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Sphingolipid Metabolism and Signaling: Role in Health and Diseases
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Sphingolipid Metabolism and Signaling: Role in Health and Diseases

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

Deadline for manuscript submissions: 30 June 2024 | Viewed by 6087

Special Issue Editor

Dr. Paola Giussani

E-Mail Website
Guest Editor
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, LITA Segrate, Via Fratelli Cervi, 93, 20090 Segrate, Italy
Interests: sphingolipids; sphingosine-1-phosphate; ceramide; signaling; cancer; multiple sclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sphingolipids are a class of lipids that are highly expressed in eukaryotic cells. Sphingolipids are ubiquitous components of cell membranes as well as bioactive molecules involved in the control of cell fate in physiological and pathophysiological processes. Sphingolipid metabolism and signaling are crucial for the maintenance of physiological conditions, but, on the other hand, the dysregulation of sphingolipid metabolism, leading to altered sphingolipid patterns, is associated with different pathological conditions. Sphingolipid levels are regulated via the modulation of the metabolism of specific enzymes as well as that of the specific receptors or transporters involved in their transport within or outside cells; however, the exact molecular mechanisms mediated by sphingolipids with which to modulate cell homeostasis are still not completely understood. New knowledge on the metabolism and signaling of sphingolipids will help in finding therapeutic solutions in a variety of human diseases.

For this Special Issue, “Sphingolipid Metabolism and Signaling: Role in Health and Diseases”, we welcome your contributions in the form of original research and review articles on all aspects of sphingolipids and their roles in physiological and pathophysiological processes.

Dr. Paola Giussani
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sphingolipids
  • sphingosine-1-phosphate
  • ceramide
  • glycosphingolipids
  • sphingolipid-mediated signaling
  • cancer
  • neurodegenerative diseases
  • inflammatory diseases
  • diabetes

Published Papers (5 papers)

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Research

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29 pages, 5550 KiB  
Article
Development of Genetically Encoded Fluorescent KSR1-Based Probes to Track Ceramides during Phagocytosis
by Vladimir Girik, Larissa van Ek, Isabelle Dentand Quadri, Maral Azam, María Cruz Cobo, Marion Mandavit, Isabelle Riezman, Howard Riezman, Anne-Claude Gavin and Paula Nunes-Hasler
Int. J. Mol. Sci. 2024, 25(5), 2996; https://doi.org/10.3390/ijms25052996 - 05 Mar 2024
Viewed by 779
Abstract
Ceramides regulate phagocytosis; however, their exact function remains poorly understood. Here, we sought (1) to develop genetically encoded fluorescent tools for imaging ceramides, and (2) to use them to examine ceramide dynamics during phagocytosis. Fourteen enhanced green fluorescent protein (EGFP) fusion constructs based [...] Read more.
Ceramides regulate phagocytosis; however, their exact function remains poorly understood. Here, we sought (1) to develop genetically encoded fluorescent tools for imaging ceramides, and (2) to use them to examine ceramide dynamics during phagocytosis. Fourteen enhanced green fluorescent protein (EGFP) fusion constructs based on four known ceramide-binding domains were generated and screened. While most constructs localized to the nucleus or cytosol, three based on the CA3 ceramide-binding domain of kinase suppressor of ras 1 (KSR1) localized to the plasma membrane or autolysosomes. C-terminally tagged CA3 with a vector-based (C-KSR) or glycine-serine linker (C-KSR-GS) responded sensitively and similarly to ceramide depletion and accumulation using a panel of ceramide modifying drugs, whereas N-terminally tagged CA3 (N-KSR) responded differently to a subset of treatments. Lipidomic and liposome microarray analysis suggested that, instead, N-KSR may preferentially bind glucosyl-ceramide. Additionally, the three probes showed distinct dynamics during phagocytosis. Despite partial autolysosomal degradation, C-KSR and C-KSR-GS accumulated at the plasma membrane during phagocytosis, whereas N-KSR did not. Moreover, the weak recruitment of C-KSR-GS to the endoplasmic reticulum and phagosomes was enhanced through overexpression of the endoplasmic reticulum proteins stromal interaction molecule 1 (STIM1) and Sec22b, and was more salient in dendritic cells. The data suggest these novel probes can be used to analyze sphingolipid dynamics and function in living cells. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)
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17 pages, 2216 KiB  
Article
Sphingomyelin Metabolism Modifies Luminal A Breast Cancer Cell Line under a High Dose of Vitamin C
by Michela Codini, Federico Fiorani, Martina Mandarano, Samuela Cataldi, Cataldo Arcuri, Alessandra Mirarchi, Maria Rachele Ceccarini, Tommaso Beccari, Toshihide Kobayashi, Nario Tomishige, Angelo Sidoni and Elisabetta Albi
Int. J. Mol. Sci. 2023, 24(24), 17263; https://doi.org/10.3390/ijms242417263 - 08 Dec 2023
Viewed by 814
Abstract
The role of sphingomyelin metabolism and vitamin C in cancer has been widely described with conflicting results ranging from a total absence of effect to possible preventive and/or protective effects. The aim of this study was to establish the possible involvement of sphingomyelin [...] Read more.
The role of sphingomyelin metabolism and vitamin C in cancer has been widely described with conflicting results ranging from a total absence of effect to possible preventive and/or protective effects. The aim of this study was to establish the possible involvement of sphingomyelin metabolism in the changes induced by vitamin C in breast cancer cells. The MCF7 cell line reproducing luminal A breast cancer and the MDA-MB-231 cell line reproducing triple-negative breast cancer were used. Cell phenotype was tested by estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 expression, and proliferation index percentage. Sphingomyelin was localized by an EGFP-NT-Lys fluorescent probe. Sphingomyelin metabolism was analyzed by RT-PCR, Western blotting and UFLC-MS/MS. The results showed that a high dose of vitamin C produced reduced cell viability, modulated cell cycle related genes, and changed the cell phenotype with estrogen receptor downregulation in MCF7 cell. In these cells, the catabolism of sphingomyelin was promoted with a large increase in ceramide content. No changes in viability and molecular expression were observed in MB231 cells. In conclusion, a high dose of vitamin C induces changes in the luminal A cell line involving sphingomyelin metabolism. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)
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22 pages, 5291 KiB  
Article
Ceramide Is Involved in Temozolomide Resistance in Human Glioblastoma U87MG Overexpressing EGFR
by Rosaria Bassi, Michele Dei Cas, Cristina Tringali, Federica Compostella, Rita Paroni and Paola Giussani
Int. J. Mol. Sci. 2023, 24(20), 15394; https://doi.org/10.3390/ijms242015394 - 20 Oct 2023
Viewed by 933
Abstract
Glioblastoma multiforme (GBM) is the most frequent and deadly brain tumor. Many sphingolipids are crucial players in the regulation of glioma cell growth as well as in the response to different chemotherapeutic drugs. In particular, ceramide (Cer) is a tumor suppressor lipid, able [...] Read more.
Glioblastoma multiforme (GBM) is the most frequent and deadly brain tumor. Many sphingolipids are crucial players in the regulation of glioma cell growth as well as in the response to different chemotherapeutic drugs. In particular, ceramide (Cer) is a tumor suppressor lipid, able to induce antiproliferative and apoptotic responses in different types of tumors including GBM, most of which overexpress the epidermal growth factor receptor variant III (EGFRvIII). In this paper, we investigated whether Cer metabolism is altered in the U87MG human glioma cell line overexpressing EGFRvIII (EGFR+ cells) to elucidate their possible interplay in the mechanisms regulating GBM survival properties and the response to the alkylating agent temozolomide (TMZ). Notably, we demonstrated that a low dose of TMZ significantly increases Cer levels in U87MG cells but slightly in EGFR+ cells (sensitive and resistant to TMZ, respectively). Moreover, the inhibition of the synthesis of complex sphingolipids made EGFR+ cells sensitive to TMZ, thus involving Cer accumulation/removal in TMZ resistance of GBM cells. This suggests that the enhanced resistance of EGFR+ cells to TMZ is dependent on Cer metabolism. Altogether, our results indicate that EGFRvIII expression confers a TMZ-resistance phenotype to U87MG glioma cells by counteracting Cer increase. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)
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Review

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34 pages, 1521 KiB  
Review
Circulating Sphingolipids in Insulin Resistance, Diabetes and Associated Complications
by Samar M. Hammad and Maria F. Lopes-Virella
Int. J. Mol. Sci. 2023, 24(18), 14015; https://doi.org/10.3390/ijms241814015 - 13 Sep 2023
Cited by 4 | Viewed by 1378
Abstract
Sphingolipids play an important role in the development of diabetes, both type 1 and type 2 diabetes, as well as in the development of both micro- and macro-vascular complications. Several reviews have been published concerning the role of sphingolipids in diabetes but most [...] Read more.
Sphingolipids play an important role in the development of diabetes, both type 1 and type 2 diabetes, as well as in the development of both micro- and macro-vascular complications. Several reviews have been published concerning the role of sphingolipids in diabetes but most of the emphasis has been on the possible mechanisms by which sphingolipids, mainly ceramides, contribute to the development of diabetes. Research on circulating levels of the different classes of sphingolipids in serum and in lipoproteins and their importance as biomarkers to predict not only the development of diabetes but also of its complications has only recently emerged and it is still in its infancy. This review summarizes the previously published literature concerning sphingolipid-mediated mechanisms involved in the development of diabetes and its complications, focusing on how circulating plasma sphingolipid levels and the relative content carried by the different lipoproteins may impact their role as possible biomarkers both in the development of diabetes and mainly in the development of diabetic complications. Further studies in this field may open new therapeutic avenues to prevent or arrest/reduce both the development of diabetes and progression of its complications. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)
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16 pages, 1514 KiB  
Review
Circulating Sphingolipids and Glucose Homeostasis: An Update
by Sarah Ali-Berrada, Jeanne Guitton, Sophie Tan-Chen, Anna Gyulkhandanyan, Eric Hajduch and Hervé Le Stunff
Int. J. Mol. Sci. 2023, 24(16), 12720; https://doi.org/10.3390/ijms241612720 - 12 Aug 2023
Cited by 4 | Viewed by 1370
Abstract
Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance [...] Read more.
Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles. Plasma concentrations of these sphingolipids can be altered upon metabolic disorders and could serve as predictive biomarkers of these diseases. Recent important advances suggest that circulating sphingolipids not only serve as biomarkers but could also serve as mediators in the dysregulation of glucose homeostasis. In this review, advances of molecular mechanisms involved in the regulation of ceramides and S1P association to lipoproteins or extracellular vesicles and how they could alter glucose metabolism are discussed. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases)
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