09.09.08
Biosynthesis of the long chain polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), from their shorter precursor polyunsaturated fatty acid alpha-linolenic acid (ALA) has been a subject of debate in both the health food industry, as well as the scientific community. Rigorous scientific research has been done with both humans and animals to determine the limitations of ALA metabolism, and its conversion rate into EPA and DHA.
The purpose of this paper is to provide a scientific basis for ALA conversion in humans, its limitations, variability, and biological benefit as a source of the beneficial omega-3 fatty acids. A comprehensive review of the literature has determined that ALA appears to be a very limited source of the long chain n-3 (omega-3) fatty acid EPA, and provides no DHA. Additionally, several factors make the metabolism of ALA highly un-reliable and extremely variable from person to person.
ALA concentration in the body
The concentration of ALA in lipid blood and cellular membranes is generally less than 0.05%. This suggests that ALA itself has a very limited role, if any in cellular survival, and biological function. To the contrary, EPA and DHA, its longer chain derivatives are present in much larger amounts, particularly DHA, which makes up 30% of the fatty acids found in both the retina and the human brain (Uauy, Hoffman, Peirano & Birch, 2001).
ALA metabolism
Alpha-linolenic acid has three metabolic fates, desaturation and elongation into longer chain fatty acids such as EPA and DHA, ß-oxidation, or incorporation into structural pools (Burdge, 2004). Given that ALA is a substrate for ß-oxidation, it is a source of energy for the human body, and thus provides calories. A surprising 24% of consumed ALA is oxidized in humans meaning that only ¾ of ALA is available for conversion into EPA and DHA (Bretillon et al, 2001; DeLany et al, 2001; Burdge et al, 2002; Burdge et, al. 2003).
The enzymatic conversion of ALA to EPA has been described to occur at the endoplasmic reticulum, while the conversion to DHA requires peroxisomes (Sprecher, 2002). The rate limiting reaction is the initial desaturation by delta-6-desaturase at the 6th carbon position, followed by addition of a carbon-carbon bond (elongation) and desaturation at the 5th carbon position to form EPA. EPA is next converted to DPA by the addition of another carbon-carbon bond. Synthesis of DHA requires further addition of a carbon-carbon bond to form 24:5n-3 and further delta-6 desaturation to form 24:6n-3. Synthesis of DHA requires the translocation of 24:6n-3 to peroxisomes from the endoplasmic reticulum where the fatty acid chain is shorten to 22:6n-3 (DHA) via ß-oxidation (Burdge, 2004).
The amount of ALA that converts to EPA and DHA
Numerous studies have been done to assess the conversion rate of ALA to the biologically active fatty acids EPA and DHA. Evidence has been gathered from primarily two types of studies, those where an oral flax supplement is given to healthy volunteers, and the concentration of EPA and DHA is measured in the blood, and those where volunteers are given a bolus of ALA which is labeled with a stable isotope. Of the studies conducted; ALA conversion to EPA was on average 3.8%, and the conversion to DHA was a mere 1% - refer to table 1 for details (Petra et al. 2005; Burdge, et al. 2003; Fokkema et al, 2000; Burdge, et al 2002; Burdge , Jones & Wooton, 2002; Pawlosky, et al. 2001; Harper, et al. 2006; Goyens et.al, 2006, Hussein, et al. 2005; Tarpila, et al. 2002; Emken et al, 1994; Petra et al, 2005).
Scientific analysis of ALA conversion has led to several methodological challenges. Many studies have used doses of flax which are unrealistically high and would in fact cause severe weight gain if administered long term (Nordstrom, et. al 1995). Additionally, factors such as cohort size, outcome measurement, and the control of characteristics such as weight and diet among each participant have complicated the interpretation and comparison of results.
What affects the conversion of ALA
The human body is inefficient at converting ALA into EPA and DHA, and what is converted, is highly variable and inconsistent due to several bioconversion factors. ALA is affected by a diverse array of metabolic factors such as carbon recycling, oxidation and desaturation (Delany, et al. 2000; Vermunt et al). It is also greatly affected by dietary factors such as the amount of saturated fatty acids, the amount of LA, the ratio of saturated to polyunsaturated fats (Layne et al, 1996) and the amount of cholesterol (Garg et al, 1988). Additionally, a significant amount of ALA is either found distributed throughout several major tissue lipid pools, such as adipose, carcass, and skin, or as mentioned is destined for b-oxidation, rendering it useless for conversion (Burdge et al, 2005). Perhaps the most significant factor in ALA metabolism is the competitive inhibitor linolenic acid (LA), the omega-6 long-chain polyunsaturated fatty acid precursor. LA and ALA both require delta-6-desaturase activity to form their longer chain derivatives, and because LA is found extensively in the human diet, a greater net conversion of LA to its longer chain fatty acid arachidonic acid (AA) occurs, diminishing the net conversion of ALA to EPA and DHA (Chan et al, 1993).
Conclusion
Given the extreme variability in ALA metabolism, its inefficient conversion, and the numerous extraneous variables affecting its elongation and desaturation, a direct source of EPA and DHA is the obvious choice for these beneficial and essential fatty acids.
References
Bretillon L, Chardigny JM, Sebedio JL, et al. Isomerization increases the postprandial oxidation of linoleic acid but not a-linolenic acid in men. J Lipid Res 2001; 42:995–997.
Burdge, G.C, and Calder, P.C. (2005). Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reprod. Nutr. Dev. 45, 581–597
Burdge, G. (2004). Alpha-linolenic acid metabolism in men and women: nutritional and biological implications. Current Opinion in Clinical Nutrition and Metabolic Care, 7, 137-144.
Burdge GC,Wootton SA. (2002). Conversion of alpha-linolenic acid to eicosapentaenoic,
docosapentaenoic and docosahexaenoic acids in young
women. Br J Nutr, 88:411–20.
Burdge GC, Jones AE, Wootton SA. (2002). Eicosapentaenoic and docosapentaenoic acids are the principal products of a-linolenic acid metabolism in young men. Br J Nutr, 88:355–363.
Burdge GC, Finnegan YE, Minihane AM (2003). Effect of altered dietary n-3 fatty aid intake upon plasma lipid fatty acid composition, conversion of [13C]a-linolenic acid to longer-chain fatty acids and partitioning towards b-oxidation in older men. Br J Nutr, 90:311–321.
Chan JK, McDonald BE, Gerrard JM, Bruce VM, Weaver BJ, Holub BJ. (1993). Effect of dietary alpha-linolenic acid and its ratio to linoleic acid on platelet and plasma fatty acids and thrombogenesis. Lipids, 28: 811–817.
DeLany, J.P., Windhauser, M.M., Champage, C.M., and Bray, G.A. (2001). Differential oxidation of individual dietary fatty acids in humans. Am J Clin Nutr, 72, 905-911.
Emken, E.A., Adlof R.O, Duvala, S.M., Shaneb, J.M., Walkerb, P.M., and Beckerc C (1994). Effect of Triacylglycerol Structure on Absorption and Metabolism of Isotope-Labeled Palmitic and Linoleic Acids by Humans. Biochim Biophys Acta4, 1213, 277-88.
Fokkema MR, Brouwer DA, Hasperhoven MB, Martini IA, Muskiet FA. (2000). Short-term supplementation of low-dose γ -linolenic acid (GLA), α -linolenic acid (ALA), or GLA plus ALA does not augment LCP ω 3 status of Dutch vegans to an appreciable extent. Prostaglandins Leukot Essent Fatty Acids, 63(5):287-92.
Garg ML, Thomson ABR, Clandinin MT. (1990). Interactions of saturated, n-
6 and n-3 polyunsaturated fatty acids to modulate arachidonic acid
Metabolism. J Lipid Res 31: 271–277.
Goyens, P.L., Spilker, M.E., Zock, P.L., Katan, M.B. and Mensink, R.P. (2006).
Conversion of -linolenic acid in humans is influenced by the absolute amounts of -linolenic acid and linoleic acid in the diet and not by their ratio
Am. J. Clinical Nutrition, 84, 44 - 53.
Harper,-C-R; Edwards,-M-J; DeFilipis,-A-P; Jacobson,-T-A. (2006). Flaxseed oil increases the plasma concentrations of cardioprotective (n-3) fatty acids in humans. Journal-of-Nutrition, 136(1): 83-87.
Hussein, N., Ah-Sing, E., Wilkinson, P., Leach, C., Griffin, B.A., and Millward, D.J. (2005). Long-chain conversion of [13C] linoleic acid and alpha linolenic acid in response to marked changes in their dietary intake in men. Journal of Lipid Research Volume 46, 269-280.
Layne KS, Goh YK, Jumpsen JA, Ryan EA, Chow P, Clandinin MT. (1996). Normal subjects consuming physiological levels of 18:3(n-3) and 20:5 (n-3) from flaxseed or fish oils have characteristic differences in plasma lipid and lipoprotein fatty acid levels. J Nutr 126: 2130–2140.
Nordstrom, D.C.E, Honkanen, E.A., Antila, N.E., C. Friman Y.T. and Konttinen (1995). Alpha-linolenic acid in the treatment of rheumatoid arthritis. A double.blind, placebo-controlled and randomized study: flaxseed vs. safflower seed. Rheumatol Int, 14, 231-234.
Pawlosky RJ, Hibbeln JR, Novotny JA, Salem N Jr. (2001). Physiological
compartmental analysis of α-linolenic acid metabolism in adult humans.
J Lipid Res 42: 1257–1265.
Petra L. L. Goyens, Mary E. Spilker,Peter L. Zock, Martijn B. Katan, and Ronald P. (2005). Mensink Alpha-linolenic acid conversion after longer term intake of multiple tracer boluses Journal of Lipid Research Volume 46, 1474-1483.
Sprecher, H. (2002). The roles of anabolic and catabolic reactions in the synthesis and recycling of polyunsaturated fatty acids. Prostaglandins Leukot Essent Fatty Acids, 67-79083.
Tarpila S, Aro A, Salminen I, Tarpila A, Kleemola P, Akkila J, Adlercreutz H. (2002). The effect of flaxseed supplementation in processed foods on serum fatty acids and enterolactone.Eur J Clin Nutr, 56(2):157-65.
Uauy, R., Hoffman, D.R., Peirano, P., Birch, E.E. (2001). Essential fatty acids in visual and brain development. Lipids, 36, 885-895.
Vermunt SHF, Mensink RP, Simonis MMG, Hornstra G. (2000). Effects of dietary α-linolenic acid on the conversion and oxidation of 13C-α-linolenic acid. Lipids 35: 137–142.