docosahexaenoic acid ( dha , 22:6w3 ) is a long - chain fatty acid of the omega-3 family derived from the essential precursor linolenic acid ( lna , 18:3w3 ) . dha is the main end - product of lna after successive desaturations and elongations , a metabolic cascade that is assumed to be weak in humans [ 1 , 2 ] . dha is mainly esterified in membrane phospholipids of the brain , retina , and spermatozoa . its function in the two former structures has been well documented , and it is assumed to play an important role in brain development , learning ability , and visual acuity . one outstanding issue , however , remains unresolved , namely to understand how dha specifically accumulates in these organs , especially in brain which is tightly separated from the blood circulation by the blood  brain barrier . furthermore , dha , being highly unsaturated , has the potential to be oxygenated by various lipoxygenases to produce diverse oxylipins . a pioneer work has shown that dha can be converted by the so - called 5-lipoxygenase ( responsible for leukotriene production from arachidonic acid ) into 7-hydroperoxy - dha and its 7-hydroxy derivative 7-hdohe . a further report has described the formation of both 11- and 14-hydroperoxy - dha and their hydroxy derivatives 11- and 14-hdohe by platelet lipoxygenase . more recently , a series of di- and tri - hydroxy derivatives of dha have been described as conjugated trienes and tetraenes derived from double or triple oxidation . the most bioactive of these have been termed resolvins because they promote the resolution of inflammation   and protectin d1 ( pd1 ) or neuroprotectin d1 ( npd1 ) because of a potent anti - inflammatory potential   and potent neuroprotective effect , respectively . the anti - inflammatory effects of these compounds could beneficially affect the function of neurological tissues including brain . the present paper reports on the targeting of the brain with dha - containing phospholipids and on the oxygenation of dha by an omega-6 lipoxygenase , forming an isomer of pd1 that we have named pdx . it is generally assumed that the transport of fatty acids to the brain occurs from the non - esterified pool ( nefa ) bound to serum albumin . brain barrier ( bbb ) as a result of competition between the hydrophobic domain of albumin and that of the endothelial layer of the bbb , as reported for other organs . however , serum albumin also binds lysophospholipids , mainly lysophosphatidylcholine ( lysopc ) , also called lysolecithin . it has been known for years that lysopc is produced by lecithin cholesterol acyl transferase as a result of transferring , within high - density lipoproteins ( hdl ) , the acyl chain from the sn-2 position of hdl - pc to free cholesterol , producing cholesterylester and lysopc ; the latter is further transferred to albumin . however , the release of unsaturated lysopc resulting from the cleavage of pc by the liver phospholipase a1 could not be excluded , so we have considered the possibility that unsaturated lysopc , including dha - containing lysopc ( lysopc - dha ) , can become associated with albumin and transfer across the bbb as do nefa . first , a series of c - labeled fa ( arachidonic , linoleic , oleic , and palmitic acids ) , either as nefa or esterified at the sn-2 position of lysopc , were bound to albumin and injected into the rat to look at the brain accretion of each fa . the three unsaturated fa , but not palmitic acid , were taken up by the brain more efficiently ( from 5- to 10-fold ) when in lysopc compared to the nefa form . secondly , dha in both forms was injected to another set of rats , and its incorporation into the brain , heart , kidney , and liver was measured . again , dha uptake by the brain was around 10-fold more efficient when injected as lysopc - dha compared to dha . this was specific for the brain , since there was no preference between the accumulation of the two forms of dha in the kidney , and the heart and liver even preferred dha to lyso pc - dha . this approach clearly showed that lysopc - dha is a privileged form of transport of dha to the brain . in another approach , c - labeled dha esterified in triacylglycerols ( tg ) , the form of dha in fish oil , was ingested by rats , and the c - dha was followed in various blood compartments and brain phospholipids by gas - chromatography combustion isotope ratio mass spectrometry . focusing on the serum albumin pool , it could be seen that dha accumulated in lysopc - dha with only a slight decrease over time ( evaluated for 72  h ) , while non - esterified dha transiently peaked with a return to basal by 12  h post - intake . in parallel , c - dha was followed in brain phospholipids and was found to increase in the main glycerophospholipids / phosphatidylcholine ( pc ) and phosphatidylethanolamine , until 72  h post - intake . this fits with the hypothesis that lysopc - dha , rather than non - esterified dha , is the main carrier of dha transported by albumin . the same approach was then used in humans with measurement of c - dha accumulation in blood platelets and red cells , the former compartment being known to rapidly accumulate pufa from the nefa pool bound to albumin , whereas the latter compartment is accepted as an index of the brain dha accretion . the pattern for the kinetic accumulation of c - dha in serum albumin was quite similar to that observed in rats , with a transient peak in the nefa pool and return to basal by 12  h post - intake , and accumulation in lysopc with a slow decrease over time . the incorporation of dha into platelet phospholipids was rapid and attained a plateau when c - dha in the nefa pool of albumin had returned to basal ; a lag phase of 8  h followed by a constant rise until 3  days post - intake could be seen in red cells . this is in good agreement with lysopc - dha being the main source of dha for red cells , whereas platelets take up dha rather uniquely from the nefa pool . the kinetics of c - dha in serum albumin nefa and lysopc , as well in platelets and red cells , were not markedly different from those obtained after ingestion of c - dha in triacylglycerols . however , we were able to detect lysopc - dha itself in red cells as additional evidence for considering lysopc as a main source of dha to red cells and in turn to the brain . we then analyzed the content of human and rat plasma for lysopc as well as their fa composition and position on the glycerol backbone . we found substantial amounts of pufa in lysopc , with linoleic , arachidonic , and docosahexaenoic acids being the main species ; around 50% of the pufa was in the sn-2 position of the glycerol moiety . provided that three quarters of the dha in the sn-2 position migrates to the sn-1 position within 20  min at 37c and physiological ph  7.4 , this means that the main form of production of lysopc - dha is the one with dha at the sn-2 position . in summary , we came to the following scheme in which , once absorbed at the intestinal stage , dha may circulate in different forms , including pc ( the main circulating glycerophospholipid ) , cholesterylesters , and tg that are rapidly hydrolyzed by lipoprotein lipase to provide non - esterified dha . part of pc - dha could then be hydrolyzed by the so - called endothelial lipase , which has recently been described as selective for dha - containing phospholipids , to release 1-lyso,2-dha - glycerophosphocholine ( lysopc - dha ) . both lysopc - dha and non - esterified dha are bound to albumin and could then provide dha to the brain , with the former being more efficient . lysopc - dha may be produced from pc - dha hydrolysis by liver phospholipase a1 and released and/or by endothelial lipase from circulating pc - dha . lysopc - dha may be taken up by the brain to be reacylated into pc and/or hydrolyzed to provide dha to be esterified into phospholipids within the brain . interconversion between brain phospholipids may also occur proposed metabolism for dha with ultimate incorporation into brain phospholipids . lysopc - dha may be produced from pc - dha hydrolysis by liver phospholipase a1 and released and/or by endothelial lipase from circulating pc - dha . lysopc - dha may be taken up by the brain to be reacylated into pc and/or hydrolyzed to provide dha to be esterified into phospholipids within the brain . interconversion between brain phospholipids may also occur considering that dha is at the sn-1 position of lysopc , the most stable form of lysopc - dha ( see above ) is not the physiological form to be reacylated in the brain , because dha is stored in tissues at the sn-2 position ; we therefore made an attempt to keep dha at this position . more recently , we set up a one - step enzymatic way to generate acedopc from pc - dha , which improved the yield of the isomer with dha at the sn-2 position   ( fig .  2 ) . acedopc is produced in order to assess its metabolism in humans ( use of c - labeled acedopc ) and to test its effects on different neurobiological disorders in rodents . pc - dha purified from the micro - algae crypthecodinium cohnii is submitted for transesterification by the action of an immobilized triglyceride lipase in the presence of ethylacetate . c - labeled dha is prepared by cultivating the micro - algae in the presence ofc - labeled acetate scheme for the preparation of acedopc from pc - dha . pc - dha purified from the micro - algae crypthecodinium cohnii is submitted for transesterification by the action of an immobilized triglyceride lipase in the presence of ethylacetate . c - labeled dha is prepared by cultivating the micro - algae in the presence ofc - labeled acetate pd1 has been shown by the group of serhan to be produced by treatment of dha by soybean lipoxygenase . this lipoxygenase is an omega-6 lipoxygenase , which produces 17(s)-hoo - docosahexa-4z,7z,10z,13z,15e,19z - enoic acid ( 17(s)-hpdohe ) from dha , which is easily reduced into its hydroxy derivative 17(s)-hdohe . pd1 has been further characterized as 10(s),17(s)-dioh - docosahexa-4z,7z,11e,13e,15z,19z - enoic acid , assuming the formation of an epoxide intermediate as is well known for leukotriene b4 formation from arachidonic acid . in the mean time , butovich et al . however , the two structures differ in their conjugated triene cis / trans geometry , which is e , z , e in the latter molecule while it is e , e , z in pd1 , according to serhan . we have reconsidered the conversion of dha by soybean lipoxygenase type 1-b and found a major product as 17(s)-hdohe and a second one as 10(s),17(s)-dioh - docosahexa-4z,7z,11e,13z,15e,19z - enoic acid in agreement with butovich , although this author did not determine the stereoconfiguration of carbon 10 . our results strongly suggest that the product we have characterized is likely to derive from a double lipoxygenation of dha . interestingly , pdx and other fatty acids having the e , z , e conjugated triene geometry are potent inhibitors of platelet aggregation , whereas those with the e , e , z geometry are not . this makes the e , z , e conjugated triene motif relevant in the inhibition of platelet aggregation by lipoxygenase products . these data follow previous evidence showing that monohydroxy derivatives of dha , produced by omega-9 and omega-6 lipoxygenases , inhibit thromboxane - induced platelet aggregation , summarized in fig .  3 . platelet aggregation is inhibited by monoxydroxy derivative of dha and by the dihydroxy derivative conjugated triene having the e , z , e geometry , issued from the double lipoxygenation of dha , called pdx , an isomer of neuroprotectin d1 inhibition of platelet activation by lipoxygenase ( lox ) products of dha . platelet aggregation is inhibited by monoxydroxy derivative of dha and by the dihydroxy derivative conjugated triene having the e , z , e geometry , issued from the double lipoxygenation of dha , called pdx , an isomer of neuroprotectin d1 altogether , our data show that dha metabolites may attenuate platelet activation , in addition to dha competition with the arachidonic acid cascade from endogenous phospholipids . it is conceivable that these metabolites may also reduce inflammatory processes in neural tissues including brain .
docosahexaenoic acid ( dha ) , the end - product of the metabolism of omega-3 family fatty acids , is the main polyunsaturated fatty acid of the brain , but its accumulation is incompletely understood . 
 this paper reviews how it could accumulate through specific uptake of dha - containing lysophosphatidylcholine ( lysopc - dha ) . 
 dha migrates very easily from the sn-2 position of lysopc , which could be considered as the physiological form of polyunsaturated lysopc , to the sn-1 position , which is much more stable . 
 an approach preventing migration by acetylating the sn-1 position , while retaining the main physico - chemical properties of the carrier , is described . 
 also , the double lipoxygenation and bond - isomerization of dha into 10(s),17(s)-docosahexa-4z,7z,11e,13z,15e,19z - enoic acid , named pdx , by soybean lipoxygenase is described . as in other e , 
 z , e conjugated trienes , pdx is shown to inhibit human blood platelet aggregation at submicromolar concentrations .