DHA Metabolism: Targeting the Brain and Lipoxygenation

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.

[1]  J. Hamilton.  New insights into the roles of proteins and lipids in membrane transport of fatty acids. , 2007, Prostaglandins, leukotrienes, and essential fatty acids.

[2]  M. Lagarde,et al.  Characterization of plasma unsaturated lysophosphatidylcholines in human and rat. , 2000, The Biochemical journal.

[3]  N. Brossard,et al.  Metabolic fate of an oral tracer dose of [13C]docosahexaenoic acid triglycerides in the rat. , 1996, The American journal of physiology.

[4]  I. Butovich.  On the structure and synthesis of neuroprotectin D1, a novel anti-inflammatory compound of the docosahexaenoic acid family Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.C500015-JLR200 , 2005, Journal of Lipid Research.

[5]  M. Lagarde,et al.  Full characterization of PDX, a neuroprotectin/protectin D1 isomer, which inhibits blood platelet aggregation , 2009, FEBS letters.

[6]  M. Lagarde,et al.  Inhibition by lipoxygenase products of TXA2-like responses of platelets and vascular smooth muscle. 14-Hydroxy from 22:6n-3 is more potent than 12-HETE. , 1988, Biochemical pharmacology.

[7]  J. Pousin,et al.  Blood compartmental metabolism of docosahexaenoic acid (DHA) in humans after ingestion of a single dose of [(13)C]DHA in phosphatidylcholine. , 1999, Journal of lipid research.

[8]  M. Lagarde,et al.  Synthesis of acetyl, docosahexaenoyl-glycerophosphocholine and its characterization using nuclear magnetic resonance , 1999, Lipids.

[9]  J. Lecerf,et al.  Preferential incorporation of sn-2 lysoPC DHA over unesterified DHA in the young rat brain. , 1994, The American journal of physiology.

[10]  C. Serhan,et al.  The Docosatriene Protectin D1 Is Produced by TH2 Skewing and Promotes Human T Cell Apoptosis via Lipid Raft Clustering* , 2005, Journal of Biological Chemistry.

[11]  S. Wootton,et al.  Eicosapentaenoic and docosapentaenoic acids are the principal products of α-linolenic acid metabolism in young men* , 2002, British Journal of Nutrition.

[12]  E. Corey,et al.  Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils. , 1984, The Journal of clinical investigation.

[13]  C. Serhan,et al.  Molecular Circuits of Resolution: Formation and Actions of Resolvins and Protectins1 , 2005, The Journal of Immunology.

[14]  J. Lecerf,et al.  Human plasma albumin transports [13C]docosahexaenoic acid in two lipid forms to blood cells. , 1997, Journal of lipid research.

[15]  S. Cunnane,et al.  alpha-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans. , 2009, Prostaglandins, leukotrienes, and essential fatty acids.

[16]  J. Lecerf,et al.  Unsaturated Fatty Acids Esterified in 2‐Acyl‐1‐Lysophosphatidylcholine Bound to Albumin Are More Efficiently Taken up by the Young Rat Brain than the Unesterified Form , 1992, Journal of neurochemistry.

[17]  P. Subbaiah,et al.  Phospholipid and fatty acid specificity of endothelial lipase: potential role of the enzyme in the delivery of docosahexaenoic acid (DHA) to tissues. , 2007, Biochimica et biophysica acta.

[18]  N. Bazan,et al.  Brain response to injury and neurodegeneration: endogenous neuroprotective signaling. , 2005, Annals of the New York Academy of Sciences.

[19]  C. Serhan,et al.  Novel Docosatrienes and 17S-Resolvins Generated from Docosahexaenoic Acid in Murine Brain, Human Blood, and Glial Cells , 2003, The Journal of Biological Chemistry.

[20]  Hee-Yong Kim,et al.  Mechanisms of action of docosahexaenoic acid in the nervous system , 2001, Lipids.

[21]  Yan Lu,et al.  Anti-Inflammatory Actions of Neuroprotectin D1/Protectin D1 and Its Natural Stereoisomers: Assignments of Dihydroxy-Containing Docosatrienes1 , 2006, The Journal of Immunology.

[22]  H. Sprecher,et al.  Synthesis of hydroxy fatty acids from 4, 7, 10, 13, 16, 19-[1-14C] docosahexaenoic acid by human platelets. , 1983, The Journal of biological chemistry.

[23]  P. Subbaiah.  Lysolecithin acyltransferase of human plasma: assay and characterization of enzyme activity. , 1986, Methods in enzymology.

[24]  N. Bazan,et al.  Brain Response to Injury and Neurodegeneration , 2005 .