How marine omega fatty acids cool the

fires of inflammation –

and clear up afterwards!

Dr Rob Winwood CSci FIFST – Scientific Communication

Manager EMEA and chair of the GOED Science

Committee

12:30 Thursday, November 19th, 2015 at Food Matter Live, Room 16, Excel, London

Page

Principal Omega-3 Fatty Acids

-Linolenic Acid (ALA; 18:3n-3)

Eicosapentaenoic Acid (EPA; 20:5n-3)

Docosahexaenoic Acid (DHA; 22:6n-3)

OH

O

OH

O

OH

O

Page 2

Key Clinical Modes of Action for EPA and DHA

1. Resolving Inflammation

2. Inter-cell signaling

3. Control of cell lifespan (Apoptosis)

4. Restoring healthy lipid profile to blood and reducing blood

pressure and viscosity

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Ω-3 & Ω-6 METABOLISM + HEALTH BENEFITS Omega-6

Vegetable Oils

Omega-3

Green Vegetables

LA

GLA

ARA2

ALA 18:3

SDA 18:4

EPA 20:5

DHA 22:6

Inflammation

inefficient

conversion

in humans

Brain Health

Eye Health

EPA+DHA:

Heart Health,

Neurological,

Others Infant Brain

Development

Skin Health

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IMPORTANT TO ‘RE-BALANCE’

3 6

Hunter/

Gatherer

Agriculture 1900

1970

initial

industrialized

food system

completely

industrialized

food system

= complete imbalance

Resolving inflammation

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Clinical symptoms of inflammation

• Heat

• Redness

• Swelling

• Pain

• Loss of Function

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Progress of Inflammation

Acute

inflammation Resolution

Return to

homeostasis

Chronic

inflammation Fibrosis

Unresolved

Active process involving specific

pro-resolving mediators (SPM)

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The basic 3 steps of Inflammation

• Step 1: Increased supply of blood to the site of the

inflammation Increased permeability of the vascular wall

• Step 2: Leukocytes, migrate from the bloodstream into the

tissue surrounding the damage site.

• Step 3: The leucocytes then release a series of

metabolites:

lipid-derived mediators (e.g. prostaglandins, leukotrienes,

endocannabinoids), platelet activating factor

peptide mediators (e.g. cytokines),

amino acid derivatives and various enzymes.

• This cocktail of metabolites is largely responsible for the

characteristic visible signs of inflammation

8

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Consequences of Unresolved Inflammation

• Ongoing, unresolved inflammation can cause serious

disease, for example:

– rheumatoid arthritis

– inflammatory bowel disease

– asthma

9

Reference: Calder PC., Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and

clinical relevance, 2015 Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1851, (4):

469-484.

Page

A brief history of Prostaglandins, Leukotrienes and Eicosanoids

• 1930s Ulf von Euler and Martin G Goldblatt discovered

Prostaglandins

• 1970-80s Sune Bergström, Bengt Samuelsson and John

Vane awarded Nobel prize for Medicine (1982) for their

work on Eicosanoids, demonstrating how prostaglandins and

thromboxanes were derived from Arachidonic Acid through

the action of COX (cyclo-oxygenase enzymes) and that

aspirin like drugs modulate their action.

• 2002 Charles Serhan of Harvard Medical University

discovered SPECIALISED RESOLVING MEDIATORS (SPMs)

produced from the omega 3 fatty acids EPA and DHA,

namely:

Resolvins

Protectins (from neutrophils)

Maresins (from macrophages)

10

"Ulf von Euler" by Unknown - V0026335. Licensed under CC BY 4.0 via Commons -

https://commons.wikimedia.org/wiki/Fil

e:Ulf_von_Euler.jpg#/media/File:Ulf_von

_Euler.jpg

Source: Karolinska Institute

www.nobelprize.org

Source: www.bcmp.med.harvard.edu

http://www.bcmp.harvard.edu/

Page

Inflammation: Initiation to Resolution

Initiation Resolution

Time

Acti

vit

y

Pro-inflammatory mediators (e.g. Prostaglandin, Thromboxanes

Leukotrienes)

Pro-resolving mediators (e.g. Lipoxin, Resolvins,

Protectins, Maresins

LT:LX

Edema Neutrophils Monocytes/Macrophages

sec-min min-hrs days

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The importance of membrane fluidity in Inflammation

• The cell nucleus triggers the inflammatory process as a

result of signaling metabolites produced from a

biochemical cascade that begins with membrane bound

phospholipids in the cell membrane.

• Alterations in the cell membrane composition lead to

changes in:

– Production of lipid metabolites

– Operation of signal transduction pathways

– Membrane fluidity/order.

• Membrane fluidity is important as it enables the transit of

lipid rafts which are thought to be important in initiating

the signal transduction pathways.

• The overall result is an altered inflammatory cell

phenotype which is turn leads to an altered inflammatory

response.

12

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Omega 6 Fatty Acids as a source of Inflammatory Metabolites

• Membrane lipids of peripheral blood mononuclear cells (PBMC) typically

contained around 10% linoleic acid (C18:2) and 20% arachidonic acid (ARA

C20:4), but only 0.5% EPA and 2% DHA.

• However, the composition was radically changed when the patients were

supplemented with 2.1g EPA and 1.g DHA per day for 12 weeks resulting in

a 20% reduction in ARA levels and consequent replacement with EPA/DHA. • (Ref: Yaqoob P, Pala HS et al., Encapsulated fish oil enriched in alpha-tocopherol alters plasma phospholipid

and mononuclear fatty acid compositions but not mononuclear functions, 2000, Eur J Clin Invest, 30|(3):260-

274.)

13

The phospholipids of the membranes of cells involved in the inflammatory

process are rich in omega 6 fatty acids.

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Membrane ARA

• ARA is a precursor of the eicosanoids intimately involved in

inflammation.

• In response to inflammatory antagonists, it is released from

its bound phospholipid state in the membrane to the free

fatty acid into the cell cytoplasm.

• The free ARA is then converted into inflammatory

eicosanoid mediators via the cyclo-oxygenase (COX), lipo-

oxygenase (LOX) and CYTP450.

• In addition, activated membrane ARA phospholipids initiate

the production of pro-inflammatory endocannabinoids.

These mechanisms are the targets of many pharmacological

interventions.

14

Page

The role of ARA in platelet aggregation

activation & aggregation

1.changes shape

“pseudopods”

“sticky”

2a. P-selectin

GPIIb/IIIa

(binds FBN)

2b. membrane

phospholipids

PL

ARA

PG2

COX

TX A2 thrombospondin

+

ADP, collagen

Ca2+ thrombin fibrin

PT CF CF FBN

Vitamin K

activated

platelet

(soft clot)

Fibrin

(firm clot)

CF

clotting factors

prothrombin

fibrinogen

PT

FBN

ASPIRIN

Page

Overview of mechanisms by which marine omega 3’s can influence cell function (adapted from Calder. P., 2014 Eur J Lipid Technol 116(10) )

Page 16

Marine Omega 3 Fatty Acid Exposure

Receptors and Sensors Membrane Composition

Raft Assembly “Fluidity” Substrate for

eicosanoids,

resolvins,

maresins etc

Cell response

Intracellular and

Extracellular signals

Page

Inflammatory stimulus

Phospholipase A2

EPA

DHA

ARA Potent eicosanoids

Weak eicosanoids

Weak eicosanoids

E resolvins

D resolvins Protectins

Action of Inflammation on membrane bilayer

Maresin

Lipoxins

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Marine Oils can resolve inflammation caused by arthritis and asthma

18

A 2013 study by Ng et al. which carefully took account of the dietary

components including micronutrients demonstrated a specific anti-

inflammatory for marine oils on lung function which was protective

against chronic airway narrowing and maintained interstitial lung

structure and function.

•Ng TP, Niti M et al, Dietary and supplemental antioxidant and anti-inflammatory nutrient intakes and pulmonary function, 2013, Public Health Nutrition, 17(9): 2081-2086.

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Direct effects of EPA and DHA

Ref: Calder PC, Proc. Nutr. Soc. 72, 326-336, 2013

Inflammatory antagonists exert

their effect on the cell

membrane by binding with Toll-

like receptor 4 (TLR4). The

binding results in formation of

NFκB (nuclear factor κB), which

makes it way to the nucleus.

DHA binds with the membrane G

coupled protein 120 (GPR120). This

specific DHA protein receptor then

produces PPARγ prevents the transit of

NFκB to the nucleus

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GPR120 as an omega-3 fatty acid receptor

Ref: Oh DY et al, Cell 142, 687-698,2010 www.cell.com

A dysfunctional

variant of

GPR120 known as

R270H does not

produce the

normal anti-

inflammatory

metabolites and

hence is thought

to cause insulin

resistance and

obesity

Page

Summary of the EPA and DHA effects

Decreased production of eicosanoids from

ARA

Increased production of (weakly

inflammatory) eicosanoids from EPA

Increased production of inflammatory

resolvins and protectins

Decreased production of inflammatory

cytokines

Decreased leucocyte chemotaxis

Decreased T-cell reactivity

Decreased antigen presentation

Effect Mechanism(s) likely to be involved

• Decreased ARA in membrane phospholipids • Inhibition of ARA acid metabolism • Decreased expression of cuclooxygenase-2 gene (via

decreased activation of NF-κB

• Increased EPA in membrane phospholipids

• Increased EPA and DHA in membrane phospholipids • Inhibition of arachidonic acid metabolism

• Decreased expression of inflammatory cytokine genes (via decreased activation of NF-κB)

- Induction and activation of PPARγ - Decreased generation of intracellular signals due to

disruption of membrane lipid rafts

- Activation of GPR120 signaling

• Decreased production of some chemo-attractants • Decreased expression of chemo-attractants receptors

• Decreased generation of intracellular signals due to disruption of membrane lipid rafts

• Decreased MHC expression due to disruption of membrane lipid rafts

Ref: Calder PC, Proc. Nutr. Soc. 72, 326-336, 2013

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