The role of dihydrosphingolipids in disease

Magaye, Ruth; Savira, Feby; Yue, Hua; Kelly, Darren J.; Reid, Christopher M.; Flynn, Bernard L.; Liew, Danny; Wang, Bing Hui

doi:10.1007/s00018-018-2984-8

Cited by 38 publications

(29 citation statements)

References 265 publications

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“…Nevertheless, S1P and dihydro-S1P remain the only measured sphingolipids showing a unique pattern of increase in SPL-kd cells under inflammatory conditions. Since several studies have indicated a positive correlation between reduced dihydro-S1P and reduced endothelial barrier function [86], further investigation is required to elucidate to what extent dihydro-S1P is involved in the biphasic resistance response of SPL-kd.…”

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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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 bioactive lipid regulating a plethora of physiological as well as pathophysiological processes via binding to 5 specific G protein-coupled receptors (S1PR1-5). [1][2][3] S1P is present at high concentrations in blood where it is mainly bound to high density lipoprotein (HDL) and albumin. 4 In the vasculature, S1P is critical to maintain the endothelial barrier function via S1PR1 signaling.…”

Section: Introductionmentioning

confidence: 99%

Determinants of Serum- and Plasma Sphingosine-1-Phosphate Concentrations in a Healthy Study Group

Daum

Winkler

Moritz

et al. 2020

TH Open

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Introduction To correctly interpret plasma- or serum-sphingosine-1-phosphate (S1P) concentrations measured in clinical studies it is critical to understand all major determinants in healthy controls. Methods Serum- and plasma-S1P from 174 healthy blood donors was measured by liquid chromatography-tandem mass spectrometry and correlated to clinical laboratory data. Selected plasma samples, 10 with high and 10 with low S1P concentrations, were fractionated into very low-density lipoprotein (VLDL)-, low density lipoprotein (LDL)-, high density lipoprotein (HDL)-, and lipoprotein-free fractions. S1P was then measured in each fraction to determine its distribution. Results The mean S1P concentration in serum (1.04 ± 0.24 nmol/mL) was found 39% higher compared with plasma (0.75 ± 0.16 nmol/mL) and overall was not different between men and women. Only when stratified for age and gender, older women were found to exhibit higher circulatory S1P levels than men. In plasma, S1P levels correlate to red blood cell (RBC) counts but not to platelet counts. Conversely, serum-S1P correlates to platelet counts but not to RBC counts. In addition, eosinophil counts are strongly associated with serum-S1P concentrations. Both serum- and plasma-S1P correlate to total cholesterol but not to HDL-C. The distribution of S1P between VLDL-, LDL-, HDL-, and lipoprotein-free fractions is independent of total plasma-S1P concentrations. S1P concentrations in HDL but not in LDL are highly variable. Conclusion These data indicate S1P concentrations in plasma and serum to be differentially associated with cell counts and S1P carrier proteins. Besides platelets, eosinophil counts are identified as a novel determinant for serum-S1P concentrations further suggesting a role for S1P in eosinophil pathologies.

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“…In the vasculature, ceramide accumulation leads to increased atherosclerotic plaques and inflammatory arteriolar dilation ( 10 – 13 ). They can also lead to increased cardiovascular disease ( 14 , 15 ), hepatic steatosis ( 16 ), and increased inflammation in immune cells ( 17 ). As opposed to other targets, skin largely benefits from increased ceramides, with increased cell differentiation and wound healing, as well as decreased senescence ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

“…Ceramides have a well-established role in the development of CVDs, including atherosclerosis ( 15 , 93 ), cardiomyopathy ( 15 , 94 , 95 ), heart failure ( 15 , 96 ), myocardial infarction ( 14 , 15 ), and stroke ( 14 , 15 ). In particular, dihydroceramides, the precursors of ceramides in the de novo biosynthetic pathway of sphingolipids, are implicated in the development of CVD ( 15 ).…”

Section: Introduction To Ceramidesmentioning

confidence: 99%

“…Other authors have reported the existence of a strong correlation between CVD and increased dihydroceramide levels. Both dihydroceramides and ceramides correlate with the release of the inflammatory cytokine interleukin 6 (IL-6), but only dihydroceramides correlates with macrophage inflammatory protein 1β (MIP-1β) release ( 13 , 15 ). Studies have also shown that dihydroceramide levels are elevated in patients with rheumatoid arthritis ( 109 ), patients with left ventricular assist devices ( 110 ) and hypertensive rats ( 13 – 15 , 41 , 111 , 112 ).…”

Section: Introduction To Ceramidesmentioning

confidence: 99%

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The Role of Ceramides in Diabetes and Cardiovascular Disease Regulation of Ceramides by Adipokines

2020

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Metabolic dysfunction is intertwined with the pathophysiology of both diabetes and cardiovascular disease. Recently, one particular lipid class has been shown to influence the development and sustainment of these diseases: ceramides. As a subtype of sphingolipids, these species are particularly central to many sphingolipid pathways. Increased levels of ceramides are known to correlate with impaired cardiovascular and metabolic health. Furthermore, the interaction between ceramides and adipokines, most notably adiponectin and leptin, appears to play a role in the pathophysiology of these conditions. Adiponectin appears to counteract the detrimental effects of elevated ceramides, largely through activation of the ceramidase activity of its receptors. Elevated ceramides appear to worsen leptin resistance, which is an important phenomenon in the pathophysiology of obesity and metabolic syndrome.

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The role of dihydrosphingolipids in disease

Cited by 38 publications

References 265 publications

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

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

Determinants of Serum- and Plasma Sphingosine-1-Phosphate Concentrations in a Healthy Study Group

The Role of Ceramides in Diabetes and Cardiovascular Disease Regulation of Ceramides by Adipokines

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