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