Differentiating omega-3 fatty acids from SPMs (specialized pro-resolving lipid mediators)

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1 NIHR Southampton Biomedical Research Centre in nutrition Differentiating omega-3 fatty acids from SPMs (specialized pro-resolving lipid mediators) Philip Calder Professor of Nutritional Immunology University of Southampton The NIHR Southampton Biomedical Research Centre in nutrition is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton

2 Disclosure I receive speaking and/or consulting fees from Fresenius- Kabi, B Braun, Baxter Healthcare, DSM, Pronova BioPharma, Solutex, Sancilio, Smartfish, Danone and Metagenics

3 To cover Introduction to omega-3 fatty acids Mechanisms of action of omega-3 fatty acids Specialized pro-resolving mediators formed from omega-3 fatty acids Differences between omega-3 fatty acids and specialized pro-resolving mediators

4 Omega-3 (ω-3, n-3) fatty acids a family of long chain & very long chain, highly unsaturated fatty acids defined by the position of the methyl terminal double bond include α-linolenic (18:3n-3), stearidonic (18:4n-3), eicosapentaenoic (20:5n-3), docosapentaenoic (22:5n-3) and docosahexaenoic (22:6n-3) acids have different dietary sources are metabolically related to one another

5 Very long chain ( marine ) ω-3 polyunsaturated fatty acids H 3 C COOH Eicosapentaenoic acid (EPA) 20:5ω-3 H 3 C COOH Docosapentaenoic acid (DPA) 22:5ω-3 H 3 C Docosahexaenoic acid (DHA) 22:6ω-3 COOH

6 Pathway of biosynthesis of EPA, DPA and DHA Only synthesized in plants: must be of dietary origin

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8 EPA, DPA and especially DHA are poorly synthesised in humans -> dietary [i.e. preformed] sources are important

9 Synthesised in plants Found in green leaves, some seeds, some nuts, some plant oils Found in meat, eggs and organ meats Found in seafood, especially oily fish, and in fish oil supplements

10 Intakes of EPA and DHA are low in most people => In most cells and tissues the content of EPA and DHA is low (compared with the content of ω-6 PUFAs) Calder PC Eur J Lipid Sci Technol 2014;116:

11 ω-6 and ω-3 PUFA contents of phospholipids of human white (mononuclear) cells % of total fatty acids Linoleic acid (18:2ω-6) 10 DGLA (20:3ω-6) 1.5 Arachidonic acid (20:4ω-6) 20 α-linolenic acid (18:3ω-3) < 0.5 EPA 1.0 DHA 2.5 Yaqoob et al. Eur J Clin Invest 2000;30:

12 But increasing EPA+DHA intake [supply] increases the EPA and DHA content of blood lipids, blood cells, and many tissues including liver, heart & skeletal muscle effect is dose, time and tissue dependent

13 Time course of incorporation of EPA and DHA into human immune cell phospholipids EPA in mononuclear cell PL (%) Time (weeks) DHA in mononuclear cell PL (%) Time (weeks) Healthy volunteers given fish oil (2.1 g EPA and 1.1 g DHA/day) for 12 weeks Yaqoob et al. Eur J Clin Invest 2000;30:

14 Dose response of incorporation of EPA into human mononuclear cells Change in EPA (% total fatty acids) EPA (g/day) Rees et al. Am J Clin Nutr 2006;83:

15 Mechanisms by which increased EPA and DHA status affect inflammatory processes Calder PC Biochim Biophys Acta 2015;1851:

16 Nat Immunol 2001;2:

17 Inflammation has two phases: initiation and resolution Initiation phase Resolution phase TIME

18 Inflammation has two phases: initiation and resolution Initiation phase Resolution phase Classical AA derived mediators (PGE 2, LTB 4 etc.) TIME

19 Inflammation has two phases: initiation and resolution Initiation phase Resolution phase Novel proresolving mediators Classical AA derived mediators (PGE 2, LTB 4 etc.) TIME

20 EPA and DHA give rise to pro-resolving mediators: Resolvins (E-series and D-series) Protectins (Neuroprotectins) Maresins

21 Semin Immunol 2015;27:

22 Serhan et al. Semin Immunol 2015;27:

23 Serhan et al. Semin Immunol 2015;27:

24 Tissue injury Microbes Acute inflammation Chronic inflammation Omega-3 derived proresolving mediators Resolution Tissue damage Persistent infection Autoimmune disease Tissue repair Healing

25 EPA+DHA SPMs Are naturally occurring Present in the diet Synthesised endogenously in humans Anti-inflammatory Inflammation resolving Concentration range for activity micromolar nanomolar/picomolar