Exosomes released from embryonic hippocampal cells under ceramide treatment carry a specific miRNA signature for sphingolipid pathway and cell differentiation
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PROVIDER: PRJNA947939 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: Identification of the miRNA signature carried by the exosomes released from embryonic hippocampal cells under ceramide treatment Outcome: We investigated the role of ceramide in amplifying the differentiation signal of HN9.10 cells. Treatment of HN9.10 cells with ceramide caused the release of exosomes carrying neutral sphingomyelinase and neutral ceramidase. The analysis of exosomal miRNAs showed that 38 miRNAs were differentially expressed in a statistically significant manner, with some overexpressed miRNAs regulating genes encoding for proteins involved in biological, homeostatic, biosynthetic and small molecule metabolic processes, embryo development and cell differentiation, all phenomena that could be relevant for HN9.10 cell differentiation.
2023-07-12 | GSE228052 | GEO
Project description:Growing evidence correlated changes in bioactive sphingolipids, particularly sphingosine-1-phosphate (S1P) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in the initiation and progression of atherosclerosis. Yet, how sphingolipid metabolism and signaling change and contribute to endothelial dysfunction and atherosclerosis remain poorly understood. By using a mouse model of coronary atherosclerosis, we demonstrated that hemodynamic stress induces an early metabolic rewiring of endothelial sphingolipid de novo biosynthesis favoring S1P signaling over ceramide as protective response. Furthermore, our data are paradigm shift from the current believe that ceramide accrual contributes to endothelial dysfunction. The de novo biosynthesis of sphingolipids is commenced by serine palmitoyltransferase (SPT), and is downregulated by NOGO-B, an ER membrane protein. We showed that Nogo-B is upregulated by hemodynamic stress in myocardial endothelial cells (EC) of ApoE-/- mice and is expressed in the endothelium lining coronary lesions in mice and human. We demonstrated that mice lacking Nogo-B specifically in EC (Nogo-A/BECKOApoE-/-) were resistant to coronary atherosclerosis development and progression, and mortality. Fibrous cap thickness was significantly increased in Nogo-A/BECKOApoE-/- mice and correlated with reduced necrotic core and macrophage infiltration. Mechanistically, the deletion of Nogo-B in EC sustained the rewiring of sphingolipid metabolism towards S1P, imparting an atheroprotective transcriptional signature that refrain coronary atherogenesis and its progression. These findings also set forth the foundation for sphingolipid-based therapeutics to reduce the treat this condition.
2024-02-12 | GSE254426 | GEO
Project description:The bioactive sphingolipid ceramide, generated by ceramide synthase, is an adaptive stress effector induced in response to various stress stimuli such as aging. In fact, ceramide synthase (CerS) was first discovered in yeast as a longevity assurance gene (LAG1), as the reduced ceramide generation consequent to LAG1 deletion increased longevity. There are six homologues of mammalian LAG1/ceramide synthases (CerS1-6) that generate ceramides with different fatty acid chain lengths with distinct functions and hydrophobicity. Ceramide can be metabolized by sphingosine kinase 1 or 2 for the generation of pro-survival sphingosine 1-phosphate (S1P), which enhances immune cell egress to the blood stream, activating immune function. Ceramide is known to induce mitophagy and cell death. Here we investigated the role of this sphingolipid pathway in immune function, specifically T cell functions, via high throughput expression profiling.
2021-01-01 | GSE148498 | GEO
Project description:Rewiring endothelial cell sphingolipid metabolism to favor S1P over ceramide signaling protects from coronary atherosclerosis
| PRJNA1070546 | ENA
Project description:Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between both processes remains unclear. Here we demonstrate that abrogation of ceramide synthase (CerS)6, which generates C16:0-sphingolipids, but not of the alternative C16:0-sphingolipid synthetizing CerS5 protects from obesity and insulin resistance, and both enzymes regulate C16:0-sphingolipid synthesis in distinct intracellular compartments. Moreover, we identify proteins, which specifically interact with C16:0-sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C16:0-sphingolipids bind the mitochondrial fission factor (Mff). CerS6- and Mff-deficiency protects from fatty acid-induced mitochondrial fragmentation in vitro, and both proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid-signaling depending on specific synthetizing enzymes, provide a mechanistic link between lipid deposition and mitochondrial dynamics in obesity, and define the CerS6/sphingolid/Mff interaction as a therapeutic target for obesity and diabetes.
2019-05-20 | PXD007158 | Pride
Project description:Ceramide is synthesized via the ceramide synthases (CerSs), six of which have been identified in mammalian cells, with each using a unique subset of acyl-CoAs for ceramide synthesis. The CerSs are part of a larger gene family, the Tram-Lag-CLN8 (TLC) domain family. We now identify a unique, C-terminal motif, the DxRSDxE motif, which is only found in CerS and not in other TLC family members. Deletion of this motif in either CerS2-HA or in CerS6-Flag did not affect the ability of either to generate ceramide using both an in vitro assay and upon metabolic labeling, but deletion of this motif did affect the activity of CerS2-HA when co-expressed with CerS6-Flag. Surprisingly, transfection of cells with either CerS2-HA or CerS6-Flag lacking the motif did not result in changes in cellular ceramide levels. CerS2-HA and CerS6-Flag interact with each other, as shown by immunoprecipitation, but deletion of the DxRSDxE motif impedes this interaction. Moreover, proteomics analysis of cells transfected with CerS6Δ338-344-Flag indicated that deletion of the C-terminal motif impacted cellular protein expression, and in particular, levels of ORMDL1, a negative regulator of sphingolipid synthesis. We suggest that this novel C-terminus motif regulates CerS dimer formation and thereby impacts ceramide synthesis.
2022-01-17 | PXD029496 | Pride
Project description:NK cells derived exosomes carry miR-207 and alleviate depression-like symptoms in mice
| PRJNA580242 | ENA
Project description:MicroRNAs (miRNAs) are 20–24 nt RNAs that can be packaged into exosomes and play important regulatory roles. Here we show that miRNA-containing exosomes from NK cells could alleviate symptoms of chronic mild stress in mice. In vivo experiment, these exosomes decreased the levels of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α in the medium of astrocytes. By microarray analysis of exosome miRNA profiles, miR-207 was found to be an overexpressed miRNA in exosomes derived from unstressed mice. Experiments confirmed that miR-207 directly targets TLR4 interactor with leucine-rich repeats (Tril) and inhibits NF-κB signaling downsream of TLRs in astrocytes. When overexpressed in astrocytes, miR-207 decreased the release of pro-inflammatory cytokines and by inclusion of miR-207 inhibitor in astrocytes, higher release of pro-inflammatory cytokines and higher expression of Tril was found in vitro experiments. When NK cells were transfected with miR-207 inhibitor, miR-207 levels in NK cells derived exosomes were also declined. These exosomes with low miR-207 levels showed a decreased antidepressant activity in the vivo experiment. Collectively, our findings revealed that exosomal miR-207 alleviated the depression symptoms of stress mice by targeting Tril to inhibit NF-κB signaling downstream of TLRs in astrocytes.
2019-10-30 | GSE139551 | GEO
Project description:Sphingosine 1-phosphate lyase (SGPL1) insufficiency (SPLIS) is a syndrome which presents with adrenal insufficiency, steroid resistant nephrotic syndrome, hypothyroidism, neurological disease, and ichthyosis. Where a skin phenotype is reported, 94% presented with abnormalities such as ichthyosis, acanthosis, and hyperpigmentation. To elucidate the disease mechanism and the role SGPL1 plays in the skin barrier we established CRISPR-Cas9 SGPL1 knock-out and a lentiviral induced SGPL1 overexpression in nTERT immortalised keratinocytes and thereafter organotypic skin equivalents. Loss of SGPL1 caused an accumulation of S1P, sphingosine and ceramide while its overexpression caused a reduction of these species. RNAseq analysis showed perturbations in sphingolipid pathway genes, particularly in SGPL1_KO and GSEA revealed polar opposite differential gene expression between SGPL1_KO and _OE in keratinocyte differentiation and Ca2+ signalling genesets. SGPL1_KO upregulated differentiation markers while SGPL1_OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum, sphingolipid accumulation in the spinous layer and a breakdown of E-cadherin junctions. We hypothesise that SPLIS associated ichthyosis is a multi-faceted disease caused by sphingolipid imbalance and excessive S1P signalling.
2023-03-06 | GSE207499 | GEO
Project description:The objective of this study was to investigate whether placental exosomes in gestational diabetes mellitus (GDM) carries a specific set of miRNAs associated with skeletal muscle insulin sensitivity. Exosomes were isolated from chorionic villi-conditioned media and plasma from normal and GDM pregnancies. A specific set of miRNAs was identified to be selectively enriched within exosomes when compared to their cells of origin indicating specific packaging of miRNAs into exosomes. In addition, miRNA expression varies in a consistent pattern in placenta, placental-derived exosomes, circulating exosomes and skeletal muscle in GDM.
2021-03-20 | GSE112168 | GEO