Analysis of the 2nd symposium ”Anomalies of fatty

acids, ageing and degenerating pathologies”

Philippe Guesnet, Jean-Marc Alessandri, Sylvie Vancassel, Nicolas Zamaria

To cite this version:

Philippe Guesnet, Jean-Marc Alessandri, Sylvie Vancassel, Nicolas Zamaria. Analysis of the2nd symposium ”Anomalies of fatty acids, ageing and degenerating pathologies”. ReproductionNutrition Development, EDP Sciences, 2004, 44 (3), pp.263-271. <10.1051/rnd:2004031>.<hal-00900467>

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263Reprod. Nutr. Dev. 44 (2004) 263–271© INRA, EDP Sciences, 2004DOI: 10.1051/rnd:2004031

Review article

Analysis of the 2nd symposium“Anomalies of fatty acids, ageing

and degenerating pathologies”

Philippe GUESNETa*, Jean-Marc ALESSANDRIa, Sylvie VANCASSELa, Nicolas ZAMARIAb

a Neurobiology of Lipids, The Nutrition & Food Safety Laboratory, Institut National de la Recherche Agronomique (INRA), CRJ, 78352 Jouy-en-Josas Cedex, France

b Laboratoire de Biologie Médicale, 49 avenue de Versailles, 75016 Paris, France

Abstract – The second symposium on anomalies of fatty acids, ageing and degenerating pathologiesfor the French-speaking community was held during January 2002 in Paris (France) and reunitedmore than 200 participants, including a majority of medical practitioners. It was organised around8 conferences treating the following subjects: a general presentation of the metabolism of fatty acidsand their biological functions (in particular polyunsaturated fatty acids or PUFA), the explorationof PUFA in man during situations of nutritional and pathological disequilibrium, and the importanceof PUFA in the aetiology and prevention of pathophysiologies such as cardiovascular, autoimmuneand inflammatory diseases, diabetes and obesity, cancer and certain neuropsychiatric affections suchas depression. Indeed, even though edible fatty acids present a common energetic function, by β-oxidation,and a structural function, as a constituent of membrane lipids, some of them have a more specificrole as an essential nutrient. These are essential fatty acids including the two families ofpolyunsaturated fatty acids (n-6 and n-3 PUFA). Their metabolism leads to the synthesis ofderivatives found in cellular membranes (structural role) and oxygenated molecules, the eicosanoids,whose main action is of the same type as that of hormones. These derivatives and oxygenatedmolecules also regulate different metabolic pathways by modulating the expression of target genesvia activation of specific transcription factors. Due to their quality and their quantity in food, thePUFA may interfere with the incidence of a large number of pathologies whose causes are varied(cardiovascular and inflammatory diseases, cancers, neuropathologies, …). The particular interestin nutrition of PUFA of the n-3 series (or ω3) and in particular of long-chain derivatives mainly foundin high quantity in fish oils (eicosapentaenoic acid and docosahexaenoic acid) is now widelyconfirmed for cardiovascular and inflammatory physiology and formed the subject of increasinginvestigations for prevention of certain pathologies of the central nervous system. In this paper, weare first going to recall the generalities of metabolism and functional properties of PUFA. Secondly,we will list the pathologies whose frequency and symptoms are susceptible to be corrected by thedietary intake of PUFA, notably by reaching the nutritional equilibrium between the family of linoleicacid (n-6 or ω6) and that of α-linolenic acid (n-3 or ω3).

polyunsaturated fatty acids (PUFA) / docosahexaenoic acid (DHA) / eicosapentaenoic acid(EPA) / metabolism / cardiovascular diseases / autoimmune and inflammatory diseases /neuropathologies / cancer / diabetes / obesity

* Corresponding author: guesnet@jouy.inra.fr

264 P. Guesnet et al.

1. THE FATTY ACIDS FAMILIES – THEIR STRUCTURE, NOMENCLATURE AND DIVERSE BIOLOGICAL EFFECTS

Fatty acids are grouped in distinct fami-lies according to the number of ethylenicbonds (unsaturations) that they contain: sat-urated fatty acids or SFA (no double bond),monounsaturated or MUFA (only one dou-ble bond) or polyunsaturated or PUFA (atleast two double bonds). Two families ofPUFA can be distinguished by the positionof the first double bond situated near themethyl extremity: the family of linoleicacid (n-6 or ω6, 6th position when countingfrom the methyl end) and that of α-linolenicacid (n-3 or ω3, 3rd position when countingfrom the methyl end) [1]. Physiologists char-acterise fatty acids using a nomenclature inwhich successively figures the number ofcarbon atoms, the number of double bondsand the position of the first double bond(counted from the methyl end) (Tab. I).

The SFA and MUFA are not essential forman because they are synthesised de novofrom glucose and acetyl-CoA in differenttissues (liver, brain, adipose tissue). How-ever, the metabolic precursors of the twofamilies of PUFA, that is linoleic acid(18:2n-6) for the n-6 family and α-linolenicacid (18:3n-3) for the n-3 family, are essen-tial fatty acids. These two fatty acids, onceabsorbed, lead to the specific synthesis oflong-chain active derivatives formed by adesaturation-elongation successive processwith double bonds and additional carbonatoms being added near the carboxyl extrem-ity (activated with CoA) (Fig. 1). The mainlong-chain PUFA derivatives formed by ani-mals are dihomo-γ-linolenic acid (20:3n-6or DGLA) and arachidonic acid (20:4n-6 orAA) for the n-6 family and eicosapentae-noic acid (20:5n-3 or EPA) and docosahex-aenoic acid (22:6n-3 or DHA) for the n-3family (Fig. 1 and Tab. I).

SFA and MUFA are major constituentsof stored triglycerides and of the phospho-

lipids of lipoproteins and cellular membranes.They are implicated in the production andstorage of energy, metabolism of lipopro-teins, synthesis of phospholipids and sphin-golipids for the assembly of cellular mem-branes and they regulate the activity of certainmembrane proteins by covalent binding [2].The PUFA have other biological propertiesthat can be resumed as follows:

– At the membrane level, they have a struc-tural effect since some of them are funda-mental constituents of membrane phosphol-ipids (linoleic acid, arachidonic acid andDHA) (Tab. I). They modulate the activityof enzymes, carriers and receptors of bio-logical membranes directly or indirectly bydetermining their physicochemical proper-ties.

– Certain PUFA with 20 carbon atoms areprecursors for the synthesis of eicosanoids(Fig. 2). These oxygenated molecules act asa messenger on the cytosolic and intercel-lular level and regroup the prostaglandins,prostacyclins, thromboxanes, and leukot-rienes. They regulate diverse functions suchas reproduction, cardiac physiology, bloodclotting, inflammation, the function of endo-crine and exocrine glands, … The nature ofthe dietary precursors is an element of cru-cial importance that needs to be consideredin nutrition since the molecules that arederived often present antagonistic effects[3]. Thus, the synthesis of thromboxanesand leukotrienes from EPA lead to the inhi-bition of the process of blood clotting, coag-ulation and inflammation, by opposing tothe effects produced by the eicosanoidssynthesised from arachidonic acid.

– Arachidonic and docosahexaenoic acidsare also substrates of non-enzymatic pathwaysof peroxidation, leading to the formationof specific endoperoxide molecules namedrespectively F(2)-isoprostanes (or F(2)-likecompounds) and neuroprostanes [4]. Thephysiological roles of these molecules arebeing unfolded and concern notably thefunctioning of platelets and blood vessels

Fatty acids and pathologies 265

Table I. Polyunsaturated fatty acid (PUFA) of physiological and nutritional importance in Humans.

Individual PUFASimplified formula*

Major physiological and/or nutritional roles

n-6 PUFA family (or ω6)

*Linoleic acid (LA) 18:2n-6 Structural role as a major constituent of membrane phospholipids. The essentiel precursor of n-6 PUFA

*γ-Linolenic acid (GLA)

18:3n-6 Anti-inflammatory effect by inducing the synthesis and accumulation of 20:3 n-6

*Dihomo-γ-linole-nic acid (DGLA)

20:3n-6 Precursor of the series 1 eicosanoids

*Arachidonic acid (AA)

20:4n-6 Structural role as a major constituent of the membrane phospholipids. Precursor of series 2 eicosanoids (prostaglandins, prostacyclins and thromboxanes) and 4 (leukotrienes) regulating

the platelet aggregation, vasoconstriction and inflammatory processes. Regulates the expression of a certain number of genes

implicated in the lipid metabolism and in the differentiation phenomena (adipocyte)

*Adrenic acid 22:4n-6 Constituent of the cerebral membranes

*Docosapentaenoic acid (n-6 DPA)

22:5n-6 Incorporated in the biological membranes in the position of 22:6n-3 when n-3 PUFA food deficiency

n-3 PUFA family (or ω3)

*α-Linolenic acid (LNA)

18: 3n-3 The essential precursor of n-3 family PUFA. Antiatherogenic effect

*Stearidonic acid 18:4n-3 –

*Eicosapentaenoic acid (EPA)

20:5n-3 Precursor of series 3 eicosanoids (prostaglandins, prostacyclins and thromboxanes) and 5 (leukotrienes) whose

effects are opposite to those of arachidonic acid (antiatherogenic and anti-inflammatory effects)

Also produces a hypotriglyceridaemia effect (represses the expression of genes responsible for the hepatic metabolism of

lipids)

*Docosapentaenoic acid (n-3 DPA)

22:5n-3 –

*Docosahexaenoic acid (DHA)

22:6n-3 Structural role as the major constituent of lipids in the central nervous system-Participates in the control of a large number of

physiological mechanisms in the tissues (ion channels, monoaminergic neurotransmission, energy metabolism,

differentiation, apoptosis, …)

* The nomenclature of physiologists successively indicates the number of carbon atoms, the number ofdouble bonds and the position of the first unsaturation by counting from the methyl end of the molecule.

266 P. Guesnet et al.

(vasoconstriction, proliferation of smoothmuscle cells, monocyte adhesion), ... [5].– At the level of cell nuclei, especially inadipose, hepatic and muscular tissues, thePUFA regulate the expression of genesimplicated in their transport and metabo-lism. By the intermediary of transcriptionfactors of the superfamily of steroid nuclearreceptors [6], the PUFA can stimulate thetranscription of enzymes of mitochondrialand peroxysomal β-oxidation, and repressthe transcription of lipogenic enzymes [7].The pathway of PUFA nuclear receptors isalso implicated in the regulation of the tran-scription of lipoprotein lipase and apolipo-proteins of HDL and VLDL.

2. IMPLICATIONS OF N-3 PUFA IN CARDIOVASCULAR AND INFLAMMATORY PATHOLOGIES, DIABETES AND OBESITY, CANCER AND NEUROPSYCHIATRIC DISEASES

The particular interest of n-3 PUFA inhuman nutrition appeared approximately30 years ago based on epidemiological obser-vations of a comparison between Greenland-ers and Danish Eskimos. These observationsshowed a lower prevalence of cardiovascularand inflammatory diseases in Eskimos thatexclusively consume marine animal fats,

Figure 1. Fatty acid metabolismof essential fatty acids of the n-6and n-3 series via the elongation-desaturation pathway.

Fatty acids and pathologies 267

rich in long-chain n-3 fatty acids [8]. Since1980, the acquisition of new scientific knowl-edge has allowed to show that this familyof fatty acids could play a preventive andcurative role in cardiovascular pathologies,hypertension, certain inflammatory andautoimmune diseases, cancer, diabetes, andobesity [3, 9]. Recently, scientists havebecome interested in psychiatric patholo-gies such as schizophrenia and depression[10, 11]. Thus, the n-3 PUFA, and notablytheir long-chain derivatives contained inproducts issued from the ocean (EPA andDHA), probably would have beneficial prop-erties notably via their anti-inflammatoryeffects, by stimulating the synthesis of lessactive derivatives at the inflammatory leveland by repressing those of the most activederivatives. These derivatives are mainlyeicosanoids issued from a balance of eicos-apentaenoic acid/arachidonic acid in favourof eicosapentaenoic acid, but also implicat-ing proinflammatory cytokines whose syn-thesis is repressed (interleukin-1, IL-1;

interleukin-6, IL-6; tumour necrosis factor,TNFα) [3].

Concerning cardiovascular diseases, thebeneficial effects of n-3 PUFA could involveother pathways: the modification of themetabolism of lipoproteins (a hypotriglyc-eridaemia effect by suppressing the expres-sion of genes in the de novo lipogenesispathway and by activating those of genes ofthe β-oxidation pathway of fatty acids), hae-mostatic functions, the interaction betweenplatelets and the vascular endothelium, thefunctioning of the cardiac muscle (againstarrhythmia), the adhesion of the leucocytesto the vascular endothelium, ... [12]. In thereview that follows, the Drs De Lorgeril andSalen report that the latest studies in sec-ondary prevention do not confirm all thebeneficial properties of long-chain n-3 PUFAdescribed previously (notably for the circu-lating lipids and the haemostatic parame-ters), and that α-linolenic acid (ALA) couldbe a nutrient that could help control functionof cardiac muscle (anti-arrhythmic effect).

Figure 2. Eicosanoids derived from oxidative metabolism of C20 n-6 and n-3 PUFA by thecyclooxygenase and 5-lipoxygenase pathways.

268 P. Guesnet et al.

The beneficial properties exercised bythe long-chain n-3 PUFA on cardiovascularfunctions have inspired interest for the treat-ment of patients with diabetes (types 1 and2) that present similar hypertriglyceridae-mia. This affection is associated with a dys-functioning of ∆6 desaturase [1], suggest-ing that the defect of the biosynthesis oflong-chain derivatives could be correctedby a correct nutritional intake of PUFAwhich has been desaturated at the ∆6 posi-tion. Clinical studies show that a daily intakeof the order of one gram of EPA and DHAcan limit the cardiovascular complicationsof disease (circulating triglycerides, plate-let aggregation, hypertension). It has beenshown that a relationship exists between theconsumption of fats and hyperinsulinemia(type 2 diabetes) and that, in animal studies,an intake of n-3 PUFA decreases the insulinresistance phenomenon by modulating sev-eral parameters of the processes of insulinsignalling. However, it seems that sucheffects are not observed in man (see thereview article [13]).

Type 2 diabetes is closely related toobesity since it is often observed in adultspresenting a metabolic syndrome (excess ofweight and non insulin-dependent diabete).During development and during the adultlife, an increase in adipose mass is generallyassociated with a diet rich in lipids. Recentexperimental data suggest that a high intakeof n-6 PUFA to the detriment of n-3 PUFAcould favour adipogenesis, in vitro as wellas in vivo during the period of perinataldevelopment (gestation-lactation) by acti-vating the process of adipocyte differenci-ation via specific peroxisome proliferator-activated receptors (PPARs) and theirendoperoxide derivatives (prostacyclins) [14].The increase in the prevalence of obesityobserved in all countries in the world overthe last thirty years, and notably in youth,with, at the same time, an increase in theconsumption of n-6 PUFA without a nota-ble change in the amounts of total fattyacids ingested, supports the hypothesis thatPUFA intake could be a nutritional factor

that should be considered in the battleagainst this pathology [9].

The n-3 PUFA, on the contrary to n-6PUFA, present marked immunomodulatingand anti-inflammatory properties, with thelong-chain derivatives such as EPA andDHA having more noticeable effects thanlinolenic acid. These effects have beenshown in a multitude of epidemiologicaland clinical studies. Generally, they aredirectly issued from the effects of EPA thatare in competition with those of arachidonicacid as the substrate of the cyclooxygenaseand 5-lipoxygenase pathways, generatinganti-inflammatory derivatives (Fig. 2) [3].These PUFA also decrease the expressionof cyclooxygenase 2 (COX-2) which limitsthe production of endoperoxide deriva-tives. They specifically inhibit the expres-sion and liberation of cytokines such asIL-1 and IL-6 and TNF, but also the syn-thesis of molecules implicated in endothe-lial adherence such as the activation and theproliferation of T lymphocytes [1, 3]. Alto-gether, these effects could explain the ben-eficial properties that this family of fattyacids has on certain inflammatory patholo-gies (rheumatoid arthritis, psoriasis, asthma,and inflammatory bowel disease, Crohndisease and ulcerative colitis) [3].

The intake of food lipids is one of the fac-tors that seems to play an important role asan adjuvant in therapeutic treatments ofcancer [1]. In the animal models for exper-imental carcinogenesis, n-6 PUFA favourtumour growth, on the contrary to long-chain n-3 PUFA that inhibit it. The mecha-nisms proposed are the effects of a compe-tition that exists between n-3 PUFA andarachidonic acid for the synthesis of eicosa-noids, and the particularity of n-3 PUFA tobe more cytotoxic for tumoral cells by rad-icalar oxidation [1]. Recently, it has beenshown that dietary DHA increased mam-mary tumor sensitivity to radiation in a ratmodel of chemically induced mammarytumors [15]. However, even though someprospective case-control studies confirmthese animal data and underline the fact that

Fatty acids and pathologies 269

the ratio between n-6 PUFA and n-3 PUFAis negatively associated with the incidence ofbreast cancer [16, 17], recent metaanalysesare not conclusive concerning a protectingeffect of food lipids for this type of cancer.In addition, they underline the interest indeveloping new prospective studies on a largescale and in including a nutritional inter-vention with genetic/genomic data [18, 19].

Finally, the n-3 PUFA and notably docosa-hexaenoic acid (22:6n-3, DHA) are nutri-ents essential for the normal developmentof the central nervous system (brain, ret-ina). Indeed, due to its exceptionally highconcentration in the excitable membranesof the brain and retina, DHA plays a funda-mental role in the physiology of nervous tis-sue [20]. Under the influence of a chronicexperimental nutritional deficiency of n-3PUFA (that is maintained during the wholeperiod of gestation and lactation), the decreasein the amount of DHA in the membrane isaccompanied by a decrease in the learningcapacities and visual discrimination in rodentsand monkeys (memory, attention, motiva-tion). Several cases of nutritional deficien-cies have been reported in man, notably innew-born infants that present a delay in thedevelopment of their visual acuity [21, 22].A neurochemical support has been advanced,allowing to establish a relationship betweenthe decrease in cerebral concentrations ofDHA and behavioural modifications observedwith animal models [23–25]. This concernsthe monoaminergic and cholinergic neuro-transmissions whose pathways would bealtered by a deficiency, probably by modi-fying the processes of storage and synapticrelease of these neurotransmitters. This typeof a relationship could also be implicated inthe appearance of neurological troubles asso-ciated with a pathology (hyperactivity in chil-dren, schizophrenia, depression, …) [26, 27].In schizophrenic patients, abnormalities ofthe metabolism of PUFA and membranephospholipids have been identified mainlyas an increased catabolism and abnormal acti-vation of phospholipase A2, possibly impli-cating a hyperfunctioning of the signallingpathway by arachidonic acid and its endoper-

oxide derivatives (prostaglandins) [3, 28].The consumption of long-chain n-3 PUFAat about one g·day–1 could improve the symp-toms of this neuropathology and would beimputed to a specific effect of EPA [29]. Fordepression, human studies describing theeffects of n-3 PUFA are only at the begin-ning, but the first clinical experiments showa promising potential effect of the consump-tion of these fatty acids as an adjuvant toantidepressants, or as an option for minordepressions [11, 30]. The mechanisms ofaction of n-3 PUFA in this pathology are notexactly known and should concern the inhi-bition of the inflammatory state. Finally,the intake of long-chain n-3 PUFA couldalso be beneficial towards the incidence ofneuropathologies associated with ageing asis suggested in recent epidemiological andprospective studies (Alzheimer disease, seniledementia) [31, 32], leaving the door open tothe possible use of dietary long-chain n-3PUFA.

3. CONCLUSIONS

The n-3 PUFA intake from food, whetherit is ingested as the essential precursor asα-linolenic acid or its long-chain deriva-tives (EPA and DHA), is important for theneurosensory development of the newborn.It can also play a role in the frequency of theoccurrence or at least in the intensity of thesymptoms of certain pathological disorderssuch as cardiovascular diseases, cancer, dia-betes, obesity, and inflammatory and centralnervous system pathologies. The absenceof a diversification of our food intake isprobably responsible for the progressiveincrease of the disequilibrium in the intakeof n-6 and n-3 PUFA. For many of us, ourfood intake is too rich in n-6 and relativelypoor in n-3 (precursor and long-chain deriv-atives). This disequilibrium is detrimentalto the synthesis of long-chain n-3 PUFAand to their incorporation in tissues [9, 33]and thus contributing to the emergence ofthese pathologies. The large variability ofthe amounts and compositions of fatty acids

270 P. Guesnet et al.

in food lipids, whether of vegetable or ani-mal origin, underline the importance of fooddiversification in order to avoid an excessor disequilibrium of fatty acid intake. More-over, the consumption of fish and oceanfood is recommended due to the interest oflong-chain n-3 PUFA (EPA + DHA) in theprevention of several diseases.

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