Submitted to: Lipids
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/4/2017
Publication Date: 4/13/2017
Citation: Adkins, Y.C., Belda, B.J., Pedersen, T.L., Mackey, B.E., Newman, J.W., Kelley, D.S. 2017. Dietary docosahexaenoic acid and trans-10, cis-12-conjugated linoleic acid alter oxylipins profiles in mouse adipose tissue. Lipids. 52(5):399-413.
Interpretive Summary: NAFLD being present in 30% of US adults is the most common liver disease, which can progress to liver cirrhosis, liver cancer and ultimately liver failure. Currently weight loss and exercise are the only validated NAFLD treatments. Diets containing the trans fatty acid (TFA) t10, c12-conjugated linoleic acid (CLA) deplete adipose tissue depots and induce nonalcoholic fatty liver disease (NAFLD) in mice. Concomitant feeding of the n-3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) with CLA prevent NAFLD development and decrease adipose tissue loss. The mechanisms by which TFA induce and n-3 PUFA prevent NAFLD in mice are poorly understood. In this study we examined the changes in adipose tissue levels of oxygenated fatty acid mediators of cellular growth and inflammation called oxylipins in response to n-3 PUFA feeding with and without CLA. Eight-week-old, pathogen-free C57BL/6N female mice (Charles River, Raleigh, NC) were fed diets with 0%, 0.5% or 1.5% DHA with or without 0.5% CLA for 4 weeks. Animals were euthanized by CO2 asphyxiation and collected tissues were frozen and stored at -80°C. Periuterine adipose tissues oxylipins were extracted, released by saponification, and quantified by UPLC-MS/MS. Dietary DHA increased DHA- and EPA-derived alcohols and epoxides and significantly (p<0.05) reduced arachidonic acid- (ARA) derived epoxides, ketones, alcohols, and 6-keto-prostaglandin (PG)F1a. CLA decreased ARA-derived ketones and epoxides, and increased PGF1a, PGF2a, F2-isoprostanes, multiple alcohols and diols of ARA. Concomitant feeding of CLA and DHA dose-dependently reduced ARA-derived oxygenated lipids but not CLA-derived oxygenated products. DHA dose-dependently increased the 12-ketoeicosatetraenoic acid: 12-hydroxyeicosatetraenoic acid ratio, an effect retarded by CLA. On the other hand CLA increased the ratio between 5-ketoeicosatetraenoic acid to 5-hydroxyeicosatetraenoic acid. Together, these results indicate that both DHA and CLA induce potent effects on AT bioactive lipid content and generation. Regulating the production of these oxylipins may provide targets for NAFLD prevention or treatment, but future studies are needed to identify specific targets in the induction and prevention of NAFLD
Technical Abstract: Diets containing high amounts of n-3 polyunsaturated fatty acids (PUFA) decrease inflammation and the incidence of chronic diseases including cardiovascular disease and nonalcoholic fatty liver disease while trans-fatty acids (TFA) intake increases the incidence of these conditions. Some n-3 PUFA-associated health benefits result from the impact of their oxygenated PUFA metabolites, i.e. oxylipins. The TFA, trans-10, cis-12-conjugated linoleic acid (CLA; 18:2n-6) is associated with adipose tissue (AT) inflammation, oxidative stress, and wasting. We examined the impact of a 4-week feeding of 0, 0.5, and 1.5% docosahexaenoic acid (DHA; 22:6n-3) in the presence and absence of 0.5% CLA on AT oxylipin profiles in female C57BL/6N mice. Esterified oxylipins in AT derived from linoleic acid (LNA), CLA, alpha-linolenic acid, arachidonic acid (ARA), eicosapentaenoic acid (EPA), and DHA were quantified. Dietary DHA significantly (p<0.05) increased EPA-derived alcohols (HEPE) and epoxides (EpETE) and DHA-derived alcohols (HDoHE) and epoxides (EpDPE) and reduced ARA-derived epoxides (EpETrE), ketones (KETE), alcohols (HETE) and 6-keto-prostaglandin (PG)F1a. Dietary CLA decreased ARA-derived KETE and EpETrE and increased PGF1a, PGF2a, F2-isoprostanes, multiple HETEs, diols of ARA (DiHETrE) and EPA (DiHETE), and CLA-derived hydroxyoctadecadieneoic acids (HODE). Concomitant feeding of CLA and DHA dose-dependently reduced ARA-derived oxygenated lipids but not CLA oxygenated product generation. Therefore, DHA feeding may have shifted product profiles without altering reactive oxygen generation. Notably, DHA dose-dependently increased the 12-KETE:12-HETE ratio, an effect retarded by CLA, while CLA increased the relative abundance of 5-KETE to 5-HETE. Together, these results indicate that both DHA and CLA induce potent effects on AT bioactive lipid generation.