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Molecular Insights into Sphingolipids
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Molecular Insights into Sphingolipids

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 4985

Special Issue Editor

Prof. Dr. Elisabetta Meacci

E-Mail Website
Guest Editor
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Molecular and Applied Biology Research Unit, University of Florence, 50121 Florence, Italy
Interests: sphingolipids; ceramide; sphingosine; sphingosine 1-phosphate; ceramide 1-phosphate; glycosphingolipids; diabetes; insulin resistance; beta-cell failure; NAFLD; cardiovascular disease; metabolic dysfunction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A strong case is emerging that bioactive sphingolipids, although only a minor constituent of the global lipid milieu in cells and tissues, play a central role in regulating metabolic functions. Specific bioactive sphingolipids have been identified as physiological and pathogenic mediators in metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), diabetes, or cardiovascular dysfunctions, as well as multifactorial disease such as cancer. Circulating mediators that are released from adipose tissue (e.g., adipokines, inflammatory cytokines) specifically modulate enzymes that are involved in sphingolipid synthesis and degradation. The accumulation of specific sphingolipid species in tissues, such as the liver, muscle, heart, pancreas, and vasculature, may contribute to the onset and development of metabolic diseases, including insulin resistance, pancreatic β-cell failure, liver dysfunction, neuro-muscolar degeneration, cardiomyopathy, and vascular and microenviromental dysfunction. Striking progress has been made over the last few years in elucidating the complex crosstalk between sphingolipids, especially sphingosine 1-phosphate (S1P) and its specific receptors, and the development of several diseases, as scientists have discerned that pharmacological intervention (or the genetic ablation of enzymes controlling sphingolipid synthesis or degradation) and S1P signalling have beneficial effects on these disorders.

Prof. Dr. Elisabetta Meacci
Guest Editor

Manuscript Submission Information

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Keywords

  • sphingolipids
  • ceramide
  • sphingosine
  • sphingosine 1-phosphate
  • ceramide 1-phosphate
  • glycosphingolipids
  • diabetes
  • insulin resistance
  • beta-cell failure
  • NAFLD
  • cardiovascular disease
  • metabolic dysfunction

Published Papers (4 papers)

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Research

12 pages, 2490 KiB  
Article
S. epidermidis Rescues Allergic Contact Dermatitis in Sphingosine 1-Phosphate Receptor 2-Deficient Skin
by Kana Masuda-Kuroki, Shahrzad Alimohammadi and Anna Di Nardo
Int. J. Mol. Sci. 2023, 24(17), 13190; https://doi.org/10.3390/ijms241713190 - 25 Aug 2023
Cited by 1 | Viewed by 893
Abstract
Recent studies have identified a subtype of the S1P-receptor family called sphingosine-1-phosphate receptor 2 (S1PR2), which plays a crucial role in maintaining the skin barrier. It has been observed that S1PR2 and Staphylococcus epidermidis (S. epidermidis) work together to regulate the [...] Read more.
Recent studies have identified a subtype of the S1P-receptor family called sphingosine-1-phosphate receptor 2 (S1PR2), which plays a crucial role in maintaining the skin barrier. It has been observed that S1PR2 and Staphylococcus epidermidis (S. epidermidis) work together to regulate the skin barrier. However, the interaction between these two factors is still unclear. To investigate this, a study was conducted on healthy skin and allergic contact dermatitis (ACD) using 3,4-Dibutoxy-3-cyclobutene-1,2-dione (SADBE) on the ears of S1pr2fl/fl and S1pr2fl/flK14-Cre mice and using 1 × 106 CFU of S. epidermidis to examine its effects on the skin. The results showed that in S. epidermidis-conditioned ACD, the ear thickness of S1pr2fl/flK14-Cre mice was lower than that of S1pr2fl/fl mice, and mRNA expressions of Il-1β and Cxcl2 of S1pr2fl/flK14-Cre mice were lower than that of S1pr2fl/fl mice in ACD with S. epidermidis. Furthermore, the gene expression of Claudin-1 and Occludin in S1pr2fl/flK14-Cre mice was higher than that of S1pr2fl/fl mice in ACD with S. epidermidis. The study concludes that S. epidermidis colonization improves the skin barrier and prevents ACD even when S1P signaling malfunctions. Full article
(This article belongs to the Special Issue Molecular Insights into Sphingolipids)
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13 pages, 897 KiB  
Article
Ceramide Risk Score in the Evaluation of Metabolic Syndrome: An Additional or Substitutive Biochemical Marker in the Clinical Practice?
by Antonello E. Rigamonti, Michele Dei Cas, Diana Caroli, Adele Bondesan, Silvano G. Cella, Rita Paroni and Alessandro Sartorio
Int. J. Mol. Sci. 2023, 24(15), 12452; https://doi.org/10.3390/ijms241512452 - 05 Aug 2023
Viewed by 889
Abstract
Ceramide risk score (CERT1, ceramide test 1), based on specific ceramides (Cers) and their corresponding ratios in the plasma, has been reported as a promising biochemical marker for primary and secondary prediction of cardiovascular disease (CVD) risk in different populations of patients. Thus [...] Read more.
Ceramide risk score (CERT1, ceramide test 1), based on specific ceramides (Cers) and their corresponding ratios in the plasma, has been reported as a promising biochemical marker for primary and secondary prediction of cardiovascular disease (CVD) risk in different populations of patients. Thus far, limited attention has been paid to metabolic syndrome, a condition considered at high CVD risk. The aim of the present study was to evaluate CERT1 in a group of obese subjects without (OB-MetS−) and with (OB-MetS+) metabolic syndrome (according to the International Diabetes Federation (IDF) diagnostic criteria), compared to an age- and sex-matched normal-weight (NW) group. In all participants, plasma levels of Cer 16:0, Cer 18:0, Cer 24:1, and Cer 24:0 were measured, and the corresponding ratios Cer 16:0/24:0, Cer 18:0/24:0, and Cer 24:1/24:0 were calculated together with CERT1. Subjects with obesity showed higher CERT1 values than the NW group (p < 0.05), with no difference between OB-MetS− and OB-MetS+ groups. Waist circumference (WC), homeostatic model assessment of insulin-resistance (HOMA-IR) (surrogates of IDF diagnostic criteria for metabolic syndrome), and C reactive protein (CRP) (a marker of inflammation) were predictors of CERT1 (p < 0.05), with the contribution of the other IDF criteria such as arterial hypertension and dyslipidemia being negligible. Adjustment for WC resulted in a loss of the difference in CERT1 between OB-MetS− and NW subjects, with the combination of WC and HOMA-IR or CRP as covariates being necessary to yield the same effect for the difference in CERT1 between OB-MetS+ and NW subjects. Importantly, an association was found between CERT1 and vascular age (VA) (p < 0.05). Proportions of NW, OB-MetS− and OB-MetS+ subjects appeared to be distributed according to the CERT1-based risk groups (i.e., low, moderate, increased, and high risk; p < 0.05), with some OB-MetS− subjects included in the increased/high-risk group and some OB-MetS+ in the low/moderate-risk one. In conclusion, the clinical diagnosis of metabolic syndrome seems to be inaccurate to assess CVD risk in the obese population; however, further studies are needed before considering CERT1 as an additional or substitutive biochemical marker in clinical practice. Full article
(This article belongs to the Special Issue Molecular Insights into Sphingolipids)
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21 pages, 11527 KiB  
Article
The Pro-Oncogenic Sphingolipid-Metabolizing Enzyme β-Galactosylceramidase Modulates the Proteomic Landscape in BRAF(V600E)-Mutated Human Melanoma Cells
by Davide Capoferri, Paola Chiodelli, Marzia Corli, Mirella Belleri, Elisa Scalvini, Luca Mignani, Jessica Guerra, Elisabetta Grillo, Veronica De Giorgis, Marcello Manfredi and Marco Presta
Int. J. Mol. Sci. 2023, 24(13), 10555; https://doi.org/10.3390/ijms241310555 - 23 Jun 2023
Cited by 3 | Viewed by 1500
Abstract
β-Galactosylceramidase (GALC) is a lysosomal enzyme involved in sphingolipid metabolism by removing β-galactosyl moieties from β-galactosylceramide and β-galactosylsphingosine. Previous observations have shown that GALC may exert pro-oncogenic functions in melanoma and Galc silencing, leading to decreased oncogenic activity in murine B16 melanoma cells. [...] Read more.
β-Galactosylceramidase (GALC) is a lysosomal enzyme involved in sphingolipid metabolism by removing β-galactosyl moieties from β-galactosylceramide and β-galactosylsphingosine. Previous observations have shown that GALC may exert pro-oncogenic functions in melanoma and Galc silencing, leading to decreased oncogenic activity in murine B16 melanoma cells. The tumor-driving BRAF(V600E) mutation is present in approximately 50% of human melanomas and represents a major therapeutic target. However, such mutation is missing in melanoma B16 cells. Thus, to assess the impact of GALC in human melanoma in a more relevant BRAF-mutated background, we investigated the effect of GALC overexpression on the proteomic landscape of A2058 and A375 human melanoma cells harboring the BRAF(V600E) mutation. The results obtained by liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrate that significant differences exist in the protein landscape expressed under identical cell culture conditions by A2058 and A375 human melanoma cells, both harboring the same BRAF(V600E)-activating mutation. GALC overexpression resulted in a stronger impact on the proteomic profile of A375 cells when compared to A2058 cells (261 upregulated and 184 downregulated proteins versus 36 and 14 proteins for the two cell types, respectively). Among them, 25 proteins appeared to be upregulated in both A2058-upGALC and A375-upGALC cells, whereas two proteins were significantly downregulated in both GALC-overexpressing cell types. These proteins appear to be involved in melanoma biology, tumor invasion and metastatic dissemination, tumor immune escape, mitochondrial antioxidant activity, endoplasmic reticulum stress responses, autophagy, and/or apoptosis. Notably, analysis of the expression of the corresponding genes in human skin cutaneous melanoma samples (TCGA, Firehose Legacy) using the cBioPortal for Cancer Genomics platform demonstrated a positive correlation between GALC expression and the expression levels of 14 out of the 27 genes investigated, thus supporting the proteomic findings. Overall, these data indicate for the first time that the expression of the lysosomal sphingolipid-metabolizing enzyme GALC may exert a pro-oncogenic impact on the proteomic landscape in BRAF-mutated human melanoma. Full article
(This article belongs to the Special Issue Molecular Insights into Sphingolipids)
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21 pages, 4235 KiB  
Article
Irisin Is Target of Sphingosine-1-Phosphate/Sphingosine-1-Phosphate Receptor-Mediated Signaling in Skeletal Muscle Cells
by Federica Pierucci, Antony Chirco and Elisabetta Meacci
Int. J. Mol. Sci. 2023, 24(13), 10548; https://doi.org/10.3390/ijms241310548 - 23 Jun 2023
Cited by 1 | Viewed by 1116
Abstract
Irisin is a hormone-like myokine produced in abundance by skeletal muscle (SkM) in response to exercise. This myokine, identical in humans and mice, is involved in many signaling pathways related to metabolic processes. Despite much evidence on the regulators of irisin and the [...] Read more.
Irisin is a hormone-like myokine produced in abundance by skeletal muscle (SkM) in response to exercise. This myokine, identical in humans and mice, is involved in many signaling pathways related to metabolic processes. Despite much evidence on the regulators of irisin and the relevance of sphingolipids for SkM cell biology, the contribution of these latter bioactive lipids to the modulation of the myokine in SkM is missing. In particular, we have examined the potential involvement in irisin formation/release of sphingosine-1-phosphate (S1P), an interesting bioactive molecule able to act as an intracellular lipid mediator as well as a ligand of specific G-protein-coupled receptors (S1PR). We demonstrate the existence of distinct intracellular pools of S1P able to affect the expression of the irisin precursor FNDC. In addition, we establish the crucial role of the S1P/S1PR axis in irisin formation/release as well as the autocrine/paracrine effects of irisin on myoblast proliferation and myogenic differentiation. Altogether, these findings provide the first evidence for a functional crosstalk between the S1P/S1PR axis and irisin signaling, which may open new windows for potential therapeutic treatment of SkM dysfunctions. Full article
(This article belongs to the Special Issue Molecular Insights into Sphingolipids)
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