1. Fatty Acids and the Immune System

2. What Are Fatty Acids Long Chain Hydrocarbons with a carboxyl group Long Chain Fatty Acids are typically even numbered Variable Saturation Polyunsaturated/Monounsaturated –Ex. Docosahexaenoic Acid, Oleic Acid Fully Saturated –Ex. Palmitic Acid Omega-3, omega-6 and omega-9

3. Oleic Acid (OA): C18:1, n-9 or  -9 Good source: Olive oil, Peanut oil, Soy oil Linoleic Acid (LA): C18:2, n-6 or  -6. Essential Fatty Acid Alpha Linolenic Acid (ALA): C18-3, n-3 or  -3. Essential Fatty Acid Good source: Flaxseed

4. Eicosapentaenoic Acid (EPA): C20:5, n-3 or  -3. Essential Fatty Acid. Good source: Fish oil Docosahexaenoic Acid (DHA): C22:6, n-3 or  -3. Essential Fatty Acid. Good Source: Fish oil Arachidonic Acid (AA): C20:4, n-6 or  -6. Good source: Liver, Beef.

5. Fatty Acids in Blood Fatty acids are bound to albumin when in blood Can also link to glycerol as triglycerides Can also be part of phospholipids

6. How Can Fatty Acids Modulate the Immune System? Why do we need immune modulation in the first place? Answer: Similar to avoid excessive, chronic inflammation which leads to tissue destruction. FAs such as DHA and EPA can reduce production of inflammatory cytokines (IL-6, IL-12, IL-23) FAs can increase phagocytic activity FAs can decrease lymphocytic proliferation FAs can influence immune cell migration

7. Plasma Membrane

8. Phospholipids and Fatty Acids + Fatty Acid (both saturated and unsaturated Phospho Group Phosphatidylserine

9. Fatty Acids and Plasma Membrane Depending on diet, fatty acids end up in plasma membrane Consumption of hydrogenated oils results in reduction of PUFAs in plasma membrane PS is a recognition marker for apoptotic cells –It is highly prevalent in Brain tissue –Made up of predominantly Stearic Acid (C18:0) and DHA (C22:6) PS predominantly resides on the interior (cytoplasmic side of plasma membrane) –Flippase is responsible for the assymetry Upon apoptosis, more of PS translocates to the exterior facilitating uptake by scavenger cells such as macrophages and neutrophils. Reduced levels of PS with DHA, may decrease efficiency uptake by scavenger cells. Anecdotal evidence for preventing dementia

10. DHA and PS PS DHA

11. Recognition of Apoptotic Cells VIABLE CELL MEMBRANE PS predominantly on cytosolic side

12. Detecting PS on Extracellular Side Medium PGE 2 LPS+PGE 2 LPS 9 4 85 7 5 5 2 91 5 4 90

13. Apoptotic Engulfment MM M M M M Cytokines, Growth Factors, Lipid Metabolites ???

14. PositionFatty acid 16:018:018:118:220:422:6 Rat liver [1] sn-15931 sn-2629843219 Bovine brain [2] sn-138113 sn-22125trace160 1. Wood, R. and Harlow, R.D. Arch. Biochem. Biophys., 135, 272-281 (1969). 2. Yabuuchi, H. and O'Brien, J.S. J. Lipid Res., 9, 65-67 (1968). Positional Distribution of Fatty Acids in PS

15. Arachidonic Acid (AA): C20:4, n-6 or  -6. Good source: Liver, Beef. Arachidonic Acid Metabolism  Esterified onto phospholipids  Cleaved by phospholipases  Free AA in cytosol is metabolized by numerous enzymes  The COX pathway generates several prostanoids  PGE 2 is the cause of pain and inflammation  NSAIDs inhibit the COX pathway

16. Prostaglandin Synthesis Harris S. et al., 2002

18. Hydrogenation involves: –Heating oil –Pressurizing oil –hydrogen gas –Using platinum catalyst Trans fats are a by product of hydrogenation 0 g trans fats does not mean zero It means <0.5 g per serving! Hydrogenation Plant

19. Kong W. et al, 2010 NF-  B/IkB  dimer resides in cytosol Upon stimulation, IkB  is phosphorylated/degraded NF-  B translocates to nucleus facilitating transcription of cytokines Western blot shows reduction in IkB  degradation when DHA is present Effect of DHA on I  B 

20. DHA reduces translocation of NF-  B to nucleus Reduction is likely due to increased stability of I  B  in cytosol Heterodimer does not translocate to nucleus Rosiglitazone is a PPAR  agonist (has no effect) on NF-  B translocation Effect of DHA on NF-  B Kong W. et al, 2010

21. ELISA Assays show: Reduction in IL-12 Reduction in IL-23 Reduction in IL-27 Effect diminishes below 1  M Effect of DHA on Cytokine Production

22. IUPAC, 2001