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

Kady, Nermin; Liu, Xuwen; Lydic, Todd A.; Syed, Meesum; Navitskaya, Svetlana; Wang, Qi; Hammer, Sandra S; O’Reilly, Sandra; Huang, Chao; Seregin, Sergey S.; Amalfitano, Andrea; Chiodo, Vince A.; Boye, Sanford L.; Hauswirth, William W.; Antonetti, David A.; Busik, Julia V.

doi:10.2337/db17-1034

Cited by 44 publications

(51 citation statements)

References 52 publications

(60 reference statements)

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“…This is the first report to measure VLC‐PUFA levels in human diabetic retinas, and we observed a decreasing trend in VLC‐PUFA levels and n‐3/n‐6 VLC‐PUFA ratios in diabetic retinas in comparison to age‐matched control retinas. In correlation with our study, Kady et al . reported that intravitreal delivery of human ELOVL4 reduced the diabetes‐induced increase in vascular permeability, thereby increasing VLC‐ceramides in diabetes.…”

Section: Discussionsupporting

confidence: 92%

n‐3 PUFA Supplementation Alters Retinal Very‐Long‐Chain‐PUFA Levels and Ratios in Diabetic Animal Models

Gorusupudi

Chang

Nelson

et al. 2019

Molecular Nutrition Food Res

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Scope Long‐chain (LC)‐PUFAs act as precursors for the special class of retinal lipids known as very‐long‐chain (VLC)‐PUFAs and the effect of diabetes on retinal VLC‐PUFA levels is unexplored. In order to understand the supplemental effect of omega‐3 (n‐3) LC‐PUFAs on decreasing levels of VLC‐PUFAs due to diabetes, Nile rats, which develop diabetes spontaneously, and Akita mouse, a genetic diabetes model, are chosen. Methods and results Human retinal punches from donors are collected from an eye bank; lipids are extracted and analyzed to study the alterations in VLC‐PUFAs and their omega‐3/omega‐6 (n‐3/n‐6) ratios. Nile rats are fed a high‐fat diet to induce hyperglycemia, and then an n‐3 PUFA‐rich diet is fed to the experimental group for 2 months. Diabetic male Akita mice and WT mice are fed with 5% fish‐oil mixed in with their chow for 2 months to observe the effect of n‐3 PUFAs. Results indicate that VLC‐PUFA levels are lower in human diabetic and retinopathic retinal punches compared to age‐matched controls. With supplementation of n‐3 PUFAs, there is a significant increase in n‐3/n‐6 VLC‐PUFA ratios in both animal models compared to diabetic controls. Conclusion Dietary supplementation with n‐3 LC‐PUFAs helps to prevent progression of diabetes and associated retinopathy.

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Section: Discussionsupporting

confidence: 92%

n‐3 PUFA Supplementation Alters Retinal Very‐Long‐Chain‐PUFA Levels and Ratios in Diabetic Animal Models

Gorusupudi

Chang

Nelson

et al. 2019

Molecular Nutrition Food Res

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“…To see whether the protective effect of SPL-kd under inflammatory conditions correlates with a change in certain sphingolipid subspecies, a more extended analysis of sphingolipids was performed by LC-MS/MS (Figure 8 and Table S1). Previous studies demonstrated that not only S1P, but also other sphingolipid molecules, such as sphingomyelin [83], ceramides, and very long-chain ceramides [84,85], are involved in endothelial barrier regulation. In agreement with this, other sphingolipid species may mediate the response towards inflammatory stimuli, as we have seen from the LC-MS/MS data that S1P and dihydro-S1P, which are both modestly increased by TNFα in control cells, synergistically increase by TNFα in SPL-kd ( Figure 8).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge

Stepanovska

Lange

Schwalm

et al. 2020

IJMS

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Sphingosine 1-phosphate (S1P) is a key bioactive lipid that regulates a myriad of physiological and pathophysiological processes, including endothelial barrier function, vascular tone, vascular inflammation, and angiogenesis. Various S1P receptor subtypes have been suggested to be involved in the regulation of these processes, whereas the contribution of intracellular S1P (iS1P) through intracellular targets is little explored. In this study, we used the human cerebral microvascular endothelial cell line HCMEC/D3 to stably downregulate the S1P lyase (SPL-kd) and evaluate the consequences on endothelial barrier function and on the molecular factors that regulate barrier tightness under normal and inflammatory conditions. The results show that in SPL-kd cells, transendothelial electrical resistance, as a measure of barrier integrity, was regulated in a dual manner. SPL-kd cells had a delayed barrier build up, a shorter interval of a stable barrier, and, thereafter, a continuous breakdown. Contrariwise, a protection was seen from the rapid proinflammatory cytokine-mediated barrier breakdown. On the molecular level, SPL-kd caused an increased basal protein expression of the adherens junction molecules PECAM-1, VE-cadherin, and β-catenin, increased activity of the signaling kinases protein kinase C, AMP-dependent kinase, and p38-MAPK, but reduced protein expression of the transcription factor c-Jun. However, the only factors that were significantly reduced in TNFα/SPL-kd compared to TNFα/control cells, which could explain the observed protection, were VCAM-1, IL-6, MCP-1, and c-Jun. Furthermore, lipid profiling revealed that dihydro-S1P and S1P were strongly enhanced in TNFα-treated SPL-kd cells. In summary, our data suggest that SPL inhibition is a valid approach to dampenan inflammatory response and augmente barrier integrity during an inflammatory challenge.

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“…Interestingly, dietary manipulations focusing on PUFAs caused a positive impact on pathological retinal neovascularisation in an animal model of oxygen-induced retinopathy. This effect may be related to the role of PUFAs in inflammation [70] or in the synthesis of very-long-chain ceramides, which seem to maintain vascular integrity in experimental diabetes [71].…”

Section: Rise Of the Role Of Lipid Metabolism In Diabetic Complicationsmentioning

confidence: 99%

New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism

et al. 2019

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Diabetes adversely affects multiple organs, including the kidney, eye and nerve, leading to diabetic kidney disease, diabetic retinopathy and diabetic neuropathy, respectively. In both type 1 and type 2 diabetes, tissue damage is organ specific and is secondary to a combination of multiple metabolic insults. Hyperglycaemia, dyslipidaemia and hypertension combine with the duration and type of diabetes to define the distinct pathophysiology underlying diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. Only recently have the commonalities and differences in the metabolic basis of these tissue-specific complications, particularly those involving local and systemic lipids, been systematically examined. This review focuses on recent progress made using preclinical models and human-based approaches towards understanding how bioenergetics and metabolomic profiles contribute to diabetic kidney disease, diabetic retinopathy and diabetic neuropathy. This new understanding of the biology of complication-prone tissues highlights the need for organ-specific interventions in the treatment of diabetic complications.

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

Cited by 44 publications

References 52 publications

n‐3 PUFA Supplementation Alters Retinal Very‐Long‐Chain‐PUFA Levels and Ratios in Diabetic Animal Models

n‐3 PUFA Supplementation Alters Retinal Very‐Long‐Chain‐PUFA Levels and Ratios in Diabetic Animal Models

Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge

New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism

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