Journal
JOURNAL OF LIPID RESEARCH
Volume 62, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1194/jlr.TR120001137
Keywords
adiponectin receptor 1; age-related macular degeneration; Clq tumor necrosis factor-related protein-5; elovanoids; MALDI IMS; membrane-type frizzled-related protein; neuroprotectin D1; interphotoreceptor matrix; very long-chain polyunsaturated fatty acids; Senescence gene programming
Categories
Funding
- National Institutes of Health (NIH) (National Eye Institute) [R01 EY005121]
- Ernest C. and Ivette C. Villere Chair for Retinal Degeneration
- Eye, Ear, Nose & Throat Foundation of New Orleans
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DHA is crucial for the function and biogenesis of photoreceptor cells, while ELVs play a pivotal role in protecting the retina from oxidative stress and aging-induced inflammation, highlighting their potential in therapeutic development for various eye diseases.
The essential fatty acid DHA (22:6, omega-3 or n-3) is enriched in and required for the membrane biogenesis and function of photoreceptor cells (PRCs), synapses, mitochondria, etc. of the CNS. PRC DHA becomes an acyl chain at the sn-2 of phosphatidylcholine, amounting to more than 50% of the PRC outer segment phospholipids, where phototransduction takes place. Very long chain PUFAs (n-3, >= 28 carbons) are at the sn-1 of this phosphatidylcholine molecular species and interact with rhodopsin. PRC shed their tips (DHA-rich membrane disks) daily, which in turn are phagocytized by the retinal pigment epithelium (RPE), where DHA is recycled back to PRC inner segments to be used for the biogenesis of new photoreceptor membranes. Here, we review the structures and stereochemistry of novel elovanoid (ELV)-N32 and ELV-N34 to be ELV-N32: (14Z,17Z,20R,21E,23E,25Z,27S,29Z)-20,27-dihydro xydo-triaconta-14,17,21,23,25,29-hexaenoic acid; ELV-N34: (16Z,19Z,22R,23E,25E,27Z,29S,31Z)-22,29-dihydrox ytetra-triaconta-16,19,23,25,27,31-hexaenoic acid. ELVs are low-abundance, high-potency, protective mediators. Their bioactivity includes enhancing of antiapoptotic and prosurvival protein expression with concomitant downregulation of proapoptotic proteins when RPE is confronted with uncompensated oxidative stress. ELVs also target PRC/RPE senescence gene programming, the senescence secretory phenotype in the interphotoreceptor matrix, as well as inflammaging (chronic, sterile, low-grade inflammation). An important lesson on neuroprotection is highlighted by the ELV mediators that target the terminally differentiated PRC and RPE, sustaining a beautifully synchronized renewal process. The role of ELVs in PRC and RPE viability and function uncovers insights on disease mechanisms and the development of therapeutics for age-related macular degeneration, Alzheimer's disease, and other pathologies.
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