Fatty Acids and the Immune System What Are

Fatty Acids and the Immune System

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

Linoleic Acid (LA): C 18: 2, n-6 or -6. Essential Fatty Acid Alpha Linolenic Acid (ALA): C 18 -3, n -3 or -3. Essential Fatty Acid Good source: Flaxseed Oleic Acid (OA): C 18: 1, n-9 or -9 Good source: Olive oil, Peanut oil, Soy oil

Docosahexaenoic Acid (DHA): C 22: 6, n-3 or -3. Essential Fatty Acid. Good Source: Fish oil Eicosapentaenoic Acid (EPA): C 20: 5, n-3 or -3. Essential Fatty Acid. Good source: Fish oil Arachidonic Acid (AA): C 20: 4, n-6 or -6. Good source: Liver, Beef.

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

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

Plasma Membrane

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

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 (C 18: 0) and DHA (C 22: 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

DHA and PS DHA PS

Recognition of Apoptotic Cells PS flips to Extracytoplasmic Side VIABLECELLMEMBRANE APOPTOTIC PS PS predominantly distribution on becomes cytosolic symmetrical side

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

Apoptotic Engulfment Cytokines, Growth Factors, Lipid Metabolites ? ? ? M M APOPTOTIC CELL MEMBRANE M

Positional Distribution of Fatty Acids in PS Position Fatty acid 16: 0 18: 1 18: 2 20: 4 22: 6 Rat liver [1] sn-1 5 93 1 sn-2 6 29 8 4 32 19 sn-1 3 81 13 sn-2 2 1 25 trace 1 60 Bovine brain [2] 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).

Arachidonic Acid Metabolism Arachidonic Acid (AA): C 20: 4, n-6 or -6. Good source: Liver, Beef. ØEsterified onto phospholipids ØCleaved by phospholipases ØFree AA in cytosol is metabolized by numerous enzymes ØThe COX pathway generates several prostanoids ØPGE 2 is the cause of pain and inflammation ØNSAIDs inhibit the COX pathway

Prostaglandin Synthesis Harris S. et al. , 2002

Hydrogenation Plant • 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!

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

Effect of DHA on NF- B • 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 Kong W. et al, 2010

Effect of DHA on Cytokine Production ELISA Assays show: • Reduction in IL-12 • Reduction in IL-23 • Reduction in IL-27 • Effect diminishes below 1 M Kong W. et al, 2010

IUPAC, 2001

IUPAC, 2001

IUPAC, 2001