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© 2008 American Society for Nutrition J. Nutr. 138:30-35, January 2008

Nutrition and Disease

Docosahexaenoic Acid Supplementation Decreases Remnant-Like Particle-Cholesterol and Increases the (n-3) Index in Hypertriglyceridemic Men1–3,

Darshan S. Kelley4,*, David Siegel5, Madhuri Vemuri4, Gloria H. Chung6 and Bruce E. Mackey7

4 Western Human Nutrition Research Center, Agricultural Research Service, USDA and Department of Nutrition, University of California, Davis, CA 95616; 5 Veterans Affairs Northern California Health Care System, Sacramento, CA 95655, and Department of Internal Medicine, University of California Davis, CA 95616; 6 Martek Biosciences Corporation, Columbia, MD 21045; and 7 Western Regional Research Center, Agricultural Research Service, USDA, Albany, CA 94710

* To whom correspondence should be addressed. E-mail: darshan.kelley{at}ars.usda.gov.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
Plasma remnant-like particle-cholesterol (RLP-C) and the RBC (n-3) index are novel risk factors for cardiovascular disease. Effects of docosahexaenoic acid (DHA) supplementation on these risk factors in hypertriglyceridemic men have not been studied. We determined effects of DHA supplementation on concentrations of plasma RLP-C, the RBC (n-3) index, and associations between concentrations of plasma RLP-C with those of plasma lipids and fatty acids. Hypertriglyceridemic men aged 39–66 y, participated in a randomized, placebo-controlled, parallel study. They received no supplements for 8 d and then received either 7.5 g/d DHA oil (3 g DHA/d) or olive oil (placebo) for the last 90 d. Fasting blood samples were collected on study d –7, 0 (baseline), 45 (mid-intervention), 84, and 91 (end-intervention). DHA supplementation for 45 d decreased (P < 0.05) fasting RLP-C (36%) and increased plasma eicosapentaenoic acid (EPA):arachidonic acid (AA) (100%) and the RBC (n-3) index (109%). Continued supplementation with DHA between d 45 and 91 further increased the RBC (n-3) index (162%) and plasma EPA:AA (137%) compared with baseline values. RLP-C concentration was positively associated (P < 0.01) with the plasma concentrations of triacylglycerols (Kendall's correlation coefficient or r = 0.46), triacylglycerol:HDL cholesterol (HDL-C) (r = 0.44), total cholesterol:HDL-C (r = 0.26), Apo B (r = 0.22), C III (r = 0.41), and E (r = 0.17), and 18:1(n-9) (r = 0.32); it was negatively associated (P < 0.05) with plasma concentrations of DHA (r = –0.32), EPA (r = –0.25), HDL-C (r = –0.21), LDL cholesterol:Apo B (r = –0.30), and HDL-C:Apo A (r = –0.25). Supplementation with placebo oil did not alter any of the response variables tested. Decreased atherogenic RLP-C and increased cardio-protective (n-3) index may improve cardio-vascular health.


   Introduction
TOP
 ABSTRACT
 Introduction
Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
Cardiovascular disease (CVD)8 and stroke are the leading causes of mortality in the United States, accounting for >38% of all deaths (1). Elevated total cholesterol (total-C) and LDL cholesterol (LDL-C), total and small dense LDL particles, and triacylglycerols and low HDL cholesterol (HDL-C) are established independent risk factors for the development of CVD (1–4). Additional novel blood lipid markers used as risk factors for CVD include increased plasma concentration of remnant-like particle-cholesterol (RLP-C) or remnant lipoprotein cholesterol (5–8), decreased ratio between plasma eicosapentaenoic acid (EPA) and arachidonic acid (AA) (9,10), and decreased (n-3) index [sum of EPA and docosahexaenoic acid (DHA) as a percentage of total fatty acid content] of the RBC (11–14). RLP that are produced from VLDL are the major atherogenic lipoproteins that can be taken up by macrophages to produce foam cells without oxidative modification (15). An increase in the ratio between EPA and AA reduces the inflammatory response (9). An (n-3) index of <4% was associated with a 10-fold greater risk of sudden cardiac death compared with an (n-3) index of >7–8% (12). Thus, plasma RLP-C, the ratio between EPA and AA, and the RBC (n-3) index are important risk factors for evaluating the risk for CVD.

Diets rich in (n-3) fatty acids have been shown to be cardio-protective; these diets decreased inflammation, platelet aggregation, cardiac arrhythmias, triacylglycerols, number of total LDL, and small dense LDL particles and increased the (n-3) index, endothelial relaxation, and atherosclerotic plaque stability (12,16,17). Most of the earlier studies regarding the effects of long chain (n-3) PUFA on blood lipids were conducted with fish oils that contain a mixture of EPA and DHA. Recently a number of studies have been conducted with EPA and DHA individually (18–34). Results from studies with individual fatty acids show that EPA and DHA have similar effects on some of the lipid variables, but they are assimilated to different concentrations in tissues and have different effects on lipoprotein particle size, heart rate, and blood pressure (27–33). To the best of our knowledge, the effects of DHA supplementation on the plasma concentration of RLP-C and the ratio between EPA and AA, and the RBC (n-3) index in hypertriglyceridemic men (who are at increased risk for CVD) have not been previously published. Therefore, the main aim of this study was to examine the effects of DHA supplementation on the above 3 risk factors. We further determined the associations between concentrations of plasma RLP-C and those of plasma lipids and individual fatty acids.


   Subjects and Methods
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
Results
 Discussion
 LITERATURE CITED
 
    Study design and subjects. The study protocol was approved by the Institutional Review Boards of the University of California Davis and the Veterans Administration Medical Center, Mather, CA. It was a double blind, placebo-controlled, parallel study with 2 metabolic periods: baseline (first 8 d) and intervention (last 90 d). Group codes were revealed to the primary investigator and the statistician after sample collection from all subjects was completed, but the laboratory staff was unaware of group assignments until all analyses were completed. During the baseline period, subjects did not receive supplements, whereas during the intervention period, subjects' diets were supplemented with either placebo or DHA capsules. The DHA group received 7.5 g/d DHA oil (DHA 3.0 g/d and no EPA), which is produced in the microalga Crypthecodinium cohinii (Martek Biosciences). The placebo group received 7. 5 g/d olive oil. Subjects continued to consume their regular diets and were instructed not to change their usual diets and activity levels throughout the study. Prestudy physical characteristics, dietary intake, and fasting blood lipids for men who participated in the study have been reported (35). All selected subjects had fasting serum triacylglycerol concentrations of 150–400 mg/dL (1.70–4.53 mmol/L), total-C < 300 mg/dL (7.78 mmol/L), LDL-C < 220 mg/dL (5.69 mmol/L), and BMI between 22 and 35 kg/m2. Thirty-four men (17 in each group) completed the study, but for the analyses reported here, we had samples from only 14 subjects in each group. For the DHA group, all response variables were tested in all 14 subjects; in the placebo group, RLP-C concentrations were analyzed in 14 subjects, but the plasma and RBC fatty acids were analyzed only in 10 and 6 subjects, respectively, because these variables did not change. For the same reason, we did not analyze the RBC fatty acids composition in the placebo group at the middle of the study.

    Analysis of plasma lipids and plasma and RBC fatty acids. Blood samples were drawn from subjects after they had fasted for 12 h on d –7 and 0 (baseline), d 45 (mid-intervention), and d 84 and d 91 (end of intervention) into EDTA-containing tubes. Plasma and RBC samples were prepared, flushed with nitrogen, and stored at –70°C until lipid extraction. Total RBC lipids were extracted using the methods of Bligh and Dyer (36) and were methylated with 14% BF3/methanol at 100°C for 30 min (37). Butylated hydroxytoluene was added before saponification and all samples were purged with N2 throughout the process to minimize oxidation. Fatty acid methyl esters were analyzed by GLC using a Hewlett Packard 6890 equipped with a flame ionization detector. Plasma total lipids were extracted, transmethylated, and their fatty acids analyzed on an Agilent 6890 gas chromatograph as previously reported (20,38). We measured fatty acid concentrations for only the plasma and RBC samples obtained on study d 0, 45, and 91, which are expressed as a percentage of the total µg of fatty acids (wt%). Concentrations of lipids and lipoproteins were determined in plasma samples prepared on each of the 5 blood draw days as previously reported (35). Fasting plasma RLP-C concentrations were evaluated using the RLP-C Assay kit distributed by Polymedco (Cortlandt Manor). The RLP-C assay is a quantitative determination of cholesterol contained in remnant lipoproteins in the plasma after removal of the apoB-100 and apo-A1 lipoproteins.

    Statistical analysis. SAS version 9.1.3 (SAS Institute 2004, SAS OnlineDOC 9.1.3) was used for statistical analysis (39). The SAS proc mixed was used to fit repeated measures, mixed model with a first-order autoregressive covariance structure among the repeated measures (40). Diet, time, and the interaction were the fixed effects and subjects within diets were the random effects. Single degree of freedom contrasts were used to compare the baseline with the mid- and end-intervention means within diets using 1-tailed tests; P-values were Bonferroni corrected. Results shown are the means ± SEM. P < 0.05 (P < 0.016 after Bonferroni correction) is considered significant. Associations between concentrations of RLP-C with those of plasma lipids and individual fatty acids were determined by the Kendall's correlation coefficients (R) using the data from the DHA group only.


   Results
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
Discussion
 LITERATURE CITED
 
    Fatty acid composition of plasma and RBC lipids. At baseline, the plasma levels (wt%) of none of the fatty acids except 18:2(n-6), 20:3(n-6), and the sum of monounsaturated fatty acids (MUFA) differed between the 2 groups (Table 1). The plasma 18:2(n-6) wt% was significantly higher and those of 20:3(n-6) and the sum of MUFA were significantly lower in the DHA group compared with the placebo group. DHA supplementation significantly decreased the levels of 20:4(n-6), 22:4(n-6), and total (n-6) PUFA and significantly increased those of 18:0, 20:5(n-3), 22:6(n-3), and total (n-3) PUFA. The plasma DHA level was 255% greater than at baseline on both d 45 and 91, whereas that of EPA was 60 and 81% greater on those 2 d, respectively. Plasma concentrations of 18:1(n-9) and the sum of MUFA decreased (P = 0.002) with DHA supplementation, but the interaction between time and treatment was not significant (P = 0.056). DHA supplementation did not alter the wt% of 14:0, 16:0, 18:1(n-7), 18:2(n-6), 18:3(n-3), 20:3(n-6), 22:5(n-6), or total SFA. Continued supplementation between d 45 and 91 did not cause any further changes in the levels of any of the fatty acids other than a significant decrease in total (n-6) PUFA. Supplementation with the placebo oil did not alter plasma fatty acid composition at either time point (Table 1).


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  		TABLE 1 Effect of DHA supplementation on plasma fatty acid composition in hypertriglycerdemic men1

 
Presupplementation concentrations of the RBC fatty acids did not differ between the 2 groups except those of 18:2(n-6), and 20:4(n-6) (Table 2). Concentration of 18:2(n-6) was significantly higher and that of 20:4(n-6) was significantly lower in the DHA group compared with the corresponding values in the placebo group. DHA supplementation significantly decreased the wt% of 20:3(n-6), 20:4(n-6), 22:4(n-6), 22:5(n-6), 22:5(n-3), and total (n-6) PUFA; it significantly increased concentrations of 16:0, 20:5(n-3), 22:6(n-3), total (n-3) PUFA, and total SFA. DHA concentrations of RBC lipids were 75% greater than at baseline on d 45 and 179% greater on d 91 and those of EPA were 47 and 120% greater on those 2 d, respectively. Continued supplementation between d 45 and 91 further decreased levels of (n-6) PUFA, 20:4(n-6), 22:4(n-6), 22:5(n-6), and 22:5(n-3) and increased those of 20:5(n-3) and 22:6(n-3). Plasma concentrations of 14:0, 18:0, 18:1(n-9), 18:1(n-7), 18:2(n-6), 18:3(n-3), and the sum of MUFA in the DHA group and concentrations of all fatty acids in the placebo group did not change following fatty acid supplementation.


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  		TABLE 2 Effect of DHA supplementation on RBC fatty acid composition in hypertriglycerdemic men1

 
    (n-3) index, EPA:AA, and RLP-C. DHA supplementation for 45 d increased the RBC (n-3) index by 109% and by 162% for 91 d (Fig. 1A). During the same time periods, the ratio between plasma EPA and AA was 100 and 137% greater, respectively (Fig. 1B), and plasma RLP-C concentrations were 36 and 21% lower, respectively (Fig. 1C). Supplementation with the placebo oil did not alter the RBC (n-3) index, the ratio between plasma EPA and DHA, or the plasma RLP-C.


Figure 1
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  		FIGURE 1  Effect of DHA supplementation on the RBC (n-3) index (A), plasma EPA:AA (B), and RLP-C (C) in hypertriglyceridemic men. Values are means ± SEM, n = 14 (DHA) or for placebo, n = 6 (A), 10 (B), or 14 (C). Bars without a common letter differ, P < 0.05. For each variable, the time x treatment interaction was significant. The (n-3) index in the placebo group on d 45 was not analyzed, because it had not changed at the end of the study in this group.

 
    Associations between plasma RLP-C, lipids, and fatty acids. Plasma concentration of RLP-C showed the highest positive association with the plasma concentration of triacylglycerols, followed by the ratio of triacylglycerol:HDL-C, Apo CIII, 18:1(n-9), total-C:HDL-C, Apo B, and Apo E (Table 3). The greatest negative association of RLP-C concentration was with the plasma concentration of 22:6(n-3), followed by those of LDL-C: Apo B, 20:5(n-3), HDL-C: Apo A, and HDL-C. Plasma RLP-C concentration was not correlated with the concentrations of other plasma lipids and apo proteins (total-C, LDL-C, LDL-C:HDL-C, Apo A1, lipoprotein a) and fatty acids 18:0, 18:2(n-6), 18:3(n-6), 20:3(n-6), 20:4(n-6), 22:4(n-6), and 22:5(n-6) (not shown).


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  		TABLE 3 Kendall's correlation coefficients between plasma RLP-C and lipids or fatty acids in hypertriglyceridemic men taking DHA supplements1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
LITERATURE CITED
 
DHA supplementation significantly decreased plasma concentrations of RLP-C and increased the RBC (n-3) index and the ratio between plasma EPA and AA concentrations in hypertriglyceridemic men. The decreased plasma RLP-C was mediated through changes in both plasma lipids and fatty acid composition; some of the lipids and fatty acids were positively associated with RLP-C, whereas others were negatively associated (Table 3). We previously reported that DHA supplementation lowered fasting and postprandial triacylglycerols by 25–30% in these subjects (35). Because the RLP-C are produced from the triacylglycerol-rich chylomicrons and VLDL, the DHA-induced decreases in plasma RLP-C and triacylglycerols is in good agreement. Furthermore, blood triacylglycerol concentration showed the strongest positive association with RLP-C. Negative associations of RLP-C with the plasma concentrations of EPA and DHA were anticipated, because both these fatty acids lowered the plasma triacylglycerols, but the positive association between plasma concentrations of RLP-C and 18:1(n-9) (r = 0.32; P = 0.003; Table 3) was quite unexpected. DHA supplement provided 1.7 g/d and the placebo supplement provided 5.7 g/d of 18:1(n-9). Despite the small increase in the intake of 18:1(n-9) from the DHA oil, plasma concentrations of this fatty acid decreased following DHA supplementation (P = 0.002), although the day x treatment interaction was not significant (P = 0.058). The positive association between plasma concentrations of RLP-C and 18:1(n-9) may be due to the reduction of both these variables by DHA and not by the dietary intake of 18:1(n-9). It is generally believed that dietary 18:1(n-9) improves the lipid profile (41); this positive association between plasma 18:1(n-9) and RLP-C may be viewed as an adverse effect. The decreased plasma 18:1(n-9) in this case resulted from the altered tissue metabolism of this fatty acid and not from increased dietary intake.

Presupplement fatty acid concentrations of the RBC lipids (Table 2) were quite distinct from those of the plasma lipids. Concentration of 18:2(n-6) in plasma lipids was twice that in RBC lipids, whereas concentrations of 18:0, 20:4(n-6), 22:4(n-6), 22:5(n-3), and 22:6(n-3) in RBC lipids were 2 or more times those of the corresponding concentrations in plasma lipids (Tables 1 and 2). DHA supplementation significantly decreased plasma concentrations of 22:5(n-3) (DPA, an intermediate in the biosynthesis of DHA), but it did not change DPA concentration in plasma lipids (Table 1). The decreased RBC DPA was most likely due to inhibition of the elongase/desaturase enzymes involved in the synthesis of DHA by the end product (DHA) (42). An increase in EPA concentrations of both plasma and RBC lipids may be due to retro conversion of DHA to EPA (42). The maximum change in plasma fatty acid composition and RLP-C concentration was attained within the first 45 d of DHA supplementation, whereas changes in RBC fatty acid continued for the next 45 d. These associations suggest that plasma and not RBC fatty acid composition is a better predictor of plasma RLP-C.

Decreased plasma and RBC (n-6) PUFA and increased (n-3) PUFA after DHA supplementation in the hypertriglyceridemic subjects are similar to changes previously reported in other subject populations (20,23,32,42–44). The increase in the RBC (n-3) index by 162% in our study is much greater than the increase of 35% observed in another recent study with hypertriglyceridemic men and women who consumed a mixture of EPA and DHA (1 g/ d for 3 mo) from foods (45). This discrepancy is most likely due to the differences in the (n-3) fatty acids used, their dose, and source. The effect of DHA on plasma RLP-C concentration observed in our study is consistent with that reported with EPA in diabetic patients (46); our results differ from those of a study with patients having metabolic syndrome, in which fish oil supplementation did not alter the clearance of the stable isotope-labeled remnant-like emulsions in subjects with visceral obesity (47). This discrepancy may be due to the differences in the characteristics of the study subjects or the use of different methods (isotope ratio vs. immunological methods).

The decreased atherogenic RLP-C and increased cardio-protective (n-3) index caused by DHA may be clinically important in reducing the risk for CVD. Results previously published from this study showed that DHA decreased plasma triacylglycerols and number of total and small dense LDL particles and increased the concentration of HDL-C and the number of large LDL and HDL particles (35). Thus, the overall effect of DHA supplementation to improve cardiovascular health can be quite significant. Further studies are necessary to determine the minimum dose of DHA needed and its effectiveness in human subjects with other risk factors of CVD.


   ACKNOWLEDGMENTS
 
We thank Drs. Ellen Bonnel, Leslie Woodhouse, and their staffs in the coordination of the study and analysis of blood samples; we are grateful to Dr. Edward Nelson and Eileen Bailey, Martek Biosciences, for donating the DHA capsules and for RBC fatty acid analysis.


   FOOTNOTES
 
1 Supported by the USDA and grant number UL1 RR024146 from the National Center for Research Resources (NCRR), a component of the NIH and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp. Back

2 Reference to a company or product name does not imply approval or recommendation of the product by the USDA to the exclusion of others that may be suitable. Back

3 Author disclosures: D. S. Kelley, D. Siegel, M. Vemuri, and B. E. Mackey, no conflicts of interest. G. H. Chung is employed by Martek Corporation that donated DHA for this study. Back

8 Abbreviations used: AA, arachidonic acid; CVD, cardiovascular disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; MUFA, monounsaturated fatty acids; RLP-C, remnant-like particle-cholesterol; total-C, total cholesterol; wt%, percentage of the total µg of fatty acids. Back

Manuscript received 6 September 2007. Initial review completed 18 September 2007. Revision accepted 10 October 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 

1. AHA [monograph on the Internet]. Heart disease and stroke statistics 2007 update. AHA [cited 2007 25 Sept]. Available from:http://www.americanheart.org.

2. Schaefer EJ. Lipoproteins, nutrition, and heart disease. Am J Clin Nutr. 2002;75:191–212.[Abstract/Free Full Text]

3. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747–57.[Free Full Text]

4. Mora S, Szklo M, Otvos JD, Greenland P, Psaty BM, Goff DC Jr, O'Leary DH, Sadd MF, Tsai MY, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192:211–7.[Medline]

5. McNamara JR, Shah PK, Nakajima K, Cupples LE, Wilson PWF, Ordovas JM, Schaefer EJ. Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study. Atherosclerosis. 2001;154:229–36.[Medline]

6. Hodis HN, Mack WJ, Azen SP, Alaupovic P, Pogoda JM, LaBree L, Hemphill LC, Kramsch DM, Blankenhorn DH. Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin. Circulation. 1994;90:42–9.[Abstract/Free Full Text]

7. Nordestgaard BG, Tybjaerg-Hansen A. IDL, VLDL, chylomicrons and atherosclerosis. Eur J Epidemiol. 1992;8:92–8.[Medline]

8. Phillips NR, Waters D, Havel RJ. Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation. 1993;88:2762–70.[Abstract/Free Full Text]

9. Rupp H, Wagner D, Rupp T, Schulte LM, Maisch B. Risk stratification by the "EPA+DHA level" and the "EPA/AA ratio" focus on anti-inflammatory and antiarrhythmogenic effects of long-chain omega-3 fatty acids. Herz. 2004;29:673–85.[Medline]

10. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J. Blood levels of long-chain (n-3) fatty acids and the risk of sudden death. N Engl J Med. 2002;346:1113–8.[Abstract/Free Full Text]

11. Harris WS. Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor. Pharmacol Res. 2007;55:217–23.[Medline]

12. Harris WS, Von Schacky C. The Omega-3 Index: a new risk factor for death from coronary heart disease? Prev Med. 2004;39:212–20.[Medline]

13. von Schacky C. Omega-3 fatty acids and cardiovascular disease. Curr Opin Clin Nutr Metab Care. 2007;10:129–35.[Medline]

14. von Schacky C, Harris WS. Cardiovascular benefits of omega-3 fatty acids. Cardiovasc Res. 2007;73:310–5.[Medline]

15. Nakajima K, Nakano T, Tanaka A. The oxidative modification hypothesis of atherosclerosis: the comparison of atherogenic effects on oxidized LDL and remnant lipoproteins in plasma. Clin Chim Acta. 2006;367:36–47.[Medline]

16. Calder PC. (n-3) Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin Sci (Lond). 2004;107:1–11.[Medline]

17. Breslow JL. (n-3) Fatty acids and cardiovascular disease. Am J Clin Nutr. 2006;83:S1477–82.[Abstract/Free Full Text]

18. Buckley R, Shewring B, Turner R, Yaqoob P, Minihane AM. Circulating triacylglycerol and apoE levels in response to EPA and docosahexaenoic acid supplementation in adult human subjects. Br J Nutr. 2004;92:477–83.[Medline]

19. Conquer JA, Holub BJ. Supplementation with an algae source of docosahexaenoic acid increases ((n-3)) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects. J Nutr. 1996;126:3032–9.[Abstract/Free Full Text]

20. Nelson GJ, Schmidt PC, Bartolini GL, Kelley DS, Kyle D. The effect of dietary docosahexaenoic acid on plasma lipoproteins and tissue fatty acid composition in humans. Lipids. 1997;32:1137–46.[Medline]

21. Sanders TA, Gleason K, Griffin B, Miller GJ. Influence of an algal triacylglycerol containing docosahexaenoic acid (22: 6(n-3)) and docosapentaenoic acid (22: 5n-6) on cardiovascular risk factors in healthy men and women. Br J Nutr. 2006;95:525–31.[Medline]

22. Theobald HE, Chowienczyk PJ, Whittall R, Humphries SE, Sanders TA. LDL cholesterol-raising effect of low-dose docosahexaenoic acid in middle-aged men and women. Am J Clin Nutr. 2004;79:558–63.[Abstract/Free Full Text]

23. Geppert J, Kraft V, Demmelmair H, Koletzko B. Microalgal docosahexaenoic acid decreases plasma triacylglycerol in normolipidaemic vegetarians: a randomised trial. Br J Nutr. 2006;95:779–86.[Medline]

24. Maki KC, Van Elswyk ME, McCarthy D, Hess SP, Veith PE, Bell M, Subbaiah P, Davidson MH. Lipid responses to a dietary docosahexaenoic acid supplement in men and women with below average levels of high density lipoprotein cholesterol. J Am Coll Nutr. 2005;24:189–99.[Abstract/Free Full Text]

25. Agren JJ, Hanninen O, Julkunen A, Fogelholm L, Vidgren H, Schwab U, Pynnönen O, Uusitupa M. Fish diet, fish oil and docosahexaenoic acid rich oil lower fasting and postprandial plasma lipid levels. Eur J Clin Nutr. 1996;50:765–71.[Medline]

26. Wu WH, Lu SC, Wang TF, Jou HJ, Wang TA. Effects of docosahexaenoic acid supplementation on blood lipids, estrogen metabolism, and in vivo oxidative stress in postmenopausal vegetarian women. Eur J Clin Nutr. 2006;60:386–92.[Medline]

27. Grimsgaard S, Bonaa KH, Hansen JB, Nordoy A. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. Am J Clin Nutr. 1997;66:649–59.[Abstract/Free Full Text]

28. Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am J Clin Nutr. 2002;76:1007–15.[Abstract/Free Full Text]

29. Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Best JD, Beilin LJ. Docosahexaenoic acid but not eicosapentaenoic acid increases LDL particle size in treated hypertensive type 2 diabetic patients. Diabetes Care. 2003;26:253.[Free Full Text]

30. Mori TA, Burke V, Puddey IB, Watts GF, O'Neal DN, Best JD, Beilin LJ. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr. 2000;71:1085–94.[Abstract/Free Full Text]

31. Hansen JB, Grimsgaard S, Nilsen H, Nordoy A, Bonaa KH. Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on fatty acid absorption, incorporation into serum phospholipids and postprandial triglyceridemia. Lipids. 1998;33:131–8.[Medline]

32. Stark KD, Holub BJ. Differential eicosapentaenoic acid elevations and altered cardiovascular disease risk factor responses after supplementation with docosahexaenoic acid in postmenopausal women receiving and not receiving hormone replacement therapy. Am J Clin Nutr. 2004;79:765–73.[Abstract/Free Full Text]

33. Leigh-Firbank EC, Minihane AM, Leake DS, Wright JW, Murphy MC, Griffin BA, Williams CM. Eicosapentaenoic acid and docosahexaenoic acid from fish oils: differential associations with lipid responses. Br J Nutr. 2002;87:435–45.[Medline]

34. Cazzola R, Russo-Volpe S, Miles EA, Rees D, Banerjee T, Roynette CE, Wells SJ, Goua M, Wahle KW, et al. Age- and dose-dependent effects of an eicosapentaenoic acid-rich oil on cardiovascular risk factors in healthy male subjects. Atherosclerosis. 2007;193:159–67.[Medline]

35. Kelley DS, Siegel D, Vemuri M, Mackey BE. Docosahexaenoic acid supplementation improves fasting and postprandial lipid profiles in hypertriglyceridemic men. Am J Clin Nutr. 2007;86:324–33.[Abstract/Free Full Text]

36. Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–7.[Medline]

37. Morrison WR, Smith LM. Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride-methanol. J Lipid Res. 1964;5:600–8.[Abstract]

38. Kelley DS, Bartolini GL, Newman JW, Vemuri M, Mackey BE. Fatty acid composition of liver, adipose tissue, spleen, and heart of mice fed diets containing t10, c12-, and c9, t11-conjugated linoleic acid. Prostaglandins Leukot Essent Fatty Acids. 2006;74:331–8.[Medline]

39. SAS OnlineDoc. 9.13 ed. Cary (NC): SAS Institute; 2004.

40. Littell RC, Milliken GA, Stroup WW, Wolfinger RD. SAS system for mixed models. Cary (NC): SAS Institute; 1996.

41. Vemuri M, Kelley DS. Effect of dietary fatty acids on lipid metabolism. In: Chow CK, editor. Fatty acids in foods and their health implications. 3rd ed. New York: Marcel and Dekker; 2007. p. 589–610.

42. Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of (n-3) fatty acids in humans. Am J Clin Nutr. 2006;83:S1467–76.[Abstract/Free Full Text]

43. Vidgren HM, Agren JJ, Schwab U, Rissanen T, Hanninen O, Uusitupa MI. Incorporation of (n-3) fatty acids into plasma lipid fractions, and erythrocyte membranes and platelets during dietary supplementation with fish, fish oil, and docosahexaenoic acid-rich oil among healthy young men. Lipids. 1997;32:697–705.[Medline]

44. Marangoni F, Angeli MT, Colli S, Eligini S, Tremoli E, Sirtori CR, Galli C. Changes of (n-3) and n-6 fatty acids in plasma and circulating cells of normal subjects, after prolonged administration of 20:5 (EPA) and 22:6 (DHA) ethyl esters and prolonged washout. Biochim Biophys Acta. 1993;1210:55–62.[Medline]

45. Murphy KJ, Meyer BJ, Mori TA, Burke V, Mansour J, Patch CS, Tapsell LC, Noakes M, Clifton PA, et al. Impact of foods enriched with (n-3) long-chain polyunsaturated fatty acids on erythrocyte (n-3) levels and cardiovascular risk factors. Br J Nutr. 2007;97:749–57.[Medline]

46. Nakamura N, Hamazaki T, Kobayashi M, Ohta M, Okuda K. Effects of eicosapentaenoic acids on remnant-like particles, cholesterol concentrations and plasma fatty acid composition in patients with diabetes mellitus. In Vivo. 1998;12:311–4.[Medline]

47. Chan DC, Watts GF, Mori TA, Barrett PH, Redgrave TG, Beilin LJ. Randomized controlled trial of the effect of (n-3) fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity. Am J Clin Nutr. 2003;77:300–7.[Abstract/Free Full Text]




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D. S. Kelley, D. Siegel, D. M. Fedor, Y. Adkins, and B. E. Mackey
DHA Supplementation Decreases Serum C-Reactive Protein and Other Markers of Inflammation in Hypertriglyceridemic Men
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