ELOVL4-Mediated Production of Very Long-Chain Ceramides Stabilizes Tight Junctions and Prevents Diabetes-Induced Retinal Vascular Permeability.

Abstract

Tight junctions (TJs) involve close apposition of transmembrane proteins between cells. Although TJ proteins have been studied in detail, the role of lipids is largely unknown. We addressed the role of very long-chain (VLC ≥26) ceramides in TJs using diabetes-induced loss of the blood-retinal barrier as a model. VLC fatty acids that incorporate into VLC ceramides are produced by elongase elongation of very long-chain fatty acids protein 4 (ELOVL4). ELOVL4 is significantly reduced in the diabetic retina. Overexpression of ELOVL4 significantly decreased basal permeability, inhibited vascular endothelial growth factor (VEGF)- and interleukin-1β-induced permeability, and prevented VEGF-induced decrease in occludin expression and border staining of TJ proteins ZO-1 and claudin-5. Intravitreal delivery of AAV2-hELOVL4 reduced diabetes-induced increase in vascular permeability. Ultrastructure and lipidomic analysis revealed that ω-linked acyl-VLC ceramides colocalize with TJ complexes. Overall, normalization of retinal ELOVL4 expression could prevent blood-retinal barrier dysregulation in diabetic retinopathy through an increase in VLC ceramides and stabilization of TJs.

• Authors: Nermin M Kady, Xuwen Liu, Todd A Lydic, Meesum H Syed, Svetlana Navitskaya, Qi Wang, Sandra S Hammer, Sandra O'Reilly, Chao Huang, Sergey S Seregin, Andrea Amalfitano, Vince A Chiodo, Sanford L Boye, William W Hauswirth, David A Antonetti, Julia V Busik
• Journal: Diabetes (Diabetes) Vol. 67 Issue 4 Pg. 769-781 (04 2018) ISSN: 1939-327X [Electronic] United States
• PMID: 29362226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by the American Diabetes Association.

Chemical References

• Ceramides
• Claudin-5
• ELOVL4 protein, human
• Elovl4 protein, mouse
• Eye Proteins
• Interleukin-1beta
• Membrane Proteins
• Occludin
• Vascular Endothelial Growth Factor A
• Zonula Occludens-1 Protein

Topics

• Animals
• Blood-Retinal Barrier (metabolism)
• Capillary Permeability (genetics)
• Cattle
• Ceramides (metabolism)
• Claudin-5 (metabolism)
• Diabetes Mellitus, Experimental (complications, metabolism)
• Diabetic Retinopathy (etiology, genetics, metabolism)
• Endothelial Cells (metabolism, ultrastructure)
• Eye Proteins (genetics, metabolism)
• Humans
• Interleukin-1beta (metabolism)
• Membrane Proteins (genetics, metabolism)
• Mice
• Occludin (metabolism)
• Retina (metabolism)
• Retinal Vessels (metabolism, ultrastructure)
• Tight Junctions (metabolism, ultrastructure)
• Vascular Endothelial Growth Factor A (metabolism)
• Zonula Occludens-1 Protein (metabolism)