Transcript Acides Gras Oméga-3 et Santé

Acides Gras Oméga-3 et Santé
Yvon A. Carpentier
• Laboratoire de Chirurgie
Expérimentale ULB
• Clinique des Lipides
Hôpital Erasme
Structure et nomenclature des acides gras
H3C
COOH
9
H3C
COOH
18:0
Acide stéarique
18:1n-9
Acide oléique
18:2n-6
Acide linoléique
18:3n-3
Acide a-linolénique
H3C
6
H3C
3
COOH
COOH
Solide à température ambiante vs. Liquide à température ambiante
Elongation - unsaturation of essential FA
n-6 serie
n-3 serie
Linoleic ac.
C18:2n-6
Alpha-linolenic ac.
C18:3n-3
Gamma-linolenic ac.
C18:3n-6
Octadecatetraenoïc ac.
C18:4n-3
Dihomo-gamma-linolenic ac.
C20:3n-6
Eicosatetraenoïc ac.
C20:4n-3
Arachidonic ac.
C20:4n-6
Eicosapentaenoïc ac.
C20:5n-3
6-desaturase
Elongation
5-desaturase
AA
EPA
Elongation
Docosatetraenoïc ac.
C22:4n-6
C24:5n-6
Docosapentaenoïc ac.
C24:6n-3
C22:5n-3
DPA
Docosapentaenoïc ac.
Docosahexaenoïc ac.
DHA
C22:5n-6
C22:6n-3
Metabolism of a-linolenic acid
From Cunnane SC, J Physiol Pharmacol, 1996
Trends in the intake of fatty acids in the UK
% Energy
PUFA to SFA ratio
50
1
40
0.8
30
0.6
Total fat
20
0.4
SFA
MUFA
0.2
10
PUFA
0
0
1940
1950
1960
1970
1980
1990
Last 30 Years - Large Increase in the Intake
of n-6 PUFAs in Industrialized Countries
•Between 1972 and 1998 the n-6 fatty acids rose from
4% to 6%.
•Upsurge of Asthma in the UK, Australia, New Zealand
and Germany might be a related phenomenon.
•The unexplained increase in the incidence of edema,
allergic rhinitis, and regional differences of inflammatory
diseases within countries may relate to increased n-6
fatty acid intake.
Roberts 1991, Dept. of Health UK 1994,
Black and Sharp 1997, Lewis et al. 1996, Grimble 1998
Fü-Out-13b
Evolution des habitudes alimentaires
Paléolithique « Western » AHA
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Lipides (% cal) 21
Sat (% cal)
<10
P:S
1.4
-3/ -6
1/1-1/2
Fibres (g/j)
~46
34
<30
~13
<10
~0.5
>1.0
1/10-1/20 1/1-1/5
~20
>25
DONNEES EPIDEMIOLOGIQUES
Populations consommant bcp AG n-3
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faible incidence de pathologies cardiovasculaires
faible incidence de pathologies inflammatoires et allergiques
faible incidence de cancers (colon, sein, prostate)
faible incidence de lithiases rénales
faible incidence de diabète type I
allongement de durée de gestation
incidence accrue d’insuffisance rénale chronique
CORRELATION AVEC COMPOSITION EN ACIDES GRAS DES
MEMBRANES CELLULAIRES ET FORMATION EICOSANOIDES
Acides Gras oméga-3
Rôles-clés en Santé Humaine
• Développement cognitif
• Développement vision
• Réponses immunes/inflammatoires
• Grossesses & développement foetal
• Maladies neurodégénératives
• Aspects psychologiques
• Maladies cardio-vasculaires
Modes and sites of action of n-3 PUFA’s
• Formation of eicosanoids
(tissue level, locally and at distance)
Membrane Pool (PL)
F2-isoprostanes
Metabolic Pool (TG, FFA)
18:2 n-6
(LA)
18:3 n-6
(GLA)
20:3 n-6
(DGLA)
Cyclo-oxygenase
20:4 n-6
(AA)
Lipoxygénases
PGE1
PGI2 PGE TXA2
2
LT 4
HETES
A major role of arachidonic acid is as
a precursor for eicosanoids
Arachidonic acid in cell membrane phospholipid
Phospholipase A2
Free arachidonic acid
COX
15-LOX 12-LOX
5-LOX
PGG2
15-HPETE
12-HPETE
PGH2
15-HETE
12-HETE
PGD2
LXA4
PGE2
LTC4
5-HPETE
LTA4
5-HETE
LTB4
PGF2a
PGI2
TXA2
LTD4
LTE4
Membrane Pool (PL)
F3 - and F4 - isoprostanes
Metabolic Pool (TG, FFA)
18:3 n-3
(ALA)
20:5 n-3
(EPA)
Cyclo-oxygénases
PGI3
TXA3
PGE3
22:5 n-3
(DGLA)
Lipoxygenases
LT5
22:6 n-3
(DHA)
Eicosanoids derived from n-3 (vs. n-6) PUFAs
• Less inflammatory
• Less thrombogenic
• Less chemo-attractive
• Weaker protection of gastro-intestinal mucosa
• Retard delivery (increase pregnancy duration)
Classic view of the anti-inflammatory
action of long chain -3 PUFA
DHA
Arachidonic acid in
membrane phospholipids
Phospholipase A2
Free arachidonic acid
5-LOX
COX-2
2-series PG and TX
Inflammatory effects
4-series LT
Inflammatory effects
EPA
Resolvins & related compounds
EPA
DHA
COX-2 (& presence of aspirin)
E-series resolvins
D-series resolvins,
neuroprotectins etc.
Anti-inflammatory; inflammation resolving
Possible sites of action of n-3 & n-6 PUFAs
From J.A. Ross et al, Curr Opin Clin Nutr Metab Care, 1999
Modes and sites of action of n-3 PUFA’s
• Formation of eicosanoids
(tissue level, locally and at distance)
• Components of membrane phospholipids
(membrane physical properties & interaction with membrane proteins :
cell level)
• Second messengers in signalling pathways
(molecular level)
• Regulators of gene expression
(transcription factors : molecular level)
Signalisation cellulaire: voie des MAP-Kinases
Chemotaxis
Chemoattractants
Adhesion
Injury
Eicosanoids
Cytokines
Reactive
species
PAF
Inflammation
Nutrition et Pathologies Cardio-vasculaires
NUTRITION
Lipides plasmatiques
Pression artérielle
Tendance aux thromboses
Résistance à insuline
Oxydation
Homocystéine
Inflammation
Fonction endothéliale
Irritabilité ventriculaire
MCV
From WC Willett, 2004
Acides Gras Oméga 3 et le Coeur
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 triglycérides (4g/j)
 arythmies
 arrêts cardiaques
 réactions inflammatoires
 coagulation
Synergie avec l’aspirine
Pas d’effets secondaires
Pas d’effet sur le cholestérol
 morbidité et mortalité des maladies coronaires
The New England
Journal of Medicine
• Volume 312
May 9, 1985
Number 19
THE INVERSE RELATION BETWEEN FISH CONSUMPTION AND
20-YEAR MORTALITY FROM CORONARY HEART DISEASE
Daan KROMHOUT, PH.D., M.P.H., EDWARD B., BOSSCHIETER, M.D.,
AND COR DE LEZENNE COULANER, M.SC.
1960: town of Zutphen, the Netherlands
852 middle-aged men without CHD
dietary history
20 year follow-up:
78 deaths from CHD
(> 50%) mortality from CHD in subjects eating > 30 g fish/day
Effects of changes in fat, fish, and fibre intakes on death and
myocardial reinfarction : diet and reinfarction trial (DART)
M.L. Burr et al., The Lancet, 1989
2033 men having recovered from myocardial infarction (M.I.)
Dietary intervention in secondary prevention of M.I.
I.
fat intake (to 30% energy intake) and
II.
fatty fish intake (200-400g/week)
III.
cereal fibre intake (18g/day)
P/S ratio (to 1.0)
2 year follow-up :
29% REDUCTION OF MORTALITY (all causes) IN ‘‘FISH’’ GROUP II
Dietary intake and cell membrane levels of long-chain
n-3 Polyunsaturated Fatty Acids and the risk of
primary cardiac arrest
D.C. Siscovick et al.
« Compared with no dietary intake of eicosapentaenoic
acid (C20:5n-3) and docosahexaenoic acid (C22:6n-3),
an intake of 5.5 g of n-3 fatty acids per month (...
equivalent of one fatty fish meal per week) was
associated with a 50% reduction in the risk of primary
cardiac arrest (odds ratio [OR], 0.5; 95% confidence
interval [Cl], 0.4 to 0.8), after adjustment for potential
confounding factors. »
JAMA, 1995
Prevention and termination of arrhythmia by EPA
J.X. Kang & A. Leaf, Proc Natl Acad Sci USA, 1994
Prevention of Sudden Cardiac Death by Dietary Pure
-3 Polyunsaturated Fatty Acids in Dogs
Dog model of cardiac sudden death
surgically, large myocardial infarct + inflatable cuff around
left circumflex coronary art. (LCA)
1 month later:
Treadmill running + LCA occlusion
 Ventricular fibrillation and death in all controls &
soybean oil (n = 7)
Survival in 5/7 dogs infused for 1h with EPA
6/8 dogs infused for 1h with DHA
6/8 dogs infused for 1h with LNA
G.E. Billman et al, Circulation, 1999
Association of n-3 polyunsaturated fatty acids
with stability of atherosclerotic plaques :
a randomised controlled trial
• 188 patients en attente endartériectomie carotide (7-189j)
• Suppl. HP (1.4g EPA/DHA/j) vs. Tournesol vs. Palme/Soja
Résultats - Suppl. HP vs. 2 autres groupes:
•  EPA & DHA dans lipides de plaque (  incorporation avec temps)
• Plus de plaques avec couche fibreuse épaisse
• Moins de plaques avec couche fibreuse fine & inflammatoire
• Moins d’infiltration de macrophages dans plaques
t/o rapide des acides gras dans lipides des plaques
effet marqué de suppl. HP sur morphologie & fragilité des plaques
F. Thies et al, The Lancet, 2003
Dietary Fish Oil Supplementation Reduces
Myocardial Infarct Size in a Canine Model
of Ischemia and Reperfusion
0.06 g/kg.day EPA for 6 weeks
Occlusion of left circumflex coronary art. for 90 min followed by 6h
of reperfusion
Infarct size: 13.3% ( 3) vs 29.7% (control) (p<0.05);
no difference in regional blood flow or oxygen consumption
Protective mechanisms:
• inhibition of TXA2
• inhibition of free radical production by leucocytes?
H. J. Oskarsson et al., J Am Coll Cardiol, 1993
Acides Gras -3 et Endothélium
• Amélioration profil lipoprotéines
• Amélioration profil éicosanoïdes
• Effet sur membranes cellulaires (et Chol dans cavéoles)
• Modulation de facteurs de transcription nucléaire
• Amélioration défenses anti-oxidantes de cellule
 vasorelaxation
 coagulation,  act plaquettes & molécules adhésion
 sensibilité aux cytokines & radicaux libres
 activation CML
BENEFICIAL EFFECTS OF n-3 PUFA ( I )
 essential for maturation of foetal CNS and retina (DHA)
 reduce inflammatory response
 anti-thrombotic effect
 prevent impaired cellular immunity when caused
by PGE2 production
 decrease plasma triglyceride concentration (also post-prandial)
 decrease plasma free fatty acid concentration (also p-prandial)
BENEFICIAL EFFECTS OF n-3 PUFA ( II )
 decrease cell reactivity to various stimuli (e.g. ventricular
arrhythmia’s,...)
 prevent / reverse cancer & inflammatory cachexia
 increase tolerance to organ transplantation and improve
function of the graft
 help maintaining adequate tissue microperfusion
 reduce cellular accumulation of fat (e.g., liver)
potential interest for supplying n-3 PUFA to « acute » patients
Limitations to n-3 FA supply with Fish Oils
• Gastro-intestinal administration
FO TG : poor substrate for pancreatic lipase
slow & rather unefficient absorption
• Intravenous infusion
FO TG : poor substrate for lipoprotein lipase
slow plasma elimination
! a proportion of n-3 FA used for oxidative purposes !
Obésité, syndrome métabolique, et
insulino-résistance
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Influence du patrimoine génétique
85% des diabétiques T2 sont obèses
30% des obèses sont diabétiques (T2)
 prévalence
Différences entre ethnies (NB: asiatiques)
Influence facteurs comportementaux
(nutrition, activité physique, …)
• Relation avec stress & inflammation
Le Syndrome Métabolique
• Combinaison de  3 facteurs:
- obésité abdominale : tour taille > 94 cm (H) ou > 80 cm (F)
- conc. triglycérides  1.7 mmol/L (150 mg/dL) ou traitt
- conc. HDL-cholestérol < 1.03 mmol/L (40 mg/dL) H ou traitt
< 1.28 mmol/L (50 mg/dL) F ou traitt
- tension artérielle  130/85 mm Hg ou traitt
- conc. glucose à jeun  5.56 mmol/L (100 mg/dL) ou traitt
prévalence:  44% pour population USA > 50 ans (2003)
 prévalence coronaropathies (>>  facteurs isolés)
FACTEURS ASSOCIES AU
SYNDROME METABOLIQUE
• Insulino-résistance & risque diabète T2
• Dépôts ectopiques de TAG (foie, muscles, … )
• Altérations lipoprotéines (sd LDL athérogènes)
• Composante inflammatoire
• Dysfonction endothéliale
•  activité ortho-sympathique
Etiologie multiple (nutrition, sédentarité, …)
Serum sialic acid concentration in 263 overweight women without (0)
or with 1-3 other features of metabolic syndrome : insulin resistance;
dyslipidemia; hypertension
L. Browning, Proc Nut Soc, 2003
Gene variants, insulin resistance, and dyslipidaemia
Hypotheses: primary effect of variants on insulin resistance or on dyslipidaemia
M.Lakso, Curr Opin Lipidol, 2004
Interaction between dietary lipids and physical inactivity
on insulin sensitivity and on intramyocellular lipids in
healthy men
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8 healthy male volunteers
60h complete bed rest + high fat or high CHO diet
Hyperinsulinemic –euglycemic clamp (glucose disposal)
1H-magnetic resonance spectroscopy
Bed rest + high fat :
 glucose disposal (- 24%)
 intramyocellular lipid content (+ 32%)
R. Stettler et al, Diabetes Care, 2005
Mitochondrial dysfunction and type 2 diabetes
Maintenance of normal glucose level :
• insulin responsiveness of skeletal muscle & liver
defect  insulin resistance
• insulin secretion by pancreatic beta cells
defect  hyperglycemia
both defects may be caused by mitochondrial dysfunction
Lowell BB & Shulman GI, Science, 2005
Insulin resistance associated to
obesity and type 2 diabetes
• Molecular defects of insulin signaling in muscle
 glucose disposal and transport (role of fatty acids & metabolites)
• Insulin resistance in liver
 glucose output (overexpression of glucose-6-Pase)
• Visceral obesity & ectopic fat storage (e.g., muscle & liver)
poor modulation of fat oxidation
• Non-alcoholic fatty liver disease (NAFLD) and steato-hepatitis (NASH)
 lipolysis, oxidative stress, cytokine induction
• Altered activity of desaturases
 9 &  5  6 desaturase
DB Savage et al, Hypertension, 2005
N-3 long chain polyunsaturated fatty acids: a nutritional tool to
prevent insulin resistance associated to
type 2 diabetes and obesity ?
RAT STUDIES
• N-3 PUFAs improve molecular defects of insulin signaling in muscle
 IRS-1 phosphorylation  PI 3’-kinase act, GLUT-4 mRNA
 muscle TAG content & LCFA CoA
• N-3 PUFAs improve insulin resistance in liver
 expression & activity of G-6-Pase; normalize glucose output
• N-3 PUFAs improve visceral obesity & ectopic fat storage (muscle & liver)
 fat oxid (PPARa)
 lipogenesis, TG formation, & fat deposition
N-3 long chain polyunsaturated fatty acids: a nutritional tool to
prevent insulin resistance associated to
type 2 diabetes and obesity ?
HUMAN STUDIES (Healthy volunteers)
• 3 week supplementation w FO (1.1 g EPA + 0.7 g DHA)
• Oral glucose load (after supplementation n-3 PUFA) :
 insulin response (- 40%)
 glycemic response
 glucose oxidation
 lipid oxidation
 glycogen storage
N.B.: no effect after short-term supplementation (need for n-3 FA
incorporation in cell membranes ?)
J. Delarue et al, Reprod Nutr Dev, 2004
Changes in AUC for insulin (final-baseline) after supplementation with n-3
PUFA vs. placebo in premenopausal non-diabetic subjects
P < 0.05
Subjects :
- age : 19-51 years
- BMI : 24-44 kg/m2
Inflammatory status (IS) :
- low IS : sialic acid < 2.00 mM
- high IS : sialic acid > 2.20 mM
L. Browning, Proc Nut Soc, 2003
Fish oil prevents the adrenal activation elicited
by mental stress in healthy men
• 7 healthy volunteers
• 2 tests of mental stress, before & after suppl 7.2g FO/d (3wks)
• Before:  heart rate  blood pressure energy expenditure
 plasma cortisol  plasma epinephrine plasma NEFAs
• After n-3 PUFA supplementation :
 heart rate  blood pressure  energy expenditure
 plasma cortisol  plasma epinephrine  plasma NEFAs
blunting of sympatho-adrenal stimulation (at CNS level ?)
potential role in prevention of insulin resistance
J. Delarue et al, Diabetes Metab, 2003
Diabetogenic impact of long-chain omega-3 fatty acids on
pancreatic beta-cell function and the regulation of endogenous
glucose production
• Dietary saturated lipids in healthy subjects:
 ins resist but  ins secretion  glucose tolerance maintained
• Substitution 7% dietary lipids with n-3 PUFA (4 weeks):
reverses peripheral insulin resistance (normal glucose disposal)
HOWEVER:
no suppression of hepatic insulin resistance
no suppression glucose output
no compensatory insulin secretion (+ direct impairment ?)
 glucose level
MJ Holness et al, Endocrinology, 2003
Body weight modulates cholesterol metabolism in
non-insulin dependent type 2 diabetics
BMI, serum insulin and/or blood glucose levels:
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 cholesterol synthesis
 bile acid synthesis
 cholesterol excretion in bile
 cholesterol t/o
•  cholesterol absorption
•  serum cholestanol & plant sterols
PP Simonen et al, Obes Res, 2002
Lipoprotein metabolism in the metabolic syndrome
Chylo
LPL
Chylo-R
Visceral
adipose tissue
FA
LPL
CHO
Apo B
VLDL -TG
IDL
LDL
VLDL
apoB
TG
FA
FFA
CO2
Designed from PHR Barett & GF Watts, Curr Opin Lipidol, 2003
Lipoprotein metabolism in the metabolic syndrome : Effects
of n-3 PUFA supplementation
Chylo
LPL
Chylo-R
Visceral
adipose tissue
FA
LPL
CHO
Apo B
VLDL -TG
IDL
LDL
VLDL
apoB
TG
FA
FFA
CO2
Designed from PHR Barett & GF Watts, Curr Opin Lipidol, 2003
N-3 Fatty Acids and Plasma Lipoproteins
•  plasma triglycerides
•  plasma VLDL-TG and VLDL-cholesterol
•  or  HDL-cholesterol, but  apo A-1
•  LDL-cholesterol (generally slight)
•  fraction of small dense LDL (phenotype B subjects)
Dietary effects on postprandial triglyceride levels
SFA
n-6 PUFA
n-3 PUFA
M. Weintraub et al, J Clin Invest, 1988
Differential effects of n-3 fatty acids
• Mildly hyperlipidemic subjects
-  TAG conc. : 1.7g/d EPA+DHA > 9.5g/d ALA
 LDL sensitivity to oxidation with 1.7g EPA+DHA
YE Finnegan et al, AJCN, 2003
-  TAG conc. : comparable with 4g/d EPA and 4g/d DHA
 LDL size : only with 4g/d DHA
 forearm blood flow : only with 4g/d DHA
TA Mori et al, AJCN & Circulation, 2000
Regulatory effects of HMG CoA reductase inhibitor and Fish Oils
on apolipoprotein B-100 kinetics in insulin-resistant obese male
subjects with dyslipidemia
• 48 obese insulin-resistant subjects
6 wks Atorva 40mg vs Omacor 4g vs Atorva+Omacor
EPA/DHA :  plasma VLDL-apo B
Atorva :
 VLDL-apo B secretion
 VLDL to LDL conversion
 plasma apo B lipoproteins
 FCR of VLDL-, IDL-, LDL-apo B
Atorva + EPA/DHA : cumulative effects
DC Chan, Diabetes, 2002
Healthy Swedish Subjects with mild hyperlipidaemia
(after 4 weeks of Mediterranean vs. Swedish diet)
P < 0.05
P < 0.05
6
1,4
1,2
1
0,8
0,6
0,4
0,2
0
5
4
Swedish
3
Mediterranean
2
1
0
Triacylglycerols (mmol/l)
Total cholesterol (mmol/l)
P < 0.05
1,6
1,4
1,2
1
0,8
0,6
0,4
0,2
0
4
3,5
3
2,5
2
1,5
1
0,5
0
HDL-cholesterol (mmol/l)
P < 0.05
120
100
80
60
40
20
0
LDL-cholesterol (mmol/l)
Apo-B (mg/dl)
A. Ambring et al, Clin Sci, 2004
Effect of weight loss and lifestyle changes on vascular inflammatory
markers in obese women
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Randomized single-blind trial ;120 premenopausal obese women (BMI ≥ 30) with no diabetes,
hypertension, or hyperlipidemia
Low energy mediterranean diet +  physical activity vs. Healthy food + exercise
K Esposito et al, JAMA, 2003
Le Syndrome Métabolique: stratégie
• Unique ? AG n-3
effet préventif, non thérapeutique, sur insulino-résistance
 inflammation  défenses anti-oxydantes cellulaires
 (modérée) pression artérielle
 TAG  HDL-chol  sdLDL mais  LDL-chol
• Globale
nutrition : association avec  AG saturés et  AGMI
(alimentation type méditerranéen)
amélioration contrôle pondéral
activité physique
si indiquée, association à hypolipémiants
Le syndrome métabolique :
effets des fibres (FOS) chez le rat
•  satiété   prises alimentaires
•  absorption glucides & acides gras
•  glycémie & triglycéridémie post-prandiales
•  sécrétion insuline
•  phénomènes inflammatoires (NFkB)
 possibilité effets complémentaires et/ou
synergiques à ceux des AG w 3
Delivery of DHA and EPA via
alpha linolenic acid is not efficient
Delivery of DHA and EPA via
increased fish oil intake is very
efficient
Current intake of fish oil EPA and
DHA in the USA is ~1/3 – 1/6 of
recommended levels
General Conclusions and recommendations
Fish and Omega-3 fatty acid intake
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Clear benefits in secondary prevention
Less strong evidence in primary prevention
Include (fatty) fishes as part of healthy preventive diet
Temporary limited intake in specific subgroups
(pregnant women & children)
• Increased intake in other specific subgroups
(high risk & hypertriglyceridaemia)
• Possibility to use (good quality) supplements
Fish and Omega-3 fatty acid intake :
The unanswered questions
• Indications for primary prevention in high risk groups
(renal failure, insulin-resistance, transplantation, …) ?
• Doses in different indications ?
• Effect of DHA vs. EPA ?
• Intake of ALA (and w3/w6 intake) ?
• Prevention of lipid peroxidation ?
• Optimising intestinal absorption & cell incorporation ?