Unique Oxylipins derived from Alpha-linolenic acid

Chronic inflammation and oxidative stress are linked with age-related diseases such as cardiovascular disease CVD, obesity, diabetes, and cancer. A unifying mechanism by which flaxseed may lower the risk of these diseases is via its role in reducing inflammation (1). Alpha-linolenic acid (ALA) from flaxseed may decrease inflammation via its influence on eicosanoids – hormone-like substances that play a role in controlling inflammation. When omega-3 ALA intake is low and omega-6 linoleic acid (LA) intake is high, pro-inflammatory eicosanoid production from LA is favoured. The opposite occurs when diets are both higher in ALA and lower in LA. A pro-inflammatory environment is associated with chronic disease risk and thus, increased ALA intake may offer protection (2).

Research at the University of Manitoba over the last decade has focused on the role that oxylipins (eicosanoids are a sub-category of oxylipins) derived from ALA may play in the health effects of flaxseed. Oxylipins are bioactive lipid mediators derived in the body from polyunsaturated fatty acids (PUFA). Oxylipins and eicosanoids synthesized from the omega-6 fatty acid arachidonic acid (AA) are the most widely studied (3). Oxylipins can be produced from other PUFAs as well, such as omega-6 fatty acids LA and dihomo-γ-linolenic acid (DGLA) and omega-3 fatty acids ALA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

The objective of new work from the University of Manitoba was to determine if ALA consumption can reduce inflammation as well as to examine the accompanying alterations in oxylipin secretion (4). The focus was on activated (M1-like) macrophages derived from the human THP-1 cell line. ALA treatment lead to a reduction in lipopolysaccharide (LPS)-induced interleukin (IL)-1β, IL-6 and tumor necrosis factor-α production. These compounds are powerful inflammatory agents.

ALA is known to be converted to longer-chain PUFAs EPA and DHA which are typically found in fish oil. In this research, DHA oxylipins were reduced overall by ALA treatment, as was LPS-induced secretion of EPA oxylipins (4). In contrast, profound increases in oxylipins directly derived from ALA were reported. Lipoxygenase products of LA were also dramatically increased, and LPS-induced production of AA oxylipins, particularly prostaglandin D2, was reduced. The results suggest that ALA may act to dampen the inflammatory phenotype of M1-like macrophages by a unique set of mechanisms distinct from those of the long-chain omega-3 fatty acids EPA and DHA. The investigators conclude that there is strong rationale for investigating the functions of ALA oxylipins and lesser-known LA oxylipins since they hold promise as anti-inflammatory agents.

In another study by the same group of researchers (5), the effects of providing female and male rats with diets high in ALA, EPA or DHA for 6 weeks on oxylipins and fatty acids in kidney, liver and serum were determined. The results showed that the oxylipin profiles generally reflected fatty acid profile. However, unique effects of individual omega-3 fatty acids that were not apparent from fatty acid data alone were found. Dietary ALA increased renal and serum DHA oxylipins even though DHA itself did not increase, while dietary EPA did not increase DHA oxylipins in kidney or liver, suggesting that high EPA may inhibit this conversion.

Oxylipin data generally corroborated fatty acid data that indicated that DHA can be retroconverted to EPA and that further retroconversion to ALA is limited. Dietary n-3 fatty acids decreased n-6 fatty acids and their oxylipins (except LA and its oxylipins), in order of effectiveness of DHA > EPA > ALA. Oxylipins were higher in males, which was not reflective of fatty acids.

The work shows that in three different rat tissues, dietary ALA can increase the production of oxylipins from DHA, even if the level of DHA itself does not change. The authors note that this is important because of the belief by some scientists that ALA cannot be converted to DHA.  This paper also shows that dietary ALA increases the production of unique ALA oxylipins, which is not the case with dietary EPA or DHA.  The product/substrate ratios reported indicate that this formation is greater than for any other fatty acid/oxylipin combinations, suggesting that the physiological effects of ALA may be greater than suggested by its fatty acid level in tissues.

The findings of these new studies suggest that ALA may act via a unique set of mechanisms distinct from those of EPA and DHA. These interesting results provide further rationale for studying the unique anti-inflammatory effects of ALA and may have implications for dietary recommendations to reduce inflammatory disorders.

References

  1. Caligiuri SP, Edel AL, Aliani M, Pierce GN. 2014. Flaxseed for hypertension: implications for blood pressure regulation. Curr Hypertens Rep. 16: 499-014-0499-8.
  2. Anand R, and Kaithwas, K. 2014. Anti-inflammatory Potential of Alpha-Linolenic Acid Mediated Through Selective COX Inhibition: Computational and Experimental Data. Inflammation. 37:1297-1306.
  3. Gabbs M, Leng S, Devassy JG, Monirujjaman M, Aukema HM. 2015. Advances in our understanding of oxylipins derived from dietary PUFAs. Adv Nutrition. 6 (5): 513–540. doi:10.3945/an.114.007732.
  4. Pauls SD, Rodway LA, Winter T, Taylor CG, Zahradka P, Aukema HM. 2018. Anti-inflammatory effects of α-linolenic acid in M1-like macrophages are associated with enhanced production of oxylipins from α-linolenic and linoleic acid. J Nutr Biochem. 57:121-129. doi: 10.1016/j.jnutbio.2018.03.020.
  5. Shan Leng, Tanja Winter, Harold M. Aukema. 2018. Dietary ALA, EPA and DHA have distinct effects on oxylipin profiles in female and male rat kidney, liver and serum. J Nutr Biochem. 57:228–237.