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Acides Gras Oméga-3 et Santé Yvon A. Carpentier Laboratoire de Chirurgie Expérimentale ULB Clinique des Lipides Hôpital Erasme.

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Présentation au sujet: "Acides Gras Oméga-3 et Santé Yvon A. Carpentier Laboratoire de Chirurgie Expérimentale ULB Clinique des Lipides Hôpital Erasme."— Transcription de la présentation:

1 Acides Gras Oméga-3 et Santé Yvon A. Carpentier Laboratoire de Chirurgie Expérimentale ULB Clinique des Lipides Hôpital Erasme

2 Structure et nomenclature des acides gras COOH H3CH3C H3CH3C H3CH3C Acide stéarique18:0 Acide oléique18:1n-9 Acide linoléique18:2n-6 Acide -linolénique 18:3n-3 H3CH3C COOH 9 6 3

3 Solide à température ambiante vs. Liquide à température ambiante


5 Metabolism of -linolenic acid From Cunnane SC, J Physiol Pharmacol, 1996

6 Trends in the intake of fatty acids in the UK % Energy 50403020100 1940 1950 1960 1970 1980 1990 PUFA to SFA ratio 1 0.8 0.6 0.4 0.2 0 Total fat SFAMUFAPUFA

7 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

8 Evolution des habitudes alimentaires Paléolithique « Western » AHA Lipides (% cal) 21 34 <30 Sat (% cal) <10 ~13 <10 P:S 1.4 ~0.5 >1.0 -3/ -6 1/1-1/2 1/10-1/20 1/1-1/5 Fibres (g/j) ~46 ~20 >25

9 DONNEES EPIDEMIOLOGIQUES Populations consommant bcp AG n-3 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 dinsuffisance rénale chronique CORRELATION AVEC COMPOSITION EN ACIDES GRAS DES MEMBRANES CELLULAIRES ET FORMATION EICOSANOIDES

10 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


12 Modes and sites of action of n-3 PUFAs Formation of eicosanoids (tissue level, locally and at distance)

13 Membrane Pool (PL) F 2 -isoprostanes Metabolic Pool (TG, FFA) 18:2 n-6 18:3 n-6 20:3 n-6 20:4 n-6 (LA) (GLA) (DGLA) (AA) Cyclo-oxygenase PGI 2 PGE 2 TXA 2 PGE 1 Lipoxygénases LT 4 HETES

14 Arachidonic acid in cell membrane phospholipid Free arachidonic acid Phospholipase A 2 PGG 2 PGH 2 15-HPETE12-HPETE5-HPETE 15-HETE12-HETE LTA 4 5-HETE PGD 2 PGE 2 PGI 2 TXA 2 PGF 2 PGF 2 LXA 4 LTC 4 LTB 4 LTD 4 LTE 4 A major role of arachidonic acid is as a precursor for eicosanoids COX 15-LOX 12-LOX 5-LOX

15 Membrane Pool (PL) F 3 - and F 4 - isoprostanes Metabolic Pool (TG, FFA) 18:3 n-3 20:5 n-3 22:5 n-3 22:6 n-3 (ALA) (EPA) (DGLA) (DHA) Cyclo-oxygénases PGI 3 PGE 3 TXA 3 Lipoxygenases LT 5

16 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)

17 Arachidonic acid in membrane phospholipids Free arachidonic acid 2-series PG and TX4-series LT COX-2 5-LOX Phospholipase A 2 Inflammatory effects EPADHA Classic view of the anti-inflammatory action of long chain -3 PUFA

18 Resolvins & related compounds EPADHA E-series resolvins D-series resolvins, neuroprotectins etc. Anti-inflammatory; inflammation resolving COX-2 (& presence of aspirin)


20 From J.A. Ross et al, Curr Opin Clin Nutr Metab Care, 1999 Possible sites of action of n-3 & n-6 PUFAs

21 Modes and sites of action of n-3 PUFAs 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)

22 Signalisation cellulaire: voie des MAP-Kinases

23 Adhesion Chemoattractants Eicosanoids Cytokines Reactivespecies PAF Inflammation Chemotaxis Injury

24 Lipides plasmatiques Pression artérielle Tendance aux thromboses Résistance à insuline Oxydation Homocystéine Inflammation Fonction endothéliale Irritabilité ventriculaire NUTRITION MCV Nutrition et Pathologies Cardio-vasculaires From WC Willett, 2004

25 Acides Gras Oméga 3 et le Coeur triglycérides (4g/j) arythmies arrêts cardiaques réactions inflammatoires coagulation Synergie avec laspirine Pas deffets secondaires Pas deffet sur le cholestérol morbidité et mortalité des maladies coronaires

26 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

27 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 P/S ratio (to 1.0) II. fatty fish intake (200-400g/week) III. cereal fibre intake (18g/day) 2 year follow-up : 29% REDUCTION OF MORTALITY (all causes) IN FISH GROUP II 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

28 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

29 Prevention and termination of arrhythmia by EPA J.X. Kang & A. Leaf, Proc Natl Acad Sci USA, 1994

30 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 Prevention of Sudden Cardiac Death by Dietary Pure -3 Polyunsaturated Fatty Acids in Dogs G.E. Billman et al, Circulation, 1999

31 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 dinfiltration 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

32 Dietary Fish Oil Supplementation Reduces Myocardial Infarct Size in a Canine Model of Ischemia and Reperfusion 0.06 g/ 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

33 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

34 essential for maturation of foetal CNS and retina (DHA) reduce inflammatory response anti-thrombotic effect prevent impaired cellular immunity when caused by PGE 2 production decrease plasma triglyceride concentration (also post-prandial) decrease plasma free fatty acid concentration (also p-prandial) BENEFICIAL EFFECTS OF n-3 PUFA ( I )

35 decrease cell reactivity to various stimuli (e.g. ventricular arrhythmias,...) 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 BENEFICIAL EFFECTS OF n-3 PUFA ( II )

36 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 !


38 Obésité, syndrome métabolique, et insulino-résistance 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

39 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)

40 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, …)

41 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

42 Gene variants, insulin resistance, and dyslipidaemia M.Lakso, Curr Opin Lipidol, 2004 Hypotheses: primary effect of variants on insulin resistance or on dyslipidaemia

43 Interaction between dietary lipids and physical inactivity on insulin sensitivity and on intramyocellular lipids in healthy men 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


45 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

46 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

47 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 (PPAR ) lipogenesis, TG formation, & fat deposition

48 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

49 L. Browning, Proc Nut Soc, 2003 Changes in AUC for insulin (final-baseline) after supplementation with n-3 PUFA vs. placebo in premenopausal non-diabetic subjects Subjects : - age : 19-51 years - BMI : 24-44 kg/m 2 P < 0.05 Inflammatory status (IS) : - low IS : sialic acid < 2.00 mM - high IS : sialic acid > 2.20 mM

50 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

51 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

52 Body weight modulates cholesterol metabolism in non-insulin dependent type 2 diabetics BMI, serum insulin and/or blood glucose levels: 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

53 FFA FA FA CHO TG Apo B VLDL apoB VLDL -TG LPL FA IDL LDL Chylo-R Chylo Visceral adipose tissue Lipoprotein metabolism in the metabolic syndrome Designed from PHR Barett & GF Watts, Curr Opin Lipidol, 2003 LPL CO 2

54 FFA FA FA CO 2 TG Apo B VLDL apoB VLDL -TG LPL FA IDL LDL Chylo-R Chylo Visceral adipose tissue Designed from PHR Barett & GF Watts, Curr Opin Lipidol, 2003 Lipoprotein metabolism in the metabolic syndrome : Effects of n-3 PUFA supplementation LPL CHO

55 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)

56 Dietary effects on postprandial triglyceride levels M. Weintraub et al, J Clin Invest, 1988 SFA n-6 PUFA n-3 PUFA

57 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

58 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 VLDL-apo B secretion VLDL to LDL conversion Atorva : plasma apo B lipoproteins FCR of VLDL-, IDL-, LDL-apo B Atorva + EPA/DHA : cumulative effects DC Chan, Diabetes, 2002

59 Swedish Mediterranean Healthy Swedish Subjects with mild hyperlipidaemia (after 4 weeks of Mediterranean vs. Swedish diet) A. Ambring et al, Clin Sci, 2004 P < 0.05

60 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 Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women

61 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

62 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

63 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

64 General Conclusions and recommendations Fish and Omega-3 fatty acid intake 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

65 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 ?


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