL₂. This is supported by the fact that fibric acid derivatives, which increase HDL₂ and apo-A1 levels, have no effect on the levels of serum PON1 and LCAT (Durrington et al. 1998 ).

PON1 activity can be regulated without change in PON1 mass by the presence of inhibitors (Abbott et al. 1995 , James et al. 1998 ). For example, the presence of lipid peroxides in serum leads to the inhibition of serum PON1 and LCAT activity (McCall et al.1995 , Nishio and Watanabe 1997 ). Because fish oil contains fatty acids that are highly susceptible to peroxidation, the increased levels of serum lipid peroxides may have decreased the activity of PON1 observed in these studies. It should be noted that there were no significant differences in the levels of diene and triene conjugates in freshly obtained serum among the dietary groups (data not shown). Furthermore, the fish oil diet did not affect serum LCAT activity (Fungwe et al. 1997 ), indicating that decreased serum PON1 activity upon feeding fish oil is not likely to be due to increased levels of lipid peroxides in serum.

Earlier work from La Du’s laboratory indicated that the type as well as the fatty acid composition of phospholipids may affect plasma PON1 activity (Kuo and La Du 1995 , La Du et al. 1993 ). More recently, they demonstrated that PON1 associates with HDL through direct, N-terminal binding of phospholipids and that apo-A1 is necessary for the stabilization of PON1 activity (Sorenson et al. 1999 ). In our study, serum PON1 activity was correlated with phospholipids. Fish oil feeding, as has been shown earlier (Harris et al. 1983 , Haug and Hostmark 1987 ), decreased both serum triglycerides and phospholipids. On the other hand, although triolein and tripalmitin increased serum triglycerides to a similar extent, only triolein feeding led to an increase in phospholipids. Earlier, using primary cultures of rat hepatocytes, we reported that the production and secretion of apo-A1 is stimulated by oleic acid and inhibited by docosahexanoic acid, whereas palmitic acid had no effect (Fungwe et al. 1998 ). Thus, the changes in the secretion of apo-A1– and phospholipid-containing VHDL may be responsible for the changes in PON1 in rats fed fats with different fatty acid components.

In summary, our data show that the expression of serum PON1 can be regulated by diet. Furthermore, the modulation of serum PON1 activity by dietary fat may be mediated via the effect of fat on the synthesis and secretion of phospholipids (and apo-A1) within VHDL, which transport the majority of PON1 and LCAT molecules in the blood.

	ACKNOWLEDGMENTS

 
The authors acknowledge the expert technical assistance of Darla Rutledge.

	FOOTNOTES

 
¹ Presented in part at the 69th Scientific Sessions of the American Heart Association, November 1996, New Orleans, LA [Kudchodkar, B. J., Fungwe, T. V., Dory, L. & Lacko, A. G. (1997) Dietary fat modulates serum paraoxonase activity in rats. Circulation (suppl.) 94: I-222 (abs.)].

² Supported by National Institutes of Health grants K14-HL03389 to T.V.F. and R01-HL4551 to L.D., from the U. S. Public Health Service.

⁴ To whom reprint requests should be addressed.

⁵ Abbreviations used: apo, apolipoprotein; CHOL, cholesterol; LCAT, lecithin:cholesterol acyltransferase; PL, phospholipids; PON, paraoxonase; TG, triglyceride; VHDL, very high density lipoproteins.

Manuscript received November 22, 1999. Initial review completed January 5, 2000. Revision accepted May 31, 2000.

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