© 1996 American Heart Association, Inc.
Articles |
Effects of Fish Oil on Oxidation Resistance of VLDL in Hypertriglyceridemic Patients
the Departments of General Internal Medicine (M.-F.H., A.H.M.S., A.J.G.H.B., E.J.G.S.), Cardiology (A. Van der L.), and Pediatrics (W.O.), University Hospital, and the Gaubius Laboratory/TNO-PG (W. van D., H.M.G.P.), Leiden, Netherlands.
Correspondence to A.H.M. Smelt, University Hospital Leiden, Department of General Internal Medicine, Bldg 1, B3-Q, PO Box 9600, 2300 RC Leiden, Netherlands.
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Abstract |
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In hypertriglyceridemic (HTG) patients the addition of fish oil to the diet causes a marked reduction in the concentration of triglyceride-rich lipoproteins in the serum. To investigate the effects of fish oil on the oxidation resistance of VLDL and LDL in HTG patients, nine male patients received 1 g/d fish oil (containing 55.7% n-3 polyunsaturated fatty acids [PUFAs] and 1 U
-tocopherol/g fish oil) for 6 weeks followed by 5 g/d fish oil for an additional 6 weeks. Cu2+-induced oxidation of VLDL and LDL was measured by continuous monitoring of conjugated dienes. Supplementation with 1 g/d fish oil caused hardly any changes in the n-3 PUFA content of lipoproteins or lipoprotein concentrations in serum. However, supplementation with 5 g/d fish oil resulted in a significant increase of n-3 PUFA content in VLDL (from 2.5% to 6.4% of total fatty acids) and LDL (from 3.2% to 6.4% of total fatty acids), decreases in serum triglyceride, VLDL triglyceride, and VLDL cholesterol concentrations of 54%, 56%, and 40%, respectively, and an increase in LDL cholesterol of 23%. The lag times of VLDL and LDL oxidation decreased from 197 to 140 minutes (-29%) and 101 to 86 minutes (-15%), respectively. At the end of the 5 g/d fish oil supplementation the lag times of VLDL and LDL oxidation were correlated with their respective n-3 PUFA content (r=-.67; P<.05 and r=-.79; P<.02, respectively). Before and at the end of supplementation with 5 g/d fish oil the lag times and propagation rates of VLDL oxidation also correlated with the total number of double bonds in all PUFAs of VLDL. We conclude that fish oil supplementation strongly reduces serum concentrations of total triglycerides, VLDL triglycerides, and VLDL cholesterol. However, in HTG patients fish oil supplementation increased the serum LDL cholesterol concentration and the susceptibility of VLDL and LDL to oxidation.
Key Words: fish oil • hypertriglyceridemia • LDL oxidation • omega-3 fatty acids • VLDL oxidation
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Introduction |
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The degree of unsaturation of FAs in phospholipids, TGs, and cholesterol esters renders these FAs more susceptible to oxidation. Incorporation of n-6 PUFAs in LDL increases the susceptibility of LDL to oxidation in vitro1 2 3 and may enhance oxidative modification and subsequent atherogenicity of LDL in vivo.4 5 6 The results of studies on the effects of n-3 PUFAs on LDL oxidation in humans are less consistent.7 8 9 However, recent studies clearly show that LDL has a diminished tolerance to in vitro oxidation10 11 and macrophage-mediated oxidation after incorporation of n-3 PUFAs.10
HTG patients who receive large doses of n-3 PUFAs from fish oil have substantially reduced plasma TG levels because of decreased TG synthesis in the liver.12 In untreated HTG patients plasma LDL levels are usually normal, in contrast to their elevated plasma VLDL levels, which may contribute to the development of atherosclerotic lesions in these patients.13 14 Reduction of plasma VLDL levels by fish oil supplementation may, therefore, be an attractive approach in the treatment of HTG patients. To date, no studies are available that address the susceptibility of VLDL from plasma of HTG patients to lipid peroxidation during n-3 PUFA administration. We therefore examined whether in HTG patients supplementation with fish oil, which is rich in n-3 PUFAs, affects the resistance of VLDL to oxidation.
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Methods |
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Patients
Nine unrelated male patients with type IV hyperlipoproteinemia were consecutively recruited from the outpatient lipid clinic of Leiden University Hospital. The diagnosis of the lipoprotein disorder was based on the mean of two fasting blood samples obtained 3 weeks apart and preceded by a dietary period of at least 9 weeks (American Heart Association Step I diet: <30% of total calories/d from fat [maximum 10% saturated fat] and cholesterol <300 mg/d).15 The diagnostic criteria for type IV hyperlipoproteinemia were serum TC
7 mmol/L, serum TGs 4 to 20 mmol/L, serum VLDL-C >1 mmol/L, and serum LDL-C <4.5 mmol/L. Additional exclusion criteria were familial type III hyperlipoproteinemia and secondary hyperlipoproteinemia resulting from renal, hepatic, or thyroid disease, diabetes mellitus, or alcohol consumption >40 g/d. None of the patients used any lipid-lowering drugs before the study. The study was approved by the medical ethics committee of our institution, and informed consent was obtained from each patient.
Study Design
Blood samples were obtained between 8 and 10 AM after a 12-hour fast. Two blood samples were collected 3 weeks apart at the start of the study, after which the patients received 1 g/d fish oil for 6 weeks followed by 5 g/d fish oil for an additional 6 weeks. During the study the patients were monitored by a dietician. They were instructed to maintain the Step I diet and were allowed one fish meal a week. At the end of each 6-week period, one blood sample was collected that was used for the laboratory measurements. Each fish oil capsule contained 0.5 g fish oil with 55.7% n-3 FAs (49.6% EPA, 9.1% DPA, and 41.3% DHA, with 0.5 U -tocopherol [equivalent to 0.5 mg vitamin E] as antioxidant; Aerofako). Compliance was monitored by count of returned capsules and was 93.5% and 98%, respectively, during supplementation with 1 and 5 g/d fish oil.
Lipid and Lipoprotein Measurements
Plasma was obtained by centrifugation of venous blood samples at 1000g for 10 minutes at room temperature within 2 hours of sampling. VLDL was separated from HDL and LDL in a table-top ultracentrifuge (Beckman) at 265 000g at 15°C for 15 hours. The top fraction containing VLDL and the bottom fraction containing LDL and HDL were assayed for cholesterol and TG concentrations. HDL-C was assayed after precipitation of LDL with phosphotungstic acid and MgCl2. The VLDL fraction was characterized by measurement of TC, free cholesterol, TG, phospholipid (Boehringer Mannheim) and protein (Pierce) concentrations. The concentration of esterified cholesterol was calculated as the difference between the TC and free cholesterol concentrations. The CE concentration was estimated as 1.67x the concentration of cholesterol in the CEs (both concentrations were expressed as milligrams per liter). The particle diameter (in nanometers) of VLDL was calculated by using the formula described by Redgrave and Carlson16 : 
in which V1 is the sum of the total volume of VLDL constituents 
and V2 is the sum of the apolar constituents 
where partial specific volumes17 are multiplied with weight fractions of the constituents). LDL particle size was determined by using electrophoresis as described by McNamara et al18 with 2% to 16% nondenaturing polyacrylamide gradient gels (Isolab). The migration distance of LDL is compared with that of two standards, thyroglobulin and ferritin. Under the assumption that the logarithm of the particle size is negatively correlated with the migration distance and given the particle sizes of thyroglobulin and ferritin (170 and 120 Å, respectively), the migration distance of the major band of LDL was used to calculate the LDL particle size.
The plasma FA composition of VLDL and LDL was assessed by using gas-liquid chromatography on a CP Sil88 column (Chrompack) after methylation of the FAs.19 The total number of double bonds in VLDL and LDL equaled the relative content of each particular FA in the lipoprotein times the number of double bonds in that particular FA summed over all FA species present in the lipoprotein and was expressed as percentage double bonds. Monounsaturated FAs were not included in the calculation as they are less susceptible to oxidation.
The vitamin E contents of plasma, VLDL, and LDL were assayed by using high-performance liquid chromatography with colorimetric detection.20
ApoE phenotype was determined by using isoelectric focusing of delipidated serum samples followed by immunoblotting with polyclonal anti-apoE antiserum.21 The apoE phenotypes were E4/3 (n=3), E3/3 (n=5), and E3/2 (n=1).
Preparation and Oxidation of VLDL and LDL
The fasting blood samples were placed on ice immediately after collection and centrifuged within 2 hours; sucrose was added to the plasma in a final concentration of 10% (wt/vol), and the plasma was stored at -80°C. Cu2+-induced oxidation of VLDL and LDL was measured by serial measurement of the conjugated dienes formed. A description of the procedure for the preparation and lipid peroxidation of LDL is available.22 23 The same procedure was applied to VLDL, with the exception that a lower protein concentration (0.03 mg/mL) was used in the Cu2+ incubation to obtain a less turbid solution. VLDL and LDL were isolated by ultracentrifugation using standard methods adapted from Terpstra et al24 to assure proper separation of VLDL and LDL. The samples were stored at -80°C and rapidly thawed at 37°C. The formation of conjugated dienes was measured by continuously monitoring the change in absorbance at 234 nm in a spectrophotometer at 37°C. The time-dependent absorption curve showed three distinct phases. A lag phase, during which absorption hardly increased, indicated that the lipoprotein was resistant to oxidation; this was followed by a propagation phase, during which absorbance at 234 nm rapidly increased to a maximum value. The propagation phase was indicative of the autocatalytic chain reaction of the peroxidation process. After reaching the maximum value the conjugated dienes slowly decreased by decomposition to form aldehydes (decomposition phase). A tangent was drawn to the steep part of the curve and extrapolated to the horizontal (time) axis. The interval between the addition of Cu2+ ions and the intersection point was defined as the lag time and was expressed in minutes. The propagation rate equaled the slope of the tangent of the propagation phase and was expressed as nanomoles of dienes formed per minute per milligram of VLDL or LDL protein. In some cases, if the slope of the lag phase deviated from baseline, lag time was obtained by drawing a perpendicular line from the intercept of the tangents of the lag and propagation phases to the time axis. The oxidation maximum was defined as the total quantity of conjugated dienes in nanomoles per milligram VLDL or LDL protein that was formed. Each VLDL and LDL preparation was oxidized in three consecutive oxidation runs on the same day, and the mean values for lag time and propagation rate were calculated. In each oxidation run, one reference VLDL and LDL, prepared from a reference plasma stored at -80°C, was used as a control. The interassay coefficients of variation for the reference lag times and propagation rates for LDL were 5.4% and 6.9%, respectively, and 3.6% and 8.1%, respectively, for VLDL. Oxidation runs with reference VLDL and LDL having deviations of lag time and a propagation rate >10% from the mean value obtained earlier were discarded. By using this highly standardized method, we found no differences in lag time and propagation rate between VLDL and LDL prepared from plasma frozen in liquid nitrogen and those from freshly collected plasma from the same subject. In addition, no differences in these parameters were found after storage of plasma at -80°C for as long as 6 months.
Results are expressed as means and their 95% CIs.25 All data analyses were performed by using SPSSWIN 5.01 (SPSS Inc).
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Results |
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The mean age of the nine participants was 49.6 years (median, 47 years; range, 39 to 63 years). Their mean body mass index was 27.3 kg/m2 (95% CI, 24.5 to 30.1 kg/m2) and remained constant during the study. Six patients were nonsmokers.
At baseline serum LDL-C concentration was normal, whereas serum VLDL-C and VLDL TG concentrations were severely elevated (Table 1
). Because serum lipid concentrations had not changed compared with baseline values after the 6-week consumption of 1 g/d fish oil, we present only the data obtained at baseline and at the end of 6 weeks of 5 g/d fish oil. The increase in EPA, DPA, and DHA content in plasma after 6 weeks of 5 g/d fish oil (Table 2) implies a good dietary compliance that was already evident from the capsule count.
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Total TG, VLDL TG, VLDL-C, and TC concentrations in serum decreased by 54%, 56%, 40%, and 15%, respectively, after 5 g/d fish oil. LDL-C and HDL-C concentrations in serum increased significantly by 23% and just not significantly by 14%, respectively, and the LDL-C/HDL-C ratio did not change significantly (Table 1
).
VLDL became enriched in CEs and protein and depleted of TGs (Table 3). The calculated diameter of the VLDL particles during fish oil supplementation was significantly smaller (-23%) than at baseline. The true particle size of VLDL may be reduced somewhat more than 23% due to enrichment of the VLDL particle by PUFAs. The LDL diameter, analyzed by using nondenaturing gradient gel electrophoresis, changed nonsignificantly from 24.3 nm (95% CI, 24.0 to 24.6 nm) to 24.4 nm (95% CI, 23.8 to 25.0 nm). Our reference value for the LDL particle size (from normolipidemic control plasma) was 25.8 nm (95% CI, 25.7 to 25.9 nm).
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After 6 weeks of 5 g/d fish oil the vitamin E contents of plasma and VLDL decreased by 23.6% and 26.4%, respectively (Table 4); the vitamin E content of LDL remained unchanged. After correction for VLDL TG concentration, the vitamin E content of VLDL appeared unchanged.
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Oxidation Resistance and FA Composition of VLDL and LDL
At the end of 6 weeks of 1 g/d fish oil, lag times and propagation rates of LDL and VLDL oxidation remained unchanged compared with baseline values. After 6 weeks of 5 g/d fish oil, the lag time of VLDL oxidation decreased by 29% (-57 minutes; 95% CI, -78 to -36 minutes), and the lag time of LDL oxidation decreased by 15% (-15 minutes; 95% CI, -21 to -8 minutes) (Fig 1). The propagation rates of VLDL and LDL oxidation changed nonsignificantly from 6.9 (95% CI, 4.1 to 9.8) to 8.4 (95% CI, 5.9 to 10.8) nmol dienes·mg protein-1·min-1 and from 7.7 (95% CI, 6.5 to 8.9) to 7.5 (95% CI, 6.6 to 8.5) nmol dienes·mg protein-1·min-1, respectively. The mean oxidation maximum for VLDL at baseline and at the end of the 6-week period of 5 g/d fish oil was unchanged: 997 (95% CI, 723 to 1272) and 973 (95% CI, 772 to 1174) nmol dienes/mg protein, respectively. This result indicates that the absolute quantity of oxidizable lipids, mainly TGs, per VLDL particle declined while the number of oxidizable groups (double bonds) increased due to fish oil supplementation. The mean oxidation maximum of LDL increased significantly after fish oil: from 318 (95% CI, 292 to 345) at baseline to 353 (95% CI, 325 to 382) nmol dienes/mg protein. Since the LDL particle size and the total amount of FAs in LDL (Table 2) remained unchanged, we may assume that the number of oxidizable groups in LDL increased by 11% after fish oil supplementation.
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At the end of 6 weeks of 5 g/d fish oil the relative n-3 PUFA, EPA, and DHA contents increased in VLDL as well as LDL, whereas the relative DPA content increased in VLDL only (Table 2). The lag times of VLDL and LDL oxidation were correlated with their respective n-3 PUFA content (r=-.67; P<.05 and r=-.79; P<.02, respectively). Moreover, the lag time of VLDL oxidation correlated with the total number of double bonds in PUFAs in VLDL at baseline and at the end of the 5-g/d fish oil period (Fig 2). The change in the VLDL lag time tended to correlate with the change in the total number of double bonds in VLDL (r=-.64; P=.07). The propagation rate of VLDL oxidation correlated with the total number of double bonds in VLDL at baseline and after 6 weeks of 5 g/d fish oil (Fig 2). The lag time of VLDL oxidation correlated with VLDL diameter at the end of the 6-week period (r=.82; P=.006) but not at baseline.
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) and after 6 weeks of 5 g/d fish oil (
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At baseline and after 6 weeks of 5 g/d fish oil the correlations between LDL lag time and the total number of double bonds in PUFAs did not reach statistical significance, but the propagation rate of LDL oxidation and the total number of double bonds did (r=.76, P=.018, and r=.72, P=.029, respectively) (Fig 3).
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Discussion |
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We estimated the effect of fish oil on the susceptibility to oxidation of VLDL and LDL that were isolated from the plasma of HTG patients. The lag times of VLDL and LDL oxidation were significantly shortened by 5 g/d fish oil, which indicates an increase in the susceptibility to oxidation of VLDL and LDL. This effect in LDL has been shown.7 8 26 The relative n-3 PUFA content of VLDL and LDL increased. The increased n-3 PUFA content most likely caused the increased susceptibility to oxidation, since the degree of unsaturation is one of the main determinants of the susceptibility of the lipoproteins to oxidation.27 Moreover, we showed that the lag time and propagation rate of VLDL oxidation were closely correlated with the abundance of double bonds in this lipoprotein. In addition, the reduction of the particle size of VLDL during fish oil supplementation may account for the increase in the susceptibility to oxidation, as was shown earlier for LDL.28 29 The particle size of LDL did not change, and we may therefore assume that the decrease in oxidation resistance of LDL after 6 weeks of 5 g/d fish oil can be attributed solely to the increased unsaturation of the FAs in these particles. The vitamin E content of VLDL was also reduced during fish oil supplementation, although it remained relatively unchanged after correction for the TG concentration of VLDL. Therefore, we assume that the absolute change of vitamin E content of VLDL did not contribute to the change in the oxidation resistance of VLDL. We found no change in vitamin E content during fish oil supplementation for LDL.
The effects of dietary supplementation with fish oil on the development of atherosclerosis have been studied in various animal models. Some groups report a protective effect,30 31 whereas others report either a deleterious effect32 33 or no effect at all.34 35 In animals oxidation of LDL as well as ß-VLDL enhances the uptake of these lipoproteins in macrophages36 and their accumulation in the aortic wall.37 The involvement of VLDL particles in the process of atherosclerosis has been demonstrated by Rapp et al,38 who have shown the presence of VLDL-sized and VLDL remnant–sized particles in human endarterectomy specimens. These particles also resemble their counterparts in plasma with regard to their lipid composition. Therefore, the increased susceptibility to oxidation of VLDL from HTG patients during fish oil supplementation may be important with regard to the potential atherogenicity of VLDL.
Several studies have addressed the changes in oxidative susceptibility of LDL due to n-3 PUFA supplementation. In five studies7 8 9 39 40 LDL oxidation was induced by copper ions, and results were presented as quantities of thiobarbituric acid–reactive substances or lipid peroxides in LDL. The results of these studies are not in agreement with each other; methodological differences may at least partially explain these discrepancies. In one study7 of HTG patients, supplementation with fish oil was reported to lead to higher susceptibility of LDL to copper-induced oxidation. However, the generally low serum levels of LDL in HTG patients may be of less importance for the development of atherosclerosis than their high serum levels of VLDL. The present study shows that the resistance to oxidation of VLDL is diminished by n-3 PUFA intake.
In conclusion, ingestion of 5 g/d fish oil for 6 weeks resulted in large reductions of plasma VLDL levels in HTG patients. However, fish oil supplementation increased LDL levels and increased the oxidative susceptibility of LDL and VLDL. These adverse effects raise concerns about the long term effects of n-3 PUFA supplementation in HTG patients.
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Acknowledgments |
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We thank Ton Vroom and Leny Hollaar for their excellent technical assistance. The help of Femke Van der Sman-de Beer is kindly acknowledged.
Received August 21, 1995; accepted March 12, 1996.
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References |
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L. Mabile, A. Piolot, L. Boulet, L.-J. Fortin, N. Doyle, C. Rodriguez, J. Davignon, D. Blache, and S. Lussier-Cacan Moderate intake of n-3 fatty acids is associated with stable erythrocyte resistance to oxidative stress in hypertriglyceridemic subjects Am. J. Clinical Nutrition, October 1, 2001; 74(4): 449 - 456. [Abstract] [Full Text] [PDF]
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R. B. Weinberg, B. S. VanderWerken, R. A. Anderson, J. E. Stegner, and M. J. Thomas Pro-Oxidant Effect of Vitamin E in Cigarette Smokers Consuming a High Polyunsaturated Fat Diet Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 1029 - 1033. [Abstract] [Full Text] [PDF]
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F. H. A. F. de Man, I. J. A. M. Jonkers, E. Schwedhelm, A. H. M. Smelt, W. Onkenhout, W. van Duyvenvoorde, R. Buytenhek, J. A. G. Leuven, R. Troost, A. van der Laarse, et al. Normal Oxidative Stress and Enhanced Lipoprotein Resistance to In Vitro Oxidation in Hypertriglyceridemia : Effects of Bezafibrate Therapy Arterioscler. Thromb. Vasc. Biol., November 1, 2000; 20(11): 2434 - 2440. [Abstract] [Full Text] [PDF]
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O. Johansen, I. Seljeflot, A. T. Hostmark, and H. Arnesen The Effect of Supplementation With Omega-3 Fatty Acids on Soluble Markers of Endothelial Function in Patients With Coronary Heart Disease Arterioscler. Thromb. Vasc. Biol., July 1, 1999; 19(7): 1681 - 1686. [Abstract] [Full Text] [PDF]
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Y. Abe, B. El-Masri, K. T. Kimball, H. Pownall, C. F. Reilly, K. Osmundsen, C. W. Smith, and C. M. Ballantyne Soluble Cell Adhesion Molecules in Hypertriglyceridemia and Potential Significance on Monocyte Adhesion Arterioscler. Thromb. Vasc. Biol., May 1, 1998; 18(5): 723 - 731. [Abstract] [Full Text] [PDF]
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L. P. L. van de Vijver, A. F. M. Kardinaal, W. van Duyvenvoorde, D. A. C. M. Kruijssen, D. E. Grobbee, G. van Poppel, and H. M. G. Princen LDL Oxidation and Extent of Coronary Atherosclerosis Arterioscler. Thromb. Vasc. Biol., February 1, 1998; 18(2): 193 - 199. [Abstract] [Full Text] [PDF]
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