Effets et métabolismes spécifiques des acides gras ω3

Omega 3 fatty acids are issued from linolenic acid (18:3ω3). Nutritional interest about ω3 fatty acids has begun since the epidemiological studies of Dyerberg et al. have shown a relationship between consumption of marine fats and reduction of cardiovascular diseases. Long-chain ω3 fatty acids, mainly eicosapentaenoic (20:5ω3 or EPA) and docosahexaenoic (22:6ω3 or DHA) acids, are considered to be the main bioactive components in marine sources. Other studies have confirmed that consumption of fish ou EPA\\DHA supplements may reduce mortality in patients who have suffered from myocardial infarction. Beneficial effects of ω3 fatty acids are also recognized in inflammatory disorders. The main mechanism involved for those effects is assumed to be the interference between long-chain ω3 fatty acids and the arachidonic acid (AA) metabolism in blood and vascular cells. In those cells, AA may be released from membrane phospholipids by phospholipase A2 and subsequently oxygenated into eicosanoids (overall called AA cascade). According to the cell, oxygenated products from AA include thromboxane (platelets), prostacyclin (endothelial cells) and leukotrienes (leukocytes). EPA and DHA can interfere with AA cascade by several ways to reduce the vascular risk. However, high intake of such fatty acids may increase lipid peroxidation and have deleterious effects, in particular in subjects suffering from oxidative stress, whereas law may exert “antioxidant” activity. We conclude that a moderate consumption of long-chain ω3 fatty acids can protect against cardiovascular dysfunction

Biological relevance of double lipoxygenase products of polyunsaturated fatty acids, especially within blood vessels and brain

International audienceThe double lipoxygenation of polyunsaturated fatty acids (PUFA) is possible with PUFA having at least three methylene-interrupted double bonds. Several PUFA of the omega-3/n-3 and -6 families may be converted through this route, and the products show interesting inhibitory effects on blood platelet function and cyclooxygenase activities. This review focuses on two main omega-3 PUFA of nutritional interest, namely docosahexaenoic acid (DHA/22:6n-3) and alpha linolenic acid (ALA/18:3n-3). The chemical configuration of the double lipoxygenase end-product from DHA (protectin DX) is compared with that of protectin D1 which is produced through a mono-lipoxygenation step followed by an epoxidation and epoxide hydrolysis process. The different metabolic pathways are discussed as well as the different biological activities of both protectins

In vitro and in vivo bimodal effects of docosahexaenoic acid supplements on redox status and platelet function

International audienceDocosahexaenoic acid (DHA) is a prominent nutrient of marine lipids. Together with eicosapentaenoic acid, it is recognized as a protective molecule against atherosclerosis and thrombosis through the regulation of blood cell functions, especially platelets. Its high unsaturation index may however make it prone to peroxidation, which is usually considered as deleterious. This short review takes into consideration this possibility related to DHA concentrations both in vitro and in vivo. It is suggested that protective effects of DHA on platelet activation depend on the reduction of oxidative stress, and appear bimodal with the abolishment of such a protection when DHA is used at relatively high concentrations. Introduction Docosahexaenoic acid (DHA) is one of the long-chain polyunsaturated fatty acids (PUFA) of the omega-3 family found in marine lipids. Together with eicosapentaenoic acid (EPA), DHA is well-known for its anti-atherothrombotic potential, in particular by decreasing the arachidonic acid (ArA) content of blood cells [1], inhibiting thromboxane production in platelets, as well as leukotriene B4 formation in leukocytes [2]. In addition to these inhibitory effects on ArA metabolism, DHA may decrease athero-thrombogenesis through the action of its lipoxygenase (LOX) end-products. Mono-hydroxylated derivatives produced through 12-, and 15-LOX, namely 11-, 14-, and 17-OH-22:6 (11-, 14-, and 17-HDoHE), respectively, inhibit the thromboxane-induced platelet aggregation (induced by the stable thromboxane A2 receptor agonist U-46619), even stronger than 12-OH-20:4 and-20:5 (12-HETE and-HEPE) [3]. More recently, the double lipoxygenase product of DHA, 10(S),17(S)-diHDoHE, named protectin DX, has been shown to inhibit platelet aggregation through the inhibition of cyclooxygenase-1, which initiates prostanoid synthesis including the potent pro-aggregatory thromboxane A2, as well as the response to the thromboxane A2 mimetic U-46619 [4]. In addition, DHA is known to be oxygenated into several di/tri-OH derivatives (protectin D1, maresins, and resolvins) that are potent inhibitors of the inflammation process [5]. Supplementation of humans with long-chain omega-3 PUFA is usually considered as a positive approach to decrease the risk of atherosclerosis and thrombosis [6], as recently reviewed [7], although some controversies arose in the recent years [8]. Among the controversial issues are the intake doses of those highly unsaturated PUFA, which may be prone to peroxidation [9]. We have been especially interested in the effects of different concentrations of DHA upon blood platelets and their blood environment both in vitro and in vivo, in particular regarding the redox status

Poxytrins, a class of oxygenated products from polyunsaturated fatty acids, potently inhibit blood platelet aggregation.: PUFA conjugated trienes and platelet inhibition

International audienceDocosahexaenoic acid (DHA), an important component of marine lipids, exhibits anti-inflammatory activity related to some of its oxygenated metabolites, such as neuroprotectin/protectin D1 [NPD1/PD1; 10(R),17(S)-dihydroxy-docosa-4Z,7Z, 11E,13E,15Z,19Z-hexaenoic acid] produced through the 15-lipoxygenase pathway. However, other metabolites from DHA can be produced through this pathway, and other polyunsaturated fatty acids (PUFAs) of nutritional value may be oxygenated as well. Their biological activities remain unknown. Isomers of protectin D1 were synthesized using soybean lipoxygenase and tested for their ability to inhibit human blood platelet aggregation. A geometric isomer called PDX, previously described with the 11E,13Z,15E geometry, instead of 11E,13E,15Z in PD1, inhibited platelet aggregation at submicromolar concentrations when induced by either collagen, arachidonic acid, or thromboxane. The inhibition occurred at the level of both the cyclooxygenase activity and thromboxane receptor site. Interestingly, all the metabolites tested exhibiting the E,Z,E-conjugated triene were active, whereas E,E,Z trienes (as in PD1) or all-trans (E,E,E) trienes were inactive. We conclude that PDX and other oxygenated products from PUFAs of nutritional interest, having the E,Z,E-conjugated triene motif and collectively named poxytrins (PUFA oxygenated trienes), might have antithrombotic potential

Dose-effect and metabolism of docosahexaenoic acid: Pathophysiological relevance in blood platelets.

International audienceDocosahexaenoic acid (DHA) is known as a major nutrient from marine origin. Considering its beneficial effect in vascular risk prevention, the effect of DHA on blood components, especially platelets, will be reviewed here. Investigating the dose-effect of DHA in humans shows that daily intake lower than one gram/day brings several benefits, such as inhibition of platelet aggregation, resistance of monocytes against apoptosis, and reinforced antioxidant status in platelets and low-density lipoproteins. However, higher daily intake may be less efficient on those parameters, especially by losing the antioxidant effect. On the other hand, a focus on the inhibition of platelet aggregation by lipoxygenase end-products of DHA is made. The easy conversion of DHA by lipoxygenases and the formation of a double lipoxygenation product named protectin DX, reveal an original way for DHA to contribute in platelet inhibition through both the cyclooxygenase inhibition and the antagonism of thromboxane A(2) action

Structure-function relationships of non-cyclic dioxygenase products from polyunsaturated fatty acids: Poxytrins as a class of bioactive derivatives.

International audience: More and more attention is paid to omega-3 fatty acids because of their potential activities in preventing cardiovascular events. In this brief review, we focus on the lipoxygenase end-metabolites of two relevant nutrients belonging to the omega-3 family fatty acids: alpha-linolenic and docosahexaenoic acids, the latter being a prominent component of brain lipids. Dihydroxylated derivatives are described as well as their inhibitory effects on platelet aggregation and cyclooxygenase activities. We point out that only the dihydroxylated products with the trans,cis,trans/E,Z,E conjugated triene geometry exhibit those inhibitory activities. These properties being found with other polyunsaturated fatty acid oxygenated products sharing the same E,Z,E molecular motif, they have been collectively named poxytrins. From alpha-linolenic and docosahexaenoic acids, poxytrins are linotrins and protectin DX, respectively

Oxygenation of polyunsaturated fatty acids and oxidative stress within blood platelets

International audienceThe oxygenation metabolism of arachidonic acid (ArA) has been early described in blood platelets, in particular with its conversion into the potent labile thromboxane A2 that induces platelet aggregation and vascular smooth muscle cells contraction. In addition, the primary prostaglandins D2 and E2 have been mainly reported as inhibitors of platelet function. The platelet 12-lipoxygenase (12-LOX) product, i.e. the hydroperoxide 12-HpETE, appears to stimulate platelet ArA metabolism at the level of its release from membrane phospholipids through phospholipase A2 (cPLA2) and cyclooxygenase (COX-1) activities, the first enzymes in prostanoid production cascade. Also, 12-HpETE may regulate the oxygenation of other polyunsaturated fatty acids (PUFA) by platelets, especially that of eicosapentaenoic acid (EPA). On the other hand, the reduced product of 12-HpETE, 12-HETE, is able to antagonize TxA2 action. This is even more obvious for the 12-LOX end-products from docosahexaenoic acid (DHA), 11- and 14-HDoHE. In addition, 12-HpETE plays a key role in platelet oxidative stress as observed in pathophysiological conditions, but may be regulated by DHA with a bimodal way according to its concentration. Other oxygenated products of PUFA, especially omega-3 PUFA, produced outside platelets may affect platelet functions as well

Age-related changes in antioxidant defence mechanisms and peroxidation in isolated hepatocytes from spontaneously hypertensive and normotensive rats

International audienceThe effects of age and hypertension on the antioxidant defence systems and the lipid peroxidation in rat isolated hepatocytes were studied. Four different age groups (1, 3, 6 and 12 months) were considered in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Age-associated changes were observed on vitamin E status, glutathione (GSH) level, MDA formation and glutathione peroxidase (GSH-Px) activity in both strains. Maximal levels or activities of these parameters were found at 3 and 6 months, except for MDA which was low at 3 months. Then, a fall was observed at 12-month-old compared to 6-month values. In addition, GSH-Px activity was significantly lower in SHR than in WKY rats, except at the age of one month. The decrease of this enzyme activity could induce an increased cellular generation of radical species and lipid peroxidation, which might be link to hypertension

Omega-3 polyunsaturated fatty acids and oxygenated metabolism in atherothrombosis.

International audienceNumerous epidemiological studies and clinical trials have reported the health benefits of omega-3 polyunsaturated fatty acids (PUFA), including a lower risk of coronary heart diseases. This review mainly focuses on the effects of alpha-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on some risk factors associated with atherothrombosis, including platelet activation, plasma lipid concentrations and oxidative modification of low-density lipoproteins (LDL). Special focus is given to the effects of marine PUFA on the formation of eicosanoids and docosanoids, and to the bioactive properties of some oxygenated metabolites of omega-3 PUFA produced by cyclooxygenases and lipoxygenases. The antioxidant effects of marine omega-3 PUFA at low concentrations and the pro-oxidant effects of DHA at high concentrations on the redox status of platelets and LDL are highlighted. Non enzymatic peroxidation end-products deriving from omega-3 PUFA such as hydroxy-hexenals, neuroketals and EPA-derived isoprostanes are also considered in relation to atherosclerosis