Post on 21-Dec-2015
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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
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
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.
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 (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
DHA and PS
PS
DHA
Recognition of Apoptotic Cells
VIABLE CELL MEMBRANE
PS predominantly on cytosolic side
APOPTOTIC CELL MEMBRANE
PS distribution becomes symmetrical
PS flips to Extracytoplasmic Side
Detecting PS on Extracellular Side
Medium
PGE2LPS+PGE2
LPS
9
4
85
7
5
85
5
2
91
5
4
90
Apoptotic Engulfment
APOPTOTIC CELL MEMBRANE
M
M
M
Cytokines, Growth Factors, Lipid Metabolites ???
Position Fatty acid
16:0 18:0 18:1 18:2 20:4 22:6
Rat liver [1]
sn-1 5 93 1
sn-2 6 29 8 4 32 19
Bovine brain [2]
sn-1 3 81 13
sn-2 2 1 25 trace 1 60
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
Arachidonic Acid (AA): C20:4, n-6 or -6. Good source: Liver, Beef.
Arachidonic Acid Metabolism
Esterified onto phospholipidsCleaved by phospholipasesFree AA in cytosol is metabolized by numerous enzymesThe COX pathway generates several prostanoidsPGE2 is the cause of pain and inflammationNSAIDs inhibit the COX pathway
Prostaglandin Synthesis
Harris S. et al., 2002
• 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
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 IB
• DHA reduces translocation of NF-B to nucleus
• Reduction is likely due to increased stability of IB 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
Kong W. et al, 2010
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
IUPAC, 2001
IUPAC, 2001
IUPAC, 2001