Elovanoids are novel cell-specific lipid mediators necessary for neuroprotective signaling for photoreceptor cell integrity

Abstract

Docosahexaenoic acid (DHA, 22:6 n-3) is abundant in the retina and is enzymatically converted into pro-homeostatic docosanoids. The DHA- or eicosapentaenoic acid (EPA)-derived 26 carbon fatty acid is a substrate of elongase ELOVL4, which is expressed in photoreceptor cells and generates very long chain (≥C28) polyunsaturated fatty acids including n-3 (VLC-PUFAs,n-3). While ELOVL4 mutations are linked to vision loss and neuronal dysfunctions, the roles of VLC-PUFAs remain unknown. Here we report a novel class of lipid mediators biosynthesized in human retinal pigment epithelial (RPE) cells that are oxygenated derivatives of VLC-PUFAs,n-3; we termed these mediators elovanoids (ELV). ELVs have structures reminiscent of docosanoids but with different physicochemical properties and alternatively-regulated biosynthetic pathways. The structures, stereochemistry, and bioactivity of ELVs were determined using synthetic materials produced by stereo-controlled chemical synthesis. ELVs enhance expression of pro-survival proteins in cells undergoing uncompensated oxidative stress. Our findings unveil a novel autocrine/paracrine pro-homeostatic RPE cell signaling that aims to sustain photoreceptor cell integrity and reveal potential therapeutic targets for retinal degenerations.

International Society for the Study of Fatty Acids and Lipids 2018 Symposium: Arachidonic and Docosahexaenoic Acids in Infant Development

“…The fact that DHA is important for brain and visual acuity development in infancy was demonstrated clearly in rhesus monkeys more than 30 years ago [17] and in human infants consuming DHAsupplemented infant formula [33]. Recent studies have focused on visual and nervous system development [50], fundamental neuroprotective mechanisms at the cellular and molecular level [1], and various retinal disorders [51].…”

“…Jun et al [1] showed that they upregulate the production of several protective proteins during oxidative stress, such as sirtuin, prohibitin, and the anti-apoptotic proteins BcL2 and Bcl-xL. These and other protective activities uncovered by the Bazan's group have direct implications for juvenile macular degeneration and other neurological conditions associated with mutations in ELOVL4.…”

“…Retinal pigment epithelial cells also produce elovanoids, which are active during retinal development and also have pro-survival and pro-homeostatic activities under oxidative stress [1]. Jun et al [1] showed that they upregulate the production of several protective proteins during oxidative stress, such as sirtuin, prohibitin, and the anti-apoptotic proteins BcL2 and Bcl-xL.…”

“…This enzyme is expressed in photoreceptor cells, neurons in several brain regions, and other tissues [1][2][3]. ELOVL4 generates 32-and 34-carbon n-3 VLC-PUFA from which 2 elovanoids were synthesized and characterized in the laboratory of Nicolas Bazan, Louisiana State University Neuroscience Center of Excellence, USA [2].…”

Membrane‐type frizzled‐related protein regulates lipidome and transcription for photoreceptor function

“…32 ELOVL4 synthesizes VLC-PUFAs in retina 21,33 and testes, 34 and generates VLC-saturated fatty acids (VLC-SFAs) in skin and brain. 37 Under uncompensated oxidative stress (UOS), 32C and 34C VLC-PUFAs are released and converted to elovanoids (ELVs) through enzymatic lipoxygenation as a PRC protective response. 37 Under uncompensated oxidative stress (UOS), 32C and 34C VLC-PUFAs are released and converted to elovanoids (ELVs) through enzymatic lipoxygenation as a PRC protective response.…”