THE EFFECT OF OMEGA 3 FATTY ACIDS ON MEGAKARYOCYTE ARACHIDONIC ACID METABOLISM

Dietary omega 3 polyunsaturated fatty acids are thought to prevent atherosclerosis. It has been proposed that omega 3 fatty acids modify platelet arachidonic acid (20:4) metabolism and platelet function and thereby reduce the incidence of thrombosis. We have previously shown that megakaryocytes (MK), like platelets, contain large amounts of esterified 20:4. The study addresses the following questions: 1) Do omega 3 fatty acids have a primary action on 20:4 metabolism in MK rather than in platelets. 2) Do omega 3 marine oils, docosahexaenoic acid (22:6) and eicosapentaenoic acid (20:5), have a different effect on megakaryocyte 20:4 metabolism than does alpha linolenic acid (18:3), the major omega-3 fatty acid present in normal diets? 3) How do omega-3 fatty acids modify megakaryocyte 20:4 acid metabolism? MK and platelets were isolated from guinea pigs. Isolated cells were incubated with radiolabeled 20:4 acid and unlabeled 18:3, 20:5 or 22:6. Incubations were terminated by lipid extraction, lipid classes were separated by thin-layer chromatography and the incorporation of radiolabeled 20:4 into lipid species was measured by scintillation spectrometry.MK (106) can incorporate about 4 times more 20:4 than 109 platelets. We have previously shown that 20:4 is incorporated into all endogenous pools of 20:4 in MK while platelets appear to have a limited capacity to incorporate 20:4 into phosphatidyl-ethanolamine (PE). Marine oils, 22:6 and 20:5, had similar effects on the incorporation of radiolabeled 20:4 in MK. Both marine oils reduced the total uptake of 20:4 in megakaryocytes but the reduction occured primarily in PE and phosphatidylserine (PS) rather than in phosphatidylcholine (PC) and phosphatidylinositol (PI). Both 20:5 and 22:6 caused a 50% reduction in the incorporation of radiolabeled 20:4 into megakaryocyte PE and PS while only a 20% reduction into PC and PI. There was a striking difference in the effect of 18:3. Even though the incubation of megakaryocytes with 18:3 reduced the uptake of 20:4, the distribution of the incorporated 20:4 in phospholipids of megakaryocytes incubated with 18:3 was similar to that in controls. Thus, 18:3 did not have a selective effect on the incorporation of 20:4 into PE or PS. Whereas megakaryocyte 20:4 metabolism was significantly affected by omega-3 fatty acids, the incubation of guinea pig or human platelets with 22:6, 20:5 or 18:3 did not result in any alteration of the incorporation of 20:4 into platelet phospholipids.20:4 may be initially incorporated into megakaryocyte PC and subsequently transfered to PE and other phospholipids. Omega 3 marine oils, 20:5 and 22:6, appear to have a selective action on the incorporation or transfer of 20:4 into PE and PS. One mechanism for these observations would be an effect of marine oils on megakaryocyte acyltransferase and/or transacylases. Omega 3 linolenic acid appears to reduce the uptake of 20:4 but does not affect the transfer of 20:4 into PE and PS since there was no selective inhibition of uptake into PE or other megakaryocyte phospholipids. The observation that marine oils did not have any effect on 20:4 metabolism in platelets indicated that omega 3 polyunsaturated fatty acids primarily affect megakaryocytes. This phenomenon may result in the production of platelets with abnormal content and compartmentalization of arachidonic acid. The localization of 20:4 in different pools in these platelets could influence the availability of esterified 20:4 for the production of thromboxanes and other eicosanoids. Another implication of the study is that omega 3 fatty acids may have a greater effect on precursor cells than on differentiated cells and tissues and influence cellular maturation.