![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Nutrition, University of Tennessee, Knoxville, TN 37996-1920
* To whom correspondence should be addressed. E-mail: jwhelan{at}utk.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT IntroductionLITERATURE CITED |
|---|
-linolenic acid (ALA). World-wide agencies and scientific organizations (i.e. FDA, AHA, International Society for the Study of Fatty Acids and Lipids, Institute of Medicine, WHO, etc.) have made similar dietary recommendations for (n-3) LCPUFA; however, due to concerns regarding the safety of consuming fish, alternative sources of (n-3) LCPUFA are being investigated. One such lipid is stearidonic acid (SDA), a naturally occurring (n-3) PUFA that may have similar biological properties to eicosapentaenoic acid (EPA), a major (n-3) PUFA in fish oil. Existing and novel plant sources rich in SDA are being cultivated and promoted as potential alternatives to marine-based (n-3) PUFA. This critical review provides a direct comparison of SDA with other dietary (n-3) PUFA under similar experimental conditions. The comparative results suggest that SDA shares many of the biological effects of (n-3) LCPUFA and functions most similarly to dietary EPA compared with ALA when consumed in a typical Western diet. Therefore, although SDA may not replace fish as a major dietary source of (n-3) LCPUFA, it could become a prominent surrogate for EPA in the commercial development of foods fortified with (n-3) PUFA.
|
Introduction |
|---|
|
TOPABSTRACTIntroductionLITERATURE CITED |
|---|
-linolenic acid [ALA; 18:3(n-3)] to eicosapentaenoic acid [EPA; 20:5(n-3)] and docosahexaenoic acid [DHA; 22:6(n-3)] (Fig. 1). Highly unsaturated (n-3) PUFA (fatty acids >3 double bonds), have been linked to reductions in cardiovascular disease (1), inflammation (2), cancer (3,4), and neurological disorders (5). As a highly unsaturated (n-3) PUFA whose unsaturation index is less than that of EPA and DHA, SDA potentially will possess improved stability characteristics, enhancing its commercial value. Similarly, if its biological effects were to mimic those of its downstream cousins, EPA and DHA, SDA could become a valuable tool in meeting current recommended intakes for LCPUFA (6). The purpose of this paper is to provide a direct comparison of the effects of dietary SDA compared with other fatty acids of the (n-3) family. There are many studies demonstrating positive effects of (n-3) PUFA on health promotion and disease prevention; however, this article uniquely reviews those studies that directly compare SDA to other (n-3) fatty acids.
|
In light of the reported health benefits associated with (n-3) LCPUFA, safety, shelf life and palatability issues with fish and fish oils, and over-fishing are of concern (16,17). As such, there is a need and desire to identify and develop alternative sources of (n-3) LCPUFA. Thus, SDA has been targeted as a potential biologically active surrogate for (n-3) LCPUFA, such as EPA, because of its relatively efficient conversion following consumption. However, current plant sources that naturally contain SDA have yet to be adapted for wide-scale production and the yields are low and variable, thus compromising economic competitiveness (18).
In response to a growing need, current technology has advanced to a point where common vegetable oils now contain SDA by expressing the appropriate desaturases required for its production in the parent plants. For example, conventional canola (Brassica napus) oil has been modified to contain as much as 23% of its fatty acid pool as SDA (18). This was accomplished by generating transgenic canola lines using an expression vector containing 
6 and 12 desaturases derived from the fungus Mortierella alpina and the 15 desaturase from canola or by generating an F1 hybrid by crossing a transgenic line containing the 6 and 12 desaturases with one containing high expression of 15 desaturase (18). Alternatively, Sato et al. (19) transfected the cDNA of 6 desaturase from borage (Borago officinalis) into soybean (Glycine max), generating a variety of transgenic soybean lines with levels of SDA between 0.6 and 4.2% of the fatty acid pool. These technological breakthroughs could be important given the fact that there now is a world-wide market for foods that are enriched and fortified with (n-3) LCPUFA (6).
The ability to generate safe and inexpensive oils containing relatively high levels of SDA using this type of technology has a number of advantages compared with more highly unsaturated fatty acids from fish. Generating a stable terrestrial crop whose oil is rich in a highly unsaturated (n-3) PUFA is sustainable and cost effective. Regarding structural benefits, oxidation potential is linearly proportional to the number of methylene-interrupted double bonds in a fatty acid (20). SDA has 4 double bonds compared with 5 and 6 for EPA and DHA, respectively. The lower unsaturation index of SDA greatly enhances stability and shelf life with a concomitant reduction in off flavors and odors that result from the generation of oxidative products.
According to the FAO of the United Nations, world captures fisheries production has declined since 1989, while the world aquaculture production has dramatically increased since 1970 (21). The major commercial use of fish oil is for aquaculture, where 87% of the world's fish oil is used in fish feed (22–24). Only 6% is used for human consumption and the rest is used in animal feed (6%) and industrial uses (1%) (22,23,25). Substitution of SDA for EPA/DHA could alleviate some of the commercial pressures on fish oil and problems associated with over-fishing, particularly if dietary SDA can be converted to EPA and/or DHA.
Metabolism of dietary SDA and other (n-3) PUFA
Synthesis.
SDA is formed directly from ALA (Fig. 1). ALA is the simplest (n-3) PUFA from which all other (n-3) PUFA are metabolically derived (Fig. 1) and when consumed, it is converted to SDA via 6 desaturase, the rate-limiting enzyme in the pathway. Dietary ALA can be converted to SDA and then EPA and DHA following consumption in response to inadequate tissue levels of DHA; however, the extent of this conversion appears to be minimal when supplemented to a typical Western diet (26–29). Similarly, when evaluating changes in plasma phospholipid SDA, EPA, and DHA levels, supplementation of ALA to the typical diet has little impact (26,30–33). In fact, the major metabolic fate of supplemented ALA appears to be oxidation (27,28), not conversion to or through SDA. When tissues become adequately enriched with DHA, feedback-inhibition of 6 desaturase occurs by inhibiting the rate of transcription via a mechanism involving PPAR (34).
Downstream metabolism of SDA.
Tissue phospholipids typically contain negligible levels of SDA. When SDA enters the metabolic pathway after the 6 desaturase step, it is rapidly converted to EPA. Following consumption of SDA, EPA levels in plasma, neutrophil, heart, and erythrocyte phospholipids increase up to 5 times the initial value (10,30,35,36), and thus SDA is considered a "pro-EPA" fatty acid. When compared with dietary EPA, dietary SDA is 
17–30% as effective in humans at raising EPA levels in RBC and in plasma phospholipids (30,37). Some studies suggest similar efficacy, although these studies used less controlled blends of oils containing SDA for comparison (36,38). Similar effects are observed in dogs supplemented with SDA vs. EPA, with 20–26% efficiency of incorporation of EPA into erythrocytes by dietary SDA as compared with dietary EPA (Fig. 2) (35). When modifying tissue DHA composition in humans consuming a typical Western diet, none of the precursor (n-3) PUFA (i.e. ALA, SDA, or EPA) have an effect, indicating dietary supplementation of preformed DHA is the only way to effectively modify tissue levels of DHA (10,26,30,32,33).
|
Physiological effects of SDA vs. other (n-3) PUFA. A number of review articles have established a relationship between (n-3) PUFA and the reduction of risk for cardiovascular disease (43–48). These effects appear to be clearer for the (n-3) LCPUFA than for ALA. A number of mechanisms have been proposed, i.e. their effects on fibrinolysis and reductions in circulating triacylglycerols levels (49), platelet activation (50), coagulation (49), and the expression of vascular adhesion molecules (47,51). However, these beneficial effects may not be dependent upon (n-3) fats containing both EPA and DHA. The Japanese EPA Lipid Study, with 18,640 subjects consuming background diets relatively rich in EPA and DHA, demonstrated that long-term supplementation of pure EPA significantly reduced major coronary events in the absence of supplemental DHA in patients with a history of coronary heart disease (48). Therefore, as a metabolic surrogate for EPA, SDA has the potential to augment health promotion and mimic disease reduction observed with (n-3) LCPUFA.
Plasma lipids. Dietary EPA and DHA have distinct effects on plasma lipids with beneficial outcomes for cardiovascular diseases not shared by ALA (45,52). In hyperlipidemics, (n-3) LCPUFA are potently hypotriglyceridemic, and in general, raise HDL and LDL cholesterol levels (if at all), but LDL cholesterol is in a form that is larger and less atherogenic (53). Only 3 clinical trials involving SDA and plasma lipids have been reported in the literature (10,30,37). When mildly hypertriglyceridemic subjects were provided SDA in the form of echium oil (1.88 g/d SDA), serum triacylglycerol levels were significantly reduced by 22% with no other reported changes in the lipid profile, but this was only a preliminary open-labeled study without a parallel control group and the results are difficult to interpret (10). In contrast, when normolipidemics were provided SDA (0.75–3.7 g/d) there were no significant changes in triacylglycerols or other plasma lipids (total, HDL or LDL cholesterol) compared with groups supplemented with ALA or EPA (37,54).
Omega-3 index. Recently, a new clinical biomarker for cardiovascular disease has been proposed called the omega-3 index, the sum of EPA+DHA in erythrocyte membranes expressed as a percentage of total erythrocyte fatty acids (55). The omega-3 index correlates very well with risk for a variety of cardiovascular disease endpoints and is as good or better than other traditional circulating risk factors (i.e. C-reactive protein, LDL cholesterol, total cholesterol:HDL cholesterol ratio, etc.) for relative risk of sudden cardiac death (33). In a side-by-side experiment evaluating the impact of supplemental ALA, SDA, or EPA on changes to the omega-3 index, SDA and EPA were more effective than ALA (P = 0.0005 and P = 0.0001, respectively), which had no effect (33). Relative to each other, SDA was 17% as effective as EPA.
Inflammation and inflammatory disorders. (n-3) LCPUFA have been reported to favorably affect inflammation and inflammatory disorders (2). They have been shown to decrease the production of cytokines, adhesion molecules, reactive oxygen species, and proinflammatory eicosanoids (2). Furthermore, they appear to be important in the resolution of the inflammatory response via the formation of the newly discovered E and D series resolvins (56,57).
Only a few studies have directly compared SDA with other (n-3) PUFA on indices of inflammation. When SDA, ALA, or EPA were provided to healthy subjects, ex vivo inflammatory cytokine production [interleukin (IL)-1β and tumor necrosis factor-] in whole blood or peripheral blood monocytes were unaffected by diet (30,38). SDA-containing echium oil or EPA supplementation did not affect phagocytosis by neutrophils and monocytes, lymphocyte proliferation, and delayed-type hypersensitivity (38). The only variables that were affected by the supplemented oils were the Ig. SDA-containing echium oil and EPA decreased IgE levels, whereas Ig-
G2 concentrations increased only with EPA supplementation (38). The results of this study demonstrated that although dietary SDA significantly increased leukocyte EPA levels (125%), it did not affect indices of immune function at a dose of 1 g/d and these overall limited effects mimicked, for the most part, those observed with EPA+DHA. On the other hand, supplementation of SDA (0.13 g/d) to subjects in the form of blackcurrant seed oil (6.3 g/d) increased lymphocyte proliferation and delayed-type hypersensitivity, with no changes in IL-1β and IL-2 production (in stimulated peripheral blood monocytes) (58). It is, however, unclear whether these beneficial effects are due to the SDA. When purified ALA, SDA, or EPA were fed to Balb/c mice at a dose of 1% by weight, tumor necrosis factor production from stimulated whole blood (reduction) or production by splenocytes (no effect) were similar regardless of the type of (n-3) PUFA provided (59). Using a mouse ear inflammation model, SDA and EPA demonstrated similar efficacy (reductions in edema, erythema, and blood flow) (9). In summary, the effects of SDA on inflammatory mediators mimic those of EPA, but more studies investigating the comparative effects of SDA and other (n-3) LCPUFA are needed.
Cancers. (n-3) LCPUFA have been shown to have some beneficial effects on cancer, either by reducing risk, inhibiting tumor growth, or enhancing tumor sensitivity to radiation or chemotherapy or palliatively by reducing the symptoms of unwanted side effects to these treatments (60,61). These effects may be related to their ability to inhibit eicosanoid formation as indicated by similar effects with cyclooxygenase inhibitors (62–64).
When dietary SDA was tested side-by-side against ALA, EPA, and DHA in an experimental animal model of colorectal cancer that spontaneously develops intestinal tumors, SDA reduced tumor number by >46% (Fig. 3) (41). This effect was as good as or better than dietary EPA or DHA. Dietary ALA did not affect lowering tumor number, suggesting the importance of (n-3) PUFA with 4 or more double bonds. In another study, a xenograft model for the recurrence of prostate cancer, the proliferation index of Los Angeles Prostate Cancer-4 (LAPC-4) cells was lower and the apoptotic index higher in recurring prostate tumors with SDA-treated animals (compared with a linoleic acid control) and SDA appeared to have a protective effect because of a fewer number of animals with recurrent tumors (65). These results are very promising, because dietary (n-3) LCPUFA, but not ALA, appear to reduce risk of metastatic prostate cancer (66). Similar results were observed in NIH-3T3 cells, where cell proliferation was significantly inhibited by the addition of SDA, but not by ALA (67). In contrast, using MDA-MB-231 cells in culture, an estrogen-independent human breast cancer cell line, the effects of SDA and ALA were not much different (68), possibly due to their inability to effectively reduce prostaglandin E2 (PGE2) formation, a known tumor promoter (62). However, the expression of cyclooxygenase-2 protein was significantly reduced in those cells treated by SDA, but not ALA (68). The cyclooxygenase-2 pathway is important in maintaining tumor integrity, enhancing proliferation and angiogenesis, and inhibiting apoptosis (62,69). These results are encouraging, because a number of studies have reported inverse relationships of dietary (n-3) LCPUFA and cancer risk in humans (3,4,70,71) and these effects were linked to inhibition of the arachidonic acid cascade (3); however, a number of systematic reviews did not show efficacy with (n-3) PUFA on incidence (72,73).
|
In ApcMin/+ mice fed ethyl esters of various (n-3) PUFA (ALA, SDA, EPA, and DHA at 3% by weight) for 7 wk on a background diet already containing human equivalent doses of ALA (0.7% by energy), intestinal prostaglandin formation (PGE2 and 6-keto-prostaglandin F1) was significantly lower (50%) in all groups compared with controls and these changes coincided with reduced tissue arachidonic acid content (41). SDA and EPA were the dietary fatty acids associated with the lowest prostaglandin levels. Similarly, Ishihara et al. (59) fed Balb/c mice diets containing ALA, SDA, or EPA (1% by weight) and measured PGE formation in stimulated whole blood or isolated splenocytes. PGE levels were equivalently reduced by 50% irrespective of the (n-3) PUFA provided.
The impact of SDA compared with other (n-3) PUFA on eicosanoid formation in cultured cells is difficult to interpret because of a lack of physiological relevance. When MDA-MB-231 human mammary tumor cells were treated with ALA or SDA at levels of 50 or 200 µmol/L, PGE2 levels did not change, results consistent with minimal changes in arachidonic acid content (68). Nevertheless, the addition of fatty acids to cells in culture has a number of problems. Most cells grown in vitro are typically low in (n-3) PUFA compared with their in situ counterparts. The levels of exogenous fatty acids used are typically considerably greater than physiological levels (5 µmol/L) and when nonphysiologic levels are used, there is redirection of exogenous fatty acids into a dramatically expanded triglyceride pool, the impact of which is unclear but could be a contributing factor to observed results (67).
Platelet function. In a study investigating the exogenous treatments of SDA on platelet aggregation (human), SDA (0.5–4.0 µmol/L) inhibited platelet aggregation at a dose of 2 µmol/L in the presence of collagen or arachidonic acid when added simultaneously, but the presence of U46619, an analogue of prostaglandin H2, did not differ (75). However, if platelets were preincubated with SDA or EPA in a comparison experiment, platelet aggregation was significantly impaired with either fatty acid regardless of the type of agonist used (collagen, arachidonic acid, U46619, or thrombin). In humans fed SDA, ALA, or EPA, function was not affected in any group (33). These results suggest that SDA and EPA do not differ in platelet function modification.
In summary, (n-3) LCPUFA appear to have the greatest efficacy (compared with ALA) in prevention and/or treatment of various chronic and acute diseases; however, we are faced with the following dilemma. Although the scientific community recognizes the health promotion and disease prevention benefits of (n-3) LCPUFA, convincing people to consume fish products is challenging because of the negative aspects (real or imaginary) associated with the consumption of fish and fish oils, i.e. concerns regarding safety, shelf life (oxidizability), and palatability ("fishy" smell and taste). Furthermore, ALA is poorly converted to the biologically active EPA and DHA. This creates additional problems for many vegetarians who avoid animal products (76). Increasing development and commercialization of nontraditional foods containing (n-3) LCPUFA underscore the public's desire to include these healthy nutrients in their daily dietary regimens (6). Generating plant sources rich in LCPUFA is another mechanism to help achieve dietary recommendations for (n-3) LCPUFA without having to consume seafood.
SDA favorably compares with dietary EPA in side-by-side experiments in a limited number of studies. Similar effects were observed with the inhibition of tumorigenesis in a rodent model of colorectal cancer, in ex vivo platelet aggregation studies, changes in tissue arachidonic acid content and eicosanoid formation, similarities on biomarkers of inflammation and modification of plasma lipid profiles. However, compared with EPA, it was significantly less effective in modifying tissue EPA levels and the omega-3 index. Currently, the data justifying the use of SDA as a surrogate for EPA is promising, but not all the effects were significant. SDA appeared to be as safe as other (n-3) LCPUFA. Only 1 paper has reported self-reported adverse events, but this was with echium oil and these adverse events were no different from what was reported in the control and EPA groups (77). These data suggest that SDA may be a surrogate for EPA for health promotion and disease prevention, but more comparative studies are needed to more confidently establish dose-response parameters.
|
FOOTNOTES |
|---|
2 Author disclosures: J. Whelan has received (1998) research funding from Monsanto Company (St. Louis, Mo) and has consulted with a number of companies, including Monsanto, on the biological effects of dietary (n-6) and (n-3) PUFA.
3 Abbreviations used: ALA, -linolenic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IL, interleukin; LCPUFA, long-chain PUFA; PGE2, prostaglandin E2; SDA, stearidonic acid.
Manuscript received 10 June 2008. Initial review completed 11 July 2008. Revision accepted 15 October 2008.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTIntroductionLITERATURE CITED |
|---|
1. Wang C, Chung M, Lichtenstein A, Balk E, Kupelnick B, DeVine D, Lawrence A, Lau J. Effects of omega-3 fatty acids on cardiovascular disease. Summary, Evidence Report/Technical Assessment No. 94. Rockville (MD): Agency for Healthcare Research and Quality; 2004. p. 1–8.
2. Calder PC. n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006;83:S1505–19.
3. Hall MN, Campos H, Li H, Sesso HD, Stampfer MJ, Willett WC, Ma J. Blood levels of long-chain polyunsaturated fatty acids, aspirin, and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:314–21.
4. Fernandez E, Chatenoud L, La VC, Negri E, Franceschi S. Fish consumption and cancer risk. Am J Clin Nutr. 1999;70:85–90.
5. Hibbeln JR, Nieminen LR, Blasbalg TL, Riggs JA, Lands WE. Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity. Am J Clin Nutr. 2006;83:S1483–93.
6. Whelan J, Rust C. Innovative dietary sources of n-3 fatty acids. Annu Rev Nutr. 2006;26:75–103.[Medline]
7. Passi S, Cataudella S, Di MP, De SF, Rastrelli L. Fatty acid composition and antioxidant levels in muscle tissue of different Mediterranean marine species of fish and shellfish. J Agric Food Chem. 2002;50:7314–22.[Medline]
8. Frankel EN, Satue-Gracia T, Meyer AS, German JB. Oxidative stability of fish and algae oils containing long-chain polyunsaturated fatty acids in bulk and in oil-in-water emulsions. J Agric Food Chem. 2002;50:2094–9.[Medline]
9. Khan A, Cho J-Y, Lee M-C, Kang J-Y, Park NG, Fujii H, Hong Y-K. Isolation of two anti-inflammatory and one pro-inflammatory polyunsaturated fatty acids from the brown seaweed Undaria pinnatifida. J Agric Food Chem. 2007;55:6984–8.[Medline]
10. Surette ME, Edens M, Chilton FH, Tramposch KM. Dietary echium oil increases plasma and neutrophil long-chain (n-3) fatty acids and lowers serum triacylglycerols in hypertriglyceridemic humans. J Nutr. 2004;134:1406–11.
11. Guil-Guerrero JL, Gomez-Mercado F, Rodriguez-Garcia I, Campra-Madrid P, Garcia-Maroto F. Occurrence and characterization of oils rich in gamma-linolenic acid (III): the taxonomical value of the fatty acids in Echium (Boraginaceae). Phytochemistry. 2001;58:117–20.[Medline]
12. Guil-Guerrero JL, Gomez-Mercado F, Garcia-Maroto F, Campra-Madrid P. Occurrence and characterization of oils rich in gamma-linolenic acid. Part I: echium seeds from Macaronesia. Phytochemistry. 2000;53:451–6.[Medline]
13. Del Castillo ML, Dobson G, Brennan R, Gordon S. Fatty acid content and juice characteristics in black currant (Ribes nigrum L.) genotypes. J Agric Food Chem. 2004;52:948–52.[Medline]
14. Johansson A, Laasko P, Kallio H. Characterization of seeds of wild, edible Finnish berries. Z Lebensm-Unters Forsch A. 1997;204:300–7.
15. Sewon P, Tyystjarvi E. Stearidonic and gamma-linolenic acid contents of common borage leaves. Phytochemistry. 1993;33:1029–32.
16. McIntyre PB, Jones LE, Flecker AS, Vanni MJ. Fish extinctions alter nutrient recycling in tropical freshwaters. Proc Natl Acad Sci USA. 2007;104:4461–6.
17. Taylor BW, Flecker AS, Hall RO. Loss of a harvested fish species disrupts carbon flow in a diverse tropical river. Science. 2006;313:833–6.
18. Ursin VM. Modification of plant lipids for human health: development of functional land-based omega-3 fatty acids. J Nutr. 2003;133:4271–4.
19. Sato S, Xing A, Ye X, Sato S, Xing A, Ye X, Schweiger B, Kinney A, Graef G, et al. Production of {gamma}-linolenic acid and stearidonic acid in seeds of marker-free transgenic soybean. Crop Sci. 2004;44:646–52.
20. Frankel EN. Lipid oxidation. Bridgewater (UK): Oily Press; 2005.
21. Vannuccini S. Overview of fish production, utilization, consumptiuon and trade. Rome: FAO of the United Nations; 2003.
22. Halseth V. Current aquafeed constraints and outlooks. Presented at the Global Outlook for Aquaculture Leadership Conference in Madrid, Spain. St. Louis: Global Aquaculture Alliance; 2007.
23. Pike IH. Eco-efficiency in aquaculture: global catch of wild fish used in aquaculture. Int Aquafeed. 2005;8:38–40.
24. FAO of the United Nations [Fisheries and Aquatic Department Web site]; 2008. Available at: http://www.globefish.org/dynamisk.php4?id=2759.
25. Tacon AGJ, Hasan MR, Subasinghe RP. Use of fishery resources as feed inputs to aquaculture development: trends and policy implications. Rome: FAO of the United Nations; 2006. p. 1–99.
26. Hussein N, Ah-Sing E, Wilkinson P, Leach C, Griffin BA, Millward DJ. Long-chain conversion of [13C]linoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men. J Lipid Res. 2005;46:269–80.
27. Brenna JT. Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man. Curr Opin Clin Nutr Metab Care. 2002;5:127–32.[Medline]
28. Pawlosky RJ, Hibbeln JR, Novotny JA, Salem N. Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans. J Lipid Res. 2001;42:1257–65.
29. Pawlosky RJ, Hibbeln JR, Lin Y, Goodson S, Riggs P, Sebring N, Brown GL, Salem N. Effects of beef- and fish-based diets on the kinetics of n-3 fatty acid metabolism in human subjects. Am J Clin Nutr. 2003;77:565–72.
30. James MJ, Ursin VM, Cleland LG. Metabolism of stearidonic acid in human subjects: comparison with the metabolism of other n-3 fatty acids. Am J Clin Nutr. 2003;77:1140–5.
31. Cunnane S, Drevon CA, Harris W, Sinclair A, Spector A. Recommedations for intakes of polyunsaturated fatty acids in healthy adults. In: Visioli F, editor. ISSFAL Newsletter. Devon, (UK); 2004;11(2):12–25.
32. 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.
33. Harris WS. The omega-3 index as a risk factor for coronary heart disease. Am J Clin Nutr. 2008;87:S1997–2002.
34. Tang C, Cho HP, Nakamura MT, Clarke SD. Regulation of human delta-6 desaturase gene transcription: identification of a functional direct repeat-1 element. J Lipid Res. 2003;44:686–95.
35. Harris WS, Dirienzo MA, Sands SA, George C, Jones PG, Eapen AK. Stearidonic acid increases the red blood cell and heart eicosapentaenoic acid content in dogs. Lipids. 2007;42:325–33.[Medline]
36. Miles EA, Banerjee T, Calder PC. The influence of different combinations of gamma-linolenic, stearidonic and eicosapentaenoic acids on the fatty acid composition of blood lipids and mononuclear cells in human volunteers. Prostaglandins Leukot Essent Fatty Acids. 2004;70:529–38.[Medline]
37. Harris WS, Lemke SL, Hansen SN, Goldstein DA, Dirienzo MA, Su H, Nemeth MA, Taylor ML, Ahmed G, et al. Stearidonic acid-enriched soybean oil increased the omega-3 index, an emerging cardiovascular risk marker. Lipids. 2008;43:805–11.
38. Miles EA, Banerjee T, Dooper MM, M'Rabet L, Graus YM, Calder PC. The influence of different combinations of gamma-linolenic acid, stearidonic acid and EPA on immune function in healthy young male subjects. Br J Nutr. 2004;91:893–903.[Medline]
39. Hulbert AJ, Rana T, Couture P. The acyl composition of mammalian phospholipids: an allometric analysis. Comp Biochem Physiol B Biochem Mol Biol. 2002;132:515–27.[Medline]
40. Yamazaki K, Fujikawa M, Hamazaki T, Yano S, Shono T. Comparison of the conversion rates of alpha-linolenic acid (18:3(n - 3)) and stearidonic acid (18:4(n - 3)) to longer polyunsaturated fatty acids in rats. Biochim Biophys Acta. 1992;1123:18–26.[Medline]
41. Petrik MB, McEntee MF, Johnson BT, Obuckowicz MG, Whelan J. Highly unsaturated (n-3) fatty acids, but not alpha-linolenic, conjugated linoleic or gamma-linolenic acids, reduce tumorigenesis in Apc(Min/+) mice. J Nutr. 2000;130:2434–43.
42. Lagarde M, Sicard B, Guichardant M, Felisi O, Dechavanne M. Fatty acid composition in native and cultured human endothelial cells. In Vitro. 1984;20:33–7.[Medline]
43. GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354:447–55.[Medline]
44. Balk E, Chung M, Lichtenstein A, Chew P, Kupelnick B, Lawrence A, DeVine D, Lau J. Effects of omega-3 fatty acids on cardiovascular risk factors and intermediate markers of cardiovascular disease. Evid Rep Technol Assess (Summ):Number 93. 2004;Publication No. 04-E010-1:1–6.
45. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006;189:19–30.[Medline]
46. Harris WS. n-3 Long-chain polyunsaturated fatty acids reduce risk of coronary heart disease death: extending the evidence to the elderly. Am J Clin Nutr. 2003;77:279–80.
47. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2003;23:e20–30.
48. Yokoyama M, Origasa H. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J. 2003;146:613–20.[Medline]
49. Vanschoonbeek K, Feijge MA, Saris WH, De Maat MP, Heemskerk JW. Plasma triacylglycerol and coagulation factor concentrations predict the anticoagulant effect of dietary fish oil in overweight subjects. J Nutr. 2007;137:7–13.
50. Cerbone AM, Cirillo F, Coppola A, Rise P, Stragliotto E, Galli C, Giordano M, Tremoli E, Di Minno G. Persistent impairment of platelet aggregation following cessation of a short-course dietary supplementation of moderate amounts of N-3 fatty acid ethyl esters. Thromb Haemost. 1999;82:128–33.[Medline]
51. Vanschoonbeek K, de Maat MP, Heemskerk JW. Fish oil consumption and reduction of arterial disease. J Nutr. 2003;133:657–60.
52. Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, Lau J. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006;84:5–17.
53. Harris WS. n-3 Fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65:S1645–54.
54. Sperling P, Lee M, Girke T, Zahringer U, Stymne S, Heinz E. A bifunctional delta-fatty acyl acetylenase/desaturase from the moss Ceratodon purpureus. A new member of the cytochrome b5 superfamily. Eur J Biochem. 2000;267:3801–11.[Medline]
55. 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]
56. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007;447:869–74.[Medline]
57. Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O'Neill LA, Perretti M, Rossi AG, Wallace JL. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007;21:325–32.
58. Wu D, Meydani M, Leka LS, Nightingale Z, Handelman GJ, Blumberg JB, Meydani SN. Effect of dietary supplementation with black currant seed oil on the immune response of healthy elderly subjects. Am J Clin Nutr. 1999;70:536–43.
59. Ishihara K, Komatsu W, Saito H, Shinohara K. Comparison of the effects of dietary alpha-linolenic, stearidonic, and eicosapentaenoic acids on production of inflammatory mediators in mice. Lipids. 2002;37:481–6.[Medline]
60. Hardman WE. (n-3) fatty acids and cancer therapy. J Nutr. 2004;134:S3427–30.
61. Hardman WE, Moyer MP, Cameron IL. Consumption of an omega-3 fatty acids product, INCELL AAFA, reduced side-effects of CPT-11 (irinotecan) in mice. Br J Cancer. 2002;86:983–8.[Medline]
62. Wang D, Dubois RN. Prostaglandins and cancer. Gut. 2006;55:115–22.
63. Davis TW, Zweifel BS, O'Neal JM, Heuvelman DM, Abegg AL, Hendrich TO, Masferrer JL. Inhibition of cyclooxygenase-2 by celecoxib reverses tumor-induced wasting. J Pharmacol Exp Ther. 2004;308:929–34.
64. Trifan OC, Durham WF, Salazar VS, Horton J, Levine BD, Zweifel BS, Davis TW, Masferrer JL. Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11. Cancer Res. 2002;62:5778–84.
65. Kelavkar UP, Hutzley J, Dhir R, Kim P, Allen KG, McHugh K. Prostate tumor growth and recurrence can be modulated by the omega-6:omega-3 ratio in diet: athymic mouse xenograft model simulating radical prostatectomy. Neoplasia. 2006;8:112–24.[Medline]
66. Leitzmann MF, Stampfer MJ, Michaud DS, Augustsson K, Colditz GC, Willett WC, Giovannucci EL. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr. 2004;80:204–16.
67. Cantrill RC, Huang YS, Ells GW, Horrobin DF. Comparison of the metabolism of alpha-linolenic acid and its delta 6 desaturation product, stearidonic acid, in cultured NIH-3T3 cells. Lipids. 1993;28:163–6.[Medline]
68. Horia E, Watkins BA. Comparison of stearidonic acid and alpha-linolenic acid on PGE2 production and COX-2 protein levels in MDA-MB-231 breast cancer cell cultures. J Nutr Biochem. 2005;16:184–92.[Medline]
69. Whelan J, McEntee MF. Dietary (n-6) PUFA and intestinal tumorigenesis. J Nutr. 2004;134:S3421–6.
70. de Deckere EA. Possible beneficial effect of fish and fish n-3 polyunsaturated fatty acids in breast and colorectal cancer. Eur J Cancer Prev. 1999;8:213–21.[Medline]
71. Kato I, Akhmedkhanov A, Koenig K, Toniolo PG, Shore RE, Riboli E. Prospective study of diet and female colorectal cancer: the New York University Women's Health Study. Nutr Cancer. 1997;28:276–81.[Medline]
72. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ. 2006;332:752–60.
73. MacLean CH, Newberry SJ, Mojica WA, Khanna P, Issa AM, Suttorp M, Lim YW, Traina SB, Hilton L, et al. Effects of omega-3 fatty acids on cancer risk: a systematic review. JAMA. 2006;295:403–15.
74. Guichardant M, Traitler H, Spielmann D, Sprecher H, Finot PA. Stearidonic acid, an inhibitor of the 5-lipoxygenase pathway. A comparison with timnodonic and dihomogammalinolenic acid. Lipids. 1993;28:321–4.[Medline]
75. Kockmann V, Spielmann D, Traitler H, Lagarde M. Inhibitory effect of stearidonic acid (18:4 n-3) on platelet aggregation and arachidonate oxygenation. Lipids. 1989;24:1004–7.[Medline]
76. Li D, Sinclair A, Wilson A, Nakkote S, Kelly F, Abedin L, Mann N, Turner A. Effect of dietary alpha-linolenic acid on thrombotic risk factors in vegetarian men. Am J Clin Nutr. 1999;69:872–82.
77. Miles EA, Banerjee T, Calder PC. Self-reported health problems in young male subjects supplementing their diet with oils rich in eicosapentaenoic, gamma-linolenic and stearidonic acids. Prostaglandins Leukot Essent Fatty Acids. 2006;75:57–60.[Medline]
This article has been cited by other articles:
|
|
 |
|
  D. L. Palmquist Omega-3 Fatty Acids in Metabolism, Health, and Nutrition and for Modified Animal Product Foods Professional Animal Scientist, June 1, 2009; 25(3): 207 - 249. [Abstract] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
