Omega-3 Fatty Acids :Omega-3 Fatty Acids :Naming, sources, intakes, metabolism Naming, sources, intakes, metabolism

and health benefitsand health benefits

Philip CalderPhilip CalderProfessor of Nutritional ImmunologyProfessor of Nutritional Immunology

University of SouthamptonUniversity of Southampton

This lecture will coverThis lecture will coverThis lecture will coverThis lecture will cover

Fatty acid structure, nomenclature, sources, and Fatty acid structure, nomenclature, sources, and intakesintakes

Metabolic relationship between Metabolic relationship between -linolenic acid and -linolenic acid and long chain omega-3 fatty acidslong chain omega-3 fatty acids

Omega-3 fatty acids and cardiovascular healthOmega-3 fatty acids and cardiovascular health Omega-3 fatty acids and visual and brain Omega-3 fatty acids and visual and brain

developmentdevelopment Recommendations for omega-3 fatty acid intakeRecommendations for omega-3 fatty acid intake

Fats in the dietFats in the diet

CH2.O.CO.CH2.O.CO.R1R1

R2R2.CO.OCH.CO.OCH

CH2.O.CO.CH2.O.CO.R3R3

TriglyceridesTriglycerides

Also sphingolipidsAlso sphingolipidscholesterol and cholesterol esters cholesterol and cholesterol esters

CH2.O.CO.CH2.O.CO.R1R1

R2R2.CO.OCH.CO.OCH

CH2.O.POO.O.Base CH2.O.POO.O.Base

PhospholipidsPhospholipids

COOH

H3C

Fatty acid structureFatty acid structure

Fatty acid structure andFatty acid structure and nomenclaturenomenclature

COOH

H3C

H3C COOH

H3C

COOH

Stearic acid 18:0

Oleic acid 18:1-9

Linoleic acid 18:2-6

-Linolenic acid 18:3-3H3C COOH

Mammals cannot insert double bonds in here

9

6

3

Omega = Omega = - = n-- = n-

0 20 40 60 80 1000 20 40 60 80 100

Sunflower oilSunflower oil

Corn oilCorn oil

Soybean oilSoybean oil

Olive oilOlive oil

Pig fatPig fat

Beef fatBeef fat

ButterButter

Saturated Monounsaturated PolyunsaturatedSaturated Monounsaturated Polyunsaturated

Latest fatty acid intake data for adults in UK Latest fatty acid intake data for adults in UK (g/day)(g/day)

MalesMales FemalesFemales

Total fatTotal fat 87 (36% energy)87 (36% energy) 61 (35% energy)61 (35% energy)SaturatedSaturated 3333 2323TransTrans 33 22MonounsaturatedMonounsaturated 2929 2020Omega-6 PUFAOmega-6 PUFA 1313 99Omega-3 PUFAOmega-3 PUFA 2.32.3 1.71.7

H3C COOH

H3C COOH

H3C

COOH

H3C COOH

Omega-3 PUFAsOmega-3 PUFAs

-Linolenic acid (18:3-Linolenic acid (18:3-3)-3)

EPA (20:5EPA (20:5-3)-3)

DPA (22:5DPA (22:5-3)-3)

DHA (22:6DHA (22:6-3)-3)

These have different dietary sources These have different dietary sources

and and

their intake differs markedlytheir intake differs markedly

-Linolenic acid (18:3-Linolenic acid (18:3-3)-3)

Found in green plant tissuesFound in green plant tissues Found in some vegetable oils (e.g. soybean, Found in some vegetable oils (e.g. soybean,

rapeseed)rapeseed) Found in some nuts (e.g. walnut)Found in some nuts (e.g. walnut) Found in linseed (flaxseed) and linseed oilFound in linseed (flaxseed) and linseed oil Contributes 85 to 95% of Contributes 85 to 95% of -3 PUFA intake in -3 PUFA intake in

UK adults (ca. 2.1 g/day in males; 1.5 g/day in UK adults (ca. 2.1 g/day in males; 1.5 g/day in females)females)

Long chain Long chain -3 PUFAs (EPA, DPA, DHA)-3 PUFAs (EPA, DPA, DHA)

- oily fish are the only rich source - oily fish are the only rich source of preformed long chain of preformed long chain -3 -3 PUFAsPUFAs

- adults in the UK consume on adults in the UK consume on average 1/3 of a portion of oily average 1/3 of a portion of oily fish per week (53 g/week)fish per week (53 g/week)

- fish consumers consume 1.3 fish consumers consume 1.3 portions of oily fish per week portions of oily fish per week (about 195 g/week)(about 195 g/week)

- average long chain average long chain -3 PUFA -3 PUFA intake is < 0.2 g/day (200 mg/day)intake is < 0.2 g/day (200 mg/day)

- long chain long chain -3 PUFAs are found -3 PUFAs are found in fish oils in fish oils

Long chain Long chain -3 PUFA content of fish-3 PUFA content of fish

EPAEPA DPADPA DHADHA Total Total(g/100 g food)(g/100 g food) g/portiong/portion

CodCod 0.080.08 0.010.01 0.160.16 0.30 0.30HaddockHaddock 0.050.05 0.010.01 0.100.10 0.19 0.19HerringHerring 0.510.51 0.110.11 0.690.69 1.56 1.56MackerelMackerel 0.710.71 0.120.12 1.101.10 3.09 3.09SalmonSalmon 0.550.55 0.140.14 0.860.86 1.55 1.55CrabCrab 0.470.47 0.080.08 0.450.45 0.85 0.85PrawnsPrawns 0.060.06 0.010.01 0.040.04 0.06 0.06

-linolenic acid is metabolically -linolenic acid is metabolically related to long chain related to long chain -3 PUFAs-3 PUFAs-linolenic acid is metabolically -linolenic acid is metabolically related to long chain related to long chain -3 PUFAs-3 PUFAs

Delta 6-desaturaseDelta 6-desaturase

ElongaseElongase

Delta 5-desaturaseDelta 5-desaturase

-Linolenic acid (18:3-Linolenic acid (18:3-3)-3)

18:418:4-3-3

20:420:4-3-3

EPA (20:5EPA (20:5-3)-3)

DPA (22:5DPA (22:5-3)-3) DHA (22:6DHA (22:6-3)-3)

-Linolenic acid-Linolenic acid

EPA EPA

DHADHA

This pathway does This pathway does not work not work very well in humansvery well in humans

Key points (so far)Key points (so far)

-6 and -6 and -3 PUFAs are distinct fatty acid -3 PUFAs are distinct fatty acid familiesfamilies

Most Most -3 PUFA in the diet is in the form of -3 PUFA in the diet is in the form of --linolenic acidlinolenic acid

Long chain Long chain -3 PUFAs are found in oily fish -3 PUFAs are found in oily fish (fish oil capsules)(fish oil capsules)

Average intake of long chain Average intake of long chain -3 PUFAs is < -3 PUFAs is < 0.2 g/day0.2 g/day

-Linolenic acid is poorly converted to long -Linolenic acid is poorly converted to long chain chain -3 PUFAs in humans-3 PUFAs in humans

Omega-3 PUFAs and human healthOmega-3 PUFAs and human health

DiseaseDisease Expected Expected ActualActual

Myocardial infarctionMyocardial infarction 40 40 3 3

PsoriasisPsoriasis 40 40 2 2Bronchial asthmaBronchial asthma 25 25 1 1DiabetesDiabetes 9 9 1 1Multiple sclerosisMultiple sclerosis 2 2 0 0

From a survey of distribution of From a survey of distribution of diseases in Greenland Eskimosdiseases in Greenland Eskimos

Kromann & Green (1980) Acta Med. Scand. 208, 410-406Kromann & Green (1980) Acta Med. Scand. 208, 410-406

Many studies report an inverse correlation between fish consumption or -3 PUFA status and CHD

Kromhout et al. 1985Kromhout et al. 1985 Fish Fish CVD mortality CVD mortalityShekelle et al. 1985Shekelle et al. 1985 Fish Fish CVD mortality CVD mortalityNorelle et al. 1986Norelle et al. 1986 Fish Fish CVD mortality CVD mortalityDolecek et al. 1992Dolecek et al. 1992 Dietary Dietary -3 PUFA -3 PUFA CVD mortality CVD mortalityFeskens et al. 1993Feskens et al. 1993 Fish Fish CVD mortality CVD mortalitySiscovik et al. 1995Siscovik et al. 1995 Fish Fish CVD mortality CVD mortalityKromhout et al. 1995Kromhout et al. 1995 Fish Fish CVD mortality CVD mortalityDaviglus et al. 1997Daviglus et al. 1997 Fish Fish CVD mortality CVD mortalityAlbert et al. 1998Albert et al. 1998 Fish Fish sudden cardiac death sudden cardiac deathPedersen et al. 2000Pedersen et al. 2000 Adipose tissue Adipose tissue -3 PUFA -3 PUFA MI mortality MI mortalityAlbert et al. 2002Albert et al. 2002 Whole blood Whole blood -3 PUFA -3 PUFA sudden death sudden deathHu et al. 2002Hu et al. 2002 Fish and Fish and -3 PUFA intake -3 PUFA intake CHD mortality CHD mortalityHu et al. 2002Hu et al. 2002 Fish and Fish and -3 PUFA intake -3 PUFA intake non-fatal MI non-fatal MITavani et al. 2001Tavani et al. 2001 Fish and Fish and -3 PUFA intake -3 PUFA intake non-fatal MI non-fatal MIGualler et al. 2003Gualler et al. 2003 Adipose tissue DHA Adipose tissue DHA first MI first MILemaitre et al. 2003Lemaitre et al. 2003 Plasma EPA and DHA Plasma EPA and DHA CHD mortality CHD mortality

Prospective: Long chain Prospective: Long chain -3 PUFA -3 PUFA status and sudden deathstatus and sudden death

11

0.80.8

0.60.6

0.40.4

0.20.2

0011 2 2 33 4 4

Rel

ativ

e ri

sk o

f su

dd

en d

eath

Rel

ativ

e ri

sk o

f su

dd

en d

eath

Quartile of blood Quartile of blood -3 PUFAs-3 PUFAs

Adjusted for age & smokingAdjusted for age & smoking

Also adjusted for BMI, Also adjusted for BMI, diabetes, hypertension, diabetes, hypertension, hypercholesterolemia, alcohol, hypercholesterolemia, alcohol, exercise & family history of MIexercise & family history of MI

Albert et al. (2002) New Engl J Med 346, 1113-1118Albert et al. (2002) New Engl J Med 346, 1113-1118

Risk factors for atherosclerosisRisk factors for atherosclerosis

Elevated blood lipidsElevated blood lipids

Endothelial dysfunctionEndothelial dysfunction

InflammationInflammation

LDL-cholesterolLDL-cholesterol

TriglyceridesTriglyceridesHypertensionHypertension

Meta-analysis of trials of fish oil and blood pressureMeta-analysis of trials of fish oil and blood pressureGeleijnse et al. (2002) J. Hypertens. 20, 1493-1499Geleijnse et al. (2002) J. Hypertens. 20, 1493-1499

36 controlled trials reviewed incl. 22 double blind36 controlled trials reviewed incl. 22 double blind

Fish oil:Fish oil:- decreased systolic BP by 2.1 mm Hg - decreased systolic BP by 2.1 mm Hg (95% CI 1.0, 3.2; P < 0.01)(95% CI 1.0, 3.2; P < 0.01)- decreased diastolic BP by 1.6 mm Hg - decreased diastolic BP by 1.6 mm Hg (95% CI 1.0, 2.2; P < 0.01)(95% CI 1.0, 2.2; P < 0.01)

Effects greater in older subjectsEffects greater in older subjectsEffects greater in hypertensive subjectsEffects greater in hypertensive subjects

Conclusion “Conclusion “increased intake of fish oil may lower BP, increased intake of fish oil may lower BP, especially in older and hypertensive subjectsespecially in older and hypertensive subjects””

Relationship between dietary long chain Relationship between dietary long chain -3 PUFAs and blood TAG concentrations -3 PUFAs and blood TAG concentrations

Review of 72 placebo-controlled human trialsReview of 72 placebo-controlled human trials

All > 2 weeksAll > 2 weeks durationduration Harris (1996) Lipids 31, 243-252Harris (1996) Lipids 31, 243-252

TAG < 2 mMTAG < 2 mM TAG > 2 mMTAG > 2 mM-30-30

-20-20

-10-10

00

1010

% C

han

ge

% C

han

ge

PlaceboPlaceboFish oilFish oilDifferenceDifference

Endothelium dependent coronary vasodilatation in Endothelium dependent coronary vasodilatation in patients with CHD before and after fish oil (4 months)patients with CHD before and after fish oil (4 months)

Acetylcholine Acetylcholine

Incr

ease

in

co

ron

ary

Inc r

ease

in

co

ron

ary

blo

od

flo

w (

%)

blo

od

flo

w (

%)

300300

200200

100100

00

CHD patients after fish oilCHD patients after fish oilControlsControls

CHD patients before fish oilCHD patients before fish oil

Fish oil and an inflammatory marker Fish oil and an inflammatory marker (sVCAM-1)(sVCAM-1)

Fish oil and an inflammatory marker Fish oil and an inflammatory marker (sVCAM-1)(sVCAM-1)

Healthy subjects aged > Healthy subjects aged > 55 y55 y

Supplemented diet with Supplemented diet with a moderate amount of a moderate amount of fish oil (= 1.2 g fish oil (= 1.2 g EPA+DHA/day) for 12 EPA+DHA/day) for 12 weeksweeks

Plasma soluble VCAM-1 Plasma soluble VCAM-1 concentrations concentrations measuredmeasured

PlaceboPlacebo FOFO00

200200

400400

600600

800800

10001000

sVC

AM

-1 (

ng

/ml)

sVC

AM

-1 (

ng

/ml)

PrePre

PostPost

Miles et al. (2001) Clinical Science 100, 91-100Miles et al. (2001) Clinical Science 100, 91-100

**

Risk factors for atherosclerosisRisk factors for atherosclerosis

Elevated blood TAGElevated blood TAG

Endothelial dysfunctionEndothelial dysfunction

InflammationInflammation

N-3 PUFAN-3 PUFA

HypertensionHypertension

Secondary prevention: DARTSecondary prevention: DARTSecondary prevention: DARTSecondary prevention: DART

1015 men aged < 70 y who 1015 men aged < 70 y who had had a MIhad had a MI

Advised to eat oily fish or Advised to eat oily fish or take fish oil capsules vs. no take fish oil capsules vs. no adviceadvice

Cardiovascular events and Cardiovascular events and mortality followed for 2 yearsmortality followed for 2 years

Relative risk death 0.77Relative risk death 0.77 Relative risk IHDRelative risk IHD death 0.84death 0.84 80080060060040040020020000

8585

9090

9595

100100

Time (days)Time (days)%

Su

rviv

iors

% S

urv

ivio

rs

Burr et al. (1989) Lancet ii, 757-761Burr et al. (1989) Lancet ii, 757-761

Oily fishOily fishNo adviceNo advice

Secondary prevention: Secondary prevention: GISSI StudyGISSI Study

Secondary prevention: Secondary prevention: GISSI StudyGISSI Study

2836 men who had had 2836 men who had had a MI within the last 3 a MI within the last 3 months assigned to fish months assigned to fish oil (0.85 g LC oil (0.85 g LC -3 -3 PUFA/day) vs. placeboPUFA/day) vs. placebo

Follow up for two yearsFollow up for two years 356 deaths and non-fatal 356 deaths and non-fatal

CV events in fish oil CV events in fish oil group vs. 414 in placebo group vs. 414 in placebo groupgroup

GISSI Prevenzione Investigators (1999) Lancet 354, 447-455GISSI Prevenzione Investigators (1999) Lancet 354, 447-455

Relative risk in fish oil groupRelative risk in fish oil group

All fatal eventsAll fatal events 0.800.80CV deathCV death 0.700.70Coronary deathCoronary death 0.650.65Sudden deathSudden death 0.550.55

There are also non-cardiovascular There are also non-cardiovascular actions of long chain actions of long chain -3 PUFAs-3 PUFAs

DHA concentration in different human tissuesDHA concentration in different human tissues

Adipose Erythrocyte Placenta Liver Testis Brain Retina0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0

% T

ota

l fat

ty a

cid

s

DHA status and infant mental development DHA status and infant mental development (1 year of age)(1 year of age)

140140

120120

100100

8080

6060Bay

ley

Men

tal

Bay

ley

Men

tal

Dev

elo

pm

ent

Ind

exD

evel

op

men

t In

dex

33 6 6 9 9 12 12

Infant red cell DHA (%)Infant red cell DHA (%)

Gibson et al. (1997) Eur. J. Clin. Nutr. 51, 578-584Gibson et al. (1997) Eur. J. Clin. Nutr. 51, 578-584

““Maternal supplementation with very long chain n-3 fatty acids Maternal supplementation with very long chain n-3 fatty acids during pregnancy and lactation augments childrens IQ at 4 years of during pregnancy and lactation augments childrens IQ at 4 years of age”age”

Placebo vs. 2.4 g long chain Placebo vs. 2.4 g long chain -3 PUFAs/day (50:50 EPA & DHA) -3 PUFAs/day (50:50 EPA & DHA) from week 18 of pregnancy until 3 months post partumfrom week 18 of pregnancy until 3 months post partum

Kaufman Assessment Battery for Children performed at 4 years of Kaufman Assessment Battery for Children performed at 4 years of age - a measure of intelligence and achievement designed for age - a measure of intelligence and achievement designed for children aged 2.5 to 12.5 yearschildren aged 2.5 to 12.5 years

At 4 years of age:At 4 years of age:Children of mothers in control group = 102.3 (11.3) Children of mothers in control group = 102.3 (11.3) Children of mothers in fish oil group = 106.4 (7.4)Children of mothers in fish oil group = 106.4 (7.4)

Helland et al. (2003) Pediatrics 111, 39-44Helland et al. (2003) Pediatrics 111, 39-44

Omega-3s in children with ADHDOmega-3s in children with ADHD

Burgess et al. (2000) Am. J. Clin. Nutr. 71, 327S-330SBurgess et al. (2000) Am. J. Clin. Nutr. 71, 327S-330S

0.250.25

0.20.2

0.150.15

0.10.1

0.050.05

00Control Few ADHD Many ADHDControl Few ADHD Many ADHDE

PA

in p

las

ma

ph

os

ph

olip

ids

EP

A in

pla

sm

a p

ho

sp

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lipid

s

The Durham TrialThe Durham Trial

A randomised controlled trial of fish oil A randomised controlled trial of fish oil supplementation (vs. placebo) in children (5 – supplementation (vs. placebo) in children (5 – 12 years old) with developmental co-ordination 12 years old) with developmental co-ordination disorder (n = 117)disorder (n = 117)

Placebo vs. 550 mg EPA + 175 mg DHA/day for Placebo vs. 550 mg EPA + 175 mg DHA/day for 3 months3 months

Then all onto EPA + DHA for a further 3 monthsThen all onto EPA + DHA for a further 3 monthsRichardson & Montgomery (2005) Pediatrics 115, 1360-1366Richardson & Montgomery (2005) Pediatrics 115, 1360-1366

Reading age Spelling age

Baseline 3 mo 6 mo

120

110

100

90

Omega 3 Placebo Placebo then Omega-3

Baseline 3 mo 6 mo

105

100

95

90

Omega 3 Placebo Placebo then Omega-3

Baseline 3 mo 6 mo

HyperactivityHyperactivity

63

61

59

57

55

- membrane structure- membrane structure- brain and visual development- brain and visual development- maintenance of cognitive and neurological function - maintenance of cognitive and neurological function (during development & with aging)(during development & with aging)- regulation of- regulation of

- blood pressure- blood pressure- platelet function, thrombosis, fibrinolysis- platelet function, thrombosis, fibrinolysis - blood lipid concentrations- blood lipid concentrations- vascular function- vascular function- cardiac rhythmn- cardiac rhythmn- inflammation- inflammation- immune response- immune response- bone health- bone health- insulin sensitivity- insulin sensitivity

Long chain Long chain -3 PUFAs are important in:-3 PUFAs are important in:

- optimal brain growth- optimal brain growth- optimal visual and neural function- optimal visual and neural function

Long chain Long chain -3 PUFAs promote-3 PUFAs promote

- - hypertensionhypertension- hypertriglyceridemia- hypertriglyceridemia- thrombosis- thrombosis- vascular dysfunction- vascular dysfunction- cardiac arrhythmias- cardiac arrhythmias- cardiovascular disease- cardiovascular disease- inflammatory conditions- inflammatory conditions- allergic conditions- allergic conditions- immune dysfunction- immune dysfunction- insulin resistance- insulin resistance- psychiatric and neurological diseases of children and adults- psychiatric and neurological diseases of children and adults- neurodegenerative diseases of ageing- neurodegenerative diseases of ageing- bone loss- bone loss- some cancers- some cancers

Long chain Long chain -3 PUFAs are (or may be)-3 PUFAs are (or may be)protective againstprotective against

Summary: Long chain Summary: Long chain -3 PUFAs-3 PUFAs

-

Long chain Long chain -3 PUFAs have a number of physiological -3 PUFAs have a number of physiological effectseffects

Through their physiological effects they alter risk of a Through their physiological effects they alter risk of a wide range of human diseaseswide range of human diseases

Lowered disease risk occurs through plausible Lowered disease risk occurs through plausible biological mechanismsbiological mechanisms

There are newly emerging mechanisms of action of There are newly emerging mechanisms of action of long chain long chain -3 PUFAs in some conditions-3 PUFAs in some conditions

Long chain Long chain -3 PUFAs exert health benefits right -3 PUFAs exert health benefits right through the life cycle (womb to tomb!)through the life cycle (womb to tomb!)

Long chain Long chain -3 PUFAs-3 PUFAsCurrent intakes vs. Recommendations (g/day)Current intakes vs. Recommendations (g/day)

Current av. UK intake Current av. UK intake < 0.2< 0.2

ISSFAL 1999ISSFAL 1999 0.650.65BNF 1999 BNF 1999 1.0-1.41.0-1.4AHA 2003*AHA 2003* 1.01.0AHA 2003**AHA 2003** 2 to 42 to 4SACN/COT 2004SACN/COT 2004 0.45 (minimum)0.45 (minimum)

*For patients with CHD*For patients with CHD**For patients with hypertriglyceridaemia**For patients with hypertriglyceridaemia

What about What about -linolenic acid?-linolenic acid?

Sanderson et al. (2002) Brit. J. Nutr. 88, 573-579Sanderson et al. (2002) Brit. J. Nutr. 88, 573-579

““The studies …. suggested little, if any, benefit The studies …. suggested little, if any, benefit of of -linolenic acid, relative to linoleic acid, on -linolenic acid, relative to linoleic acid, on risk factors for cardiovascular disease ….”risk factors for cardiovascular disease ….”

Consensus statementConsensus statement

However, However, -linolenic acid may exert health benefits -linolenic acid may exert health benefits through conversion to longer chain derivativesthrough conversion to longer chain derivatives

But, this may require high intakes of But, this may require high intakes of -linolenic acid-linolenic acid