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Matthew S. Faber, Todd A. Lydic, Maria Tikhonenko, Svetlana N. Bozack, Sergey S. Seregin, Andrea Amalfitano, Vince A. Chiodo, Sanford L. Boye, William W. Hauswirth, Julia V. Busik; Normalization of Fatty Acid Elongase ELOVL4 In Diabetic Retina Prevents Vascular Degeneration and Inflammation Through Modification of Sphingolipid Metabolism. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2407.
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Fatty acid elongase ELOVL4 is the most abundant elongase in the retina, and it synthesizes ≥ C26 saturated and polyunsaturated fatty acids (PUFA). We have previously shown that dramatic diabetes-induced downregulation of ELOVL4 was associated with retinal-specific changes in lipid metabolism, retinal inflammation and blood-retina barrier breakdown. The goal of this study is to determine whether restoration of retinal ELOVL4 levels is sufficient to prevent early diabetes induced retinal vascular degeneration.
Human ELOVL4 was overexpressed in human retinal pigmented epithelial (RPE) cells by an E1- and E3-deleted adenoviral vector. Cells were challenged with 1 ng/ml IL-1β or vehicle for 48 hours. ELOVL4 and ICAM-1 mRNA were assessed by qPCR. Lipid extracts were analyzed by tandem mass spectrometry. Streptozotocin (STZ) diabetic rats received intravitreal injection of hELOVL4 packaged in adeno-associated virus type 2 containing four capsid Y-F mutations (AAV2 mut quad), or vehicle. Retinal vascular permeability was assessed by measuring extravasation of FITC-albumin after 8 weeks of diabetes, compared to controls.
Overexpression of ELOVL4 in RPE cells caused a 45 % decrease in IL-1β induced ICAM-1 mRNA expression relative to control. Intravitreal delivery of hELOVL4-AAV2 mut quad in STZ diabetic rats resulted in a 39 % reduction in diabetes-induced vascular permeability after 8 weeks of diabetes. Lipidome analysis of ELOVL4-overexpressing cells revealed a 2.5-fold increase in 26:0 ceramide relative to controls, while 16:0 ceramide decreased 1.7-fold; no effect on ≥ C26 PUFAs was observed in any lipid class.
Normalization of retinal ELOVL4 expression mitigates retinal inflammation and prevents early breakdown of the blood-retina barrier in diabetic animals by modulating retinal sphingolipid metabolism. Retinal gene delivery of ELOVL4 by capsid-modified AAV2 may represent a novel strategy for the prevention of diabetic visual impairment.
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