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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
ho
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