Docosahexaenoic Acid (DHA) Signaling

DHA, a member of the Omega-3 family of essential fatty acids, is 22 carbons long and has 6 double bonds with the n-3 configuration. In neuronal membranes, DHA accumulates in membrane phospholipids, particularly in aminophospholipids, phosphatidylethanolamine (PE), phosphatidylinositol (PI) and Phosphatidylserine (PS). DHA plays an important role in neuronal survival by modulating PS levels and by stimulating Neuroprotectin-D1 (NPD1) synthesis. The increase of PS concentration by DHA promotes the interaction of the PH domain of Akt with the plasma membrane, facilitating translocation and phosphorylation of Akt. Membrane translocation is an event that is a prerequisite for the full activation of Akt by enabling successive phosphorylation of Akt at Thr-308 and Ser-473 by PDK-1 in a PI3K- and PIP3-dependent manner. As the cascade continues, Akt phosphorylates and inactivates both α and β cytosolic forms of GSK3, pro-apoptotic regulators such as BAD, translation regulators such as mTOR, as well as the transcription factor FKHR.Inactivation of BAD results in inhibition of caspases and activation of anti-apoptotic regulators such as Bcl2 and BclXl, which ultimately promotes cell survival. Akt also inactivates Caspase9 and leads to cell survival. Insulin promotes Akt activation and causes upregulation of insulin degrading enzyme (IDE), a metalloprotease responsible for insulin degradation, presumably as a negative feedback control mechanism. IDE not only plays a major role in insulin catabolism, but also mediates degradation of A-β, which is a major activator of apoptosis. The capacity to concentrate membrane PS by DHA is an important determinant for modulating survival signaling. Significant neurological deficits have been observed in n-3 fatty acid deficiency.Besides regulating the PS level in the membrane, DHA also stimulates NPD1 formation and is required for maintaining functional integrity of the retinal pigment epithelium. PLA2 activated by growth factor receptors such as PEDFR cleave specific DHA phospholipids, leading to the synthesis of NPD1. Formation of NPD1 from DHA occurs via intermediates like 17S-HpDHA and 16S,17S-DHA epoxide, which is catalyzed by 15-LOX.NPD1 inhibits oxidative-stress-mediated proinflammatory gene induction and apoptosis, and consequently promotes RPE cell survival. NPD1 has differential effects on the expression of Bcl2 family proteins, upregulating protective Bcl2 proteins and attenuating the expression of BAX, BAD, BID and BIK. In summary, DHA deprivation results in neurological defects, primarily in the memory, visual and sensory systems.