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

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.

• Publication year

  2018

• Venue

  Diabetes

• Publication date

  2018-01-23

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.2337/db17-1034PMID 29362226PMCID 5860862
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Imbalances in Mobilization and Activation of Pro-Inflammatory and Vascular Reparative Bone Marrow-Derived Cells in Diabetic Retinopathy

  2016cited by this paper
• Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy

  2016cited by this paper
• Lipidomic profiling of plasma and urine from patients with Gaucher disease during enzyme replacement therapy by nanoflow liquid chromatography-tandem mass spectrometry.

  2015cited by this paper
• Phenotypes and biomarkers of diabetic retinopathy.

  2014cited by this paper
• Changes in the Daily Rhythm of Lipid Metabolism in the Diabetic Retina

  2014cited by this paper
• A monophasic extraction strategy for the simultaneous lipidome analysis of polar and nonpolar retina lipids[S]

  2014cited by this paper
• ON OXIDATIVE STRESS AND DIABETIC COMPLICATIONS

  2013cited by this paper
• Examining the role of lipid mediators in diabetic retinopathy

  2012cited by this paper
• Methylglyoxal induces hyperpermeability of the blood–retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases

  2012cited by this paper
• Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability

  2012cited by this paper
• Very long-chain fatty acids: elongation, physiology and related disorders.

  2012cited by this paper
• Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic β-cells by stearoyl-CoA desaturase and Elovl6.

  2011cited by this paper
• The Unconventional Role of Acid Sphingomyelinase in Regulation of Retinal Microangiopathy in Diabetic Human and Animal Models

  2011cited by this paper
• Production of ELOVL4 transgenic pigs: a large animal model for Stargardt-like macular degeneration

  2011cited by this paper
• Essential Role of ELOVL4 Protein in Very Long Chain Fatty Acid Synthesis and Retinal Function*

  2011cited by this paper
• The role of fatty acid elongation in epidermal structure and function

  2011cited by this paper
• Quantifying transduction efficiencies of unmodified and tyrosine capsid mutant AAV vectors in vitro using two ocular cell lines

  2011cited by this paper
• Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice

  2011cited by this paper
• Hetero-oligomeric interactions of an ELOVL4 mutant protein: implications in the molecular mechanism of Stargardt-3 macular dystrophy

  2010cited by this paper
• Oxidative stress and diabetic complications.

  2010cited by this paper
• Effects of ischemic preconditioning and bevacizumab on apoptosis and vascular permeability following retinal ischemia-reperfusion injury.

  2010cited by this paper
• Very long chain sphingolipids: Tissue expression, function and synthesis

  2010cited by this paper
• TNF-α Signals Through PKCζ/NF-κB to Alter the Tight Junction Complex and Increase Retinal Endothelial Cell Permeability

  2010cited by this paper
• Inhibition of cytokine signaling in human retinal endothelial cells through downregulation of sphingomyelinases by docosahexaenoic acid.

  2010cited by this paper
• Effects of medical therapies on retinopathy progression in type 2 diabetes.

  2010cited by this paper
• Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

  2010cited by this paper
• Global analysis of retina lipids by complementary precursor ion and neutral loss mode tandem mass spectrometry.

  2009cited by this paper
• Remodeling of Retinal Fatty Acids in an Animal Model of Diabetes

  2009cited by this paper
• Occludin Phosphorylation and Ubiquitination Regulate Tight Junction Trafficking and Vascular Endothelial Growth Factor-induced Permeability*

  2009cited by this paper
• Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia.

  2008cited by this paper
• Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids

  2008influential reference
• Retinal pathology and skin barrier defect in mice carrying a Stargardt disease-3 mutation in elongase of very long chain fatty acids-4

  2007cited by this paper
• Loss of functional ELOVL4 depletes very long-chain fatty acids (> or =C28) and the unique omega-O-acylceramides in skin leading to neonatal death.

  2007cited by this paper
• Lipid‐protein cargo transfer: A mode of direct cell‐to‐cell communication for lipids and their associated proteins

  2007cited by this paper
• Loss of functional ELOVL4 depletes very long-chain fatty acids (≥C28) and the unique ω-O-acylceramides in skin leading to neonatal death

  2007cited by this paper
• Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice

  2007cited by this paper
• A Stargardt disease‐3 mutation in the mouse Elovl4 gene causes retinal deficiency of C32–C36 acyl phosphatidylcholines

  2007cited by this paper
• Proteomic and bioinformatic analysis of epithelial tight junction reveals an unexpected cluster of synaptic molecules

  2006cited by this paper
• Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity Published, JLR Papers in Press, June 21, 2006.

  2006cited by this paper
• VEGF activation of protein kinase C stimulates occludin phosphorylation and contributes to endothelial permeability.

  2006cited by this paper
• Dominant Negative Mechanism Underlies Autosomal Dominant Stargardt-like Macular Dystrophy Linked to Mutations in ELOVL4*

  2005cited by this paper
• LIPID STAINING FOR THE ELECTRON MICROSCOPE: A NEW METHOD

  2005cited by this paper
• Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration.

  2005cited by this paper
• Characterization of mouse orthologue of ELOVL4: genomic organization and spatial and temporal expression.

  2004cited by this paper
• Two approaches to double post-embedding immunogold labeling of freeze-substituted tissue embedded in low temperature Lowicryl HM20 resin.

  2003cited by this paper
• Endothelium‐specific platelet‐derived growth factor‐B ablation mimics diabetic retinopathy

  2002cited by this paper
• A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy

  2001cited by this paper
• TGF-β increases retinal endothelial cell permeability by increasing MMP-9 : Possible role of glial cells in endothelial barrier function

  2001cited by this paper
• TGF-beta increases retinal endothelial cell permeability by increasing MMP-9: possible role of glial cells in endothelial barrier function.

  2001cited by this paper
• Vascular Endothelial Growth Factor Induces Rapid Phosphorylation of Tight Junction Proteins Occludin and Zonula Occluden 1

  1999cited by this paper
• Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group.

  1998cited by this paper
• Translational diffusion measurements of a fluorescent phospholipid between MDCK-I cells support the lipid model of the tight junctions.

  1994cited by this paper
• Cytochemical evidence for the presence of phospholipids in epithelial tight junction strands.

  1993cited by this paper
• Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin?

  1991cited by this paper
• Experimental Galactosemia Produces Diabetic-like Retinopathy

  1984cited by this paper
• Junction formation between cultured normal rat hepatocytes. An ultrastructural study on the presence of cholesterol and the structure of developing tight-junction strands.

  1983cited by this paper
• Ceramides of pig epidermis: structure determination.

  1983cited by this paper
• Evidence for the lipidic nature of tight junction strands

  1982cited by this paper
• Lipid staining for the electron microscope: a new method.

  1975cited by this paper

• Diabetic Retinopathy in Focus: Update on Treatment Advances, Pharmaceutical Approaches, and New Technologies.

  2025cites this paper
• Selective association of plasma sphingolipid species with insulin sensitivity and secretion in normoglycemic Black and White American adults

  2025cites this paper
• Elevated Very-Long-Chain Ceramides in the Vitreous Humor of Patients With Proliferative Diabetic Retinopathy

  2025cites this paper
• Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy.

  2024cites this paper
• Manifestation of Pathology in Animal Models of Diabetic Retinopathy Is Delayed from the Onset of Diabetes

  2024cites this paper
• Untargeted Analysis of Lipids Containing Very Long Chain Fatty Acids in Retina and Retinal Tight Junctions.

  2023cites this paper
• Claudin-10b cation channels in tight junction strands: Octameric-interlocked pore barrels constitute paracellular channels with low water permeability

  2023cites this paper
• Circulating Sphingolipids in Insulin Resistance, Diabetes and Associated Complications

  2023influential citation
• Understanding the Roles of Very-Long-Chain Polyunsaturated Fatty Acids (VLC-PUFAs) in Eye Health

  2023cites this paper
• Cholesterol crystal formation is a unifying pathogenic mechanism in the development of diabetic retinopathy

  2023cites this paper
• Specific Deoxyceramide Species Correlate with Expression of Macular Telangiectasia Type 2 (MacTel2) in a SPTLC2 Carrier HSAN1 Family

  2023cites this paper
• trans-2-Enoyl-CoA Reductase Tecr-Driven Lipid Metabolism in Endothelial Cells Protects against Transcytosis to Maintain Blood-Brain Barrier Homeostasis

  2022cites this paper
• Glioblastoma Multiforme Tumors in Women Have a Lower Expression of Fatty Acid Elongases ELOVL2, ELOVL5, ELOVL6, and ELOVL7 than in Men

  2022cites this paper
• A Comprehensive Profiling of Cellular Sphingolipids in Mammalian Endothelial and Microglial Cells Cultured in Normal and High-Glucose Conditions

  2022influential citation
• Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis.

  2022cites this paper
• C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood–Retinal Barrier Tight Junctions

  2022cites this paper
• Sphingolipids as critical players in retinal physiology and pathology.

  2021cites this paper
• Current understanding of the molecular and cellular pathology of diabetic retinopathy

  2021cites this paper
• Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets

  2021cites this paper
• Glucose-mediated de novo lipogenesis in photoreceptors drives early diabetic retinopathy

  2021cites this paper
• Probing Physical Properties of the Cellular Membrane in Senescent Cells by Fluorescence Imaging.

  2021cites this paper
• High Glucose Reduces the Paracellular Permeability of the Submandibular Gland Epithelium via the MiR-22-3p/Sp1/Claudin Pathway

  2021cites this paper
• Digital Digital Glucose-mediated de novo lipogenesis in photoreceptors drives Glucose-mediated de novo lipogenesis in photoreceptors drives early diabetic retinopathy early diabetic retinopathy

  2021cites this paper
• Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge

  2020cites this paper
• Role of ceramides in the pathogenesis of diabetes mellitus and its complications.

  2020cites this paper
• Sphingolipids as critical players in retinal physiology and pathology

  2020cites this paper
• Tight Junction Structure and Function Revisited.

  2020cites this paper
• Diabetic photoreceptors: Mechanisms underlying changes in structure and function

  2020cites this paper
• Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes

  2020cites this paper
• Shedding light on isomeric FAHFA lipid structures using 213 nm ultraviolet photodissociation mass spectrometry

  2020cites this paper
• A Study of Correlation Ratios for Low- and High-Density Lipoprotein in Comparison with Antioxidant Vitamins A, E, C at Different Levels of Glycosylated Hemoglobin among Type 2 Diabetes Patients

  2020cites this paper
• Sphingolipids as Emerging Mediators in Retina Degeneration

  2019cites this paper
• Glycosylated sphingolipids and progression to kidney dysfunction in type 1 diabetes.

  2019cites this paper
• A family with spinocerebellar ataxia and retinitis pigmentosa attributed to an ELOVL4 mutation

  2019cites this paper
• Role of Bioactive Sphingolipids in Inflammation and Eye Diseases.

  2019cites this paper
• Endomucin restores depleted endothelial glycocalyx in the retinas of streptozotocin‐induced diabetic rats

  2019cites this paper
• Inflammatory Ocular Diseases and Sphingolipid Signaling.

  2019cites this paper
• Emerging Insights and Interventions for Diabetic Retinopathy

  2019cites this paper
• New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism

  2019cites this paper
• n-3 PUFA Supplementation Alters Retinal Very-Long-Chain-PUFA Levels and Ratios in Diabetic Animal Models.

  2019cites this paper
• Plasma Exosomes Contribute to Microvascular Damage in Diabetic Retinopathy by Activating the Classical Complement Pathway

  2018cites this paper
• Deletion of the stress‐response protein REDD1 promotes ceramide‐induced retinal cell death and JNK activation

  2018cites this paper
• ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function

  2018cites this paper