Transcript Fatty Acids and the Immune System

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): 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
Oleic Acid (OA): C18:1, n-9 or -9
Good source: Olive oil, Peanut oil,
Soy oil
Docosahexaenoic Acid (DHA): C22:6, n-3 or -3.
Essential Fatty Acid. Good Source: Fish oil
Eicosapentaenoic Acid (EPA): C20:5, 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
DHA
PS
Recognition of Apoptotic Cells
PS flips to
Extracytoplasmic Side
APOPTOTIC
VIABLECELL
CELLMEMBRANE
MEMBRANE
PS PS
predominantly
distribution on
becomes
cytosolic
symmetrical
side
Detecting PS on Extracellular Side
LPS
Medium
7
9
85
85
4
5
LPS+PGE2
PGE2
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
18:0
18:1
18:2
20:4
22:6
Rat liver [1]
sn-1
5
93
1
sn-2
6
29
8
sn-1
3
81
13
sn-2
2
1
25
4
32
19
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): C20:4, n-6 or -6.
Good source: Liver, Beef.
Esterified onto phospholipids
Cleaved by phospholipases
Free AA in cytosol is metabolized by numerous enzymes
The COX pathway generates several prostanoids
PGE2 is the cause of pain and inflammation
NSAIDs 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/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
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