Dietary α‐Linolenic Acid (ALA) Rich Flax Oil Elevates Renal and Hepatic Docsosahexaenoic Acid (DHA) Derived Bioactive Lipids

Oxylipins are bioactive lipids that are oxygenated metabolites of polyunsaturated fatty acids, and are the main mediators of their effects in the body. These bioactive molecules are involved in numerous essential physiologic processes. For example, oxylipins derived from docosahexaenoic acid (DHA), such as hydroxy DHA (HDoHE) and protectins, have anti‐proliferative, anti‐inflammatory, anti‐hyperalgesic and pro‐resolving activities. However, conclusions regarding the effects of dietary lipids are often based on their effects on tissue fatty acid composition data. Such data indicate that α‐linolenic acid (ALA) is not efficiently converted to DHA. Since tissue fatty acid composition may not accurately reflect oxylipin levels, the objective of the current studies was to determine whether dietary ALA could influence DHA derived oxylipin levels. In the first study, normal and Han:SPRD‐ Cy weanling male rats (with cystic kidney disease) were given either the AIN93G diet with soy oil as the lipid source or an experimental diet in which ALA rich flax oil replaced 80% of the soy oil. After 8 weeks of dietary treatment, renal phospholipid fatty acids were analyzed by GLC, and select oxylipins by HPLC‐MS/MS. In diseased compared to normal kidneys, DHA and DHA derived 4‐HDoHE levels were 74% lower when rats were given the soy oil diet. As expected, providing flax oil to diseased rats resulted in higher ALA and eicosapentaenoic acid (EPA), but did not alter DHA levels. Similarly, ALA and EPA derived oxylipins were elevated with dietary flax oil, but in contrast to the lack of effect on DHA, the level of 4‐HDoHE was restored to normal levels. This demonstrated that dietary ALA can increase the level of a DHA derived oxylipin. Therefore, in the second study, soy and flax oil diets identical to those in the first study were provided to two models that develop cystic liver disease: PCK rats and Mx1Cre + Pkd1 flox/flox (Pkd1) mice. In this study, a high throughput HPLC‐MS/MS based targeted lipidomic approach was used to simultaneously quantify a large number of oxylipins from the liver tissues. Providing flax oil compared to soy oil resulted in higher levels of hepatic ALA and EPA derived oxylipins in both models, and n‐6 fatty acid derived oxylipins were generally reduced. With respect to DHA derived oxylipins, in PCK rat livers, 7‐, 8‐, 10‐, 11‐, 13‐, 14‐, 16‐, and 17‐ HDoHE were elevated (by 28 – 79 %) and in Pkd1 mouse livers, 10‐, 16‐, 17‐, 13‐, 19‐ and 20‐HDoHE were elevated (by 33 – 70%) with dietary flax oil. In conclusion, although the conversion of ALA to DHA may not appear to be efficient, dietary ALA does increase DHA derived oxylipins. This demonstrates that dietary ALA can be converted to DHA in amounts sufficient to increase DHA derived bioactive lipids and may mediate physiological effects via this conversion. The implications of these findings for dietary ALA and DHA recommendations remain to be elucidated. Support or Funding Information Canadian Institutes of Health Research

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