March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Normalization of Fatty Acid Elongase ELOVL4 In Diabetic Retina Prevents Vascular Degeneration and Inflammation Through Modification of Sphingolipid Metabolism
Author Affiliations & Notes
  • Matthew S. Faber
    Physiology,
    Michigan State University, Lansing, Michigan
  • Todd A. Lydic
    Physiology,
    Michigan State University, Lansing, Michigan
  • Maria Tikhonenko
    Physiology,
    Michigan State University, Lansing, Michigan
  • Svetlana N. Bozack
    Physiology,
    Michigan State University, Lansing, Michigan
  • Sergey S. Seregin
    Microbiology and Molecular Genetics,
    Michigan State University, Lansing, Michigan
  • Andrea Amalfitano
    Microbiology and Molecular Genetics,
    Michigan State University, Lansing, Michigan
  • Vince A. Chiodo
    Ophthalmology and Molecular Genetics and Retina Gene Therapy Group, University of Florida, Gainesville, Florida
  • Sanford L. Boye
    Ophthalmology and Molecular Genetics and Retina Gene Therapy Group, University of Florida, Gainesville, Florida
  • William W. Hauswirth
    Ophthalmology and Molecular Genetics and Retina Gene Therapy Group, University of Florida, Gainesville, Florida
  • Julia V. Busik
    Physiology,
    Michigan State University, Lansing, Michigan
  • Footnotes
    Commercial Relationships  Matthew S. Faber, None; Todd A. Lydic, None; Maria Tikhonenko, None; Svetlana N. Bozack, None; Sergey S. Seregin, None; Andrea Amalfitano, None; Vince A. Chiodo, None; Sanford L. Boye, None; William W. Hauswirth, None; Julia V. Busik, None
  • Footnotes
    Support  NIH Grant (EY-016077 to J.V.B., RR-025386 to G.E.R. and J.V.B) MEAS (MICL02163 to J.V.B.)
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2407. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: diabetic retinopathy • gene transfer/gene therapy • lipids 
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