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Advances in Biological Functions of Sphingolipids

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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 July 2023) | Viewed by 9991

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Special Issue Editor

Prof. Dr. Burkhard Kleuser

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Guest Editor

Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany
Interests: sphingolipidomics; sphingosine 1-phosphate; S1P-receptors; insulin resistance; dendritic cells; epigenetics; nanotoxicology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is now well appreciated that sphingolipids are not only ubiquitous membrane lipids in eukaryotes but that they also modulate a myriad of physiological and pathophysiological processes. Sphingolipid research has grown exponentially since bioactive sphingolipid derivatives were first described just over two decades ago. Indeed, in 2010, the first sphingolipid receptor modulator, fingolimod, was employed as a human therapeutic for the treatment of multiple sclerosis. Today, it is well established that sphingolipid derivatives are critical players in immunology, inflammation, and cancer, as well as in cardiovascular and metabolic disorders. Sphingolipid research is of great complexity due to the diversity of distinct sphingolipid molecules and the interconnected metabolic pathways. The levels of sphingolipids are tightly regulated by a multitude of enzymes which are involved in the biosynthesis and degradation of sphingolipids. New knowledge around the biology and metabolism of sphingolipids is anticipated to further understand the role of this lipid class in a variety of pathophysiological conditions.

In this Special Issue, we welcome your contributions in the form of original research and review articles in all aspects of sphingolipids.

Prof. Dr. Burkhard Kleuser
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

bioactive sphingolipids
ceramides
sphingosine 1-phosphate
S1P receptors
sphingolipid metabolism
sphingolipids and metabolic disorders
sphingolipids and inflammation
sphingolipids and infections
sphingolipids and cancer

Published Papers (5 papers)

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Research

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19 pages, 4414 KiB

Open AccessArticle

Chlamydial Infection-Dependent Synthesis of Sphingomyelin as a Novel Anti-Chlamydial Target of Ceramide Mimetic Compounds

by Keigo Kumagai, Shota Sakai, Masaharu Ueno, Michiyo Kataoka, Shu Kobayashi and Kentaro Hanada

Int. J. Mol. Sci. 2022, 23(23), 14697; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314697 - 24 Nov 2022

Viewed by 1310

Abstract

The obligate intracellular bacterium Chlamydia trachomatis is the major causative agent of bacterial sexually transmitted diseases worldwide. In infected cells, the ceramide transport protein (CERT) is recruited to inclusions, where C. trachomatis replicates using host-synthesized ceramide. The ceramide is converted to sphingomyelin (SM) by a chlamydial infection-dependent SM synthesis (cidSM-synthesis) pathway, which occurs even in the absence of the SM synthases (SMS)-1 and -2 of host cells. The ceramide mimetic compound (1R,3S)-HPA-12 and the nonmimetic compound E16A, both of which are potent inhibitors of CERT, repressed the proliferation of C. trachomatis in HeLa cells. Unexpectedly, (1R,3R)-HPA-12, a ceramide mimetic compound that lacks CERT inhibitory activity, also exhibited potent anti-chlamydial activity. Using endogenous SMS-knockout mutant HeLa cells, we revealed that (1R,3R)-HPA-12 mildly inhibited cidSM-synthesis. In addition, LC-MS analysis revealed that (1R,3R)-HPA-12 is converted to a phosphocholine-conjugated metabolite in an infection-dependent manner. Imaging analysis with a fluorescent analog of ceramide suggested that cidSM-synthesis occurs in the bacterial bodies and/or inclusions. Collectively, these results suggested that (1R,3R)-HPA-12 exerts its anti-chlamydia activity not only as an inhibitor of cidSM-synthesis, but also via putative toxic effects of its phosphocholine adduct, which is most likely produced by the cidSM-synthesis route. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Sphingolipids)

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16 pages, 3341 KiB

Open AccessArticle

Modulation of Specific Sphingosine-1-Phosphate Receptors Augments a Repair Mediating Schwann Cell Phenotype

by Jessica Schira-Heinen, Luzhou Wang, Seda Akgün, Sofia Blum, Brigida Ziegler, André Heinen, Hans-Peter Hartung and Patrick Küry

Int. J. Mol. Sci. 2022, 23(18), 10311; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810311 - 07 Sep 2022

Cited by 3 | Viewed by 1489

Abstract

Transdifferentiation of Schwann cells is essential for functional peripheral nerve regeneration after injury. By activating a repair program, Schwann cells promote functional axonal regeneration and remyelination. However, chronic denervation, aging, metabolic diseases, or chronic inflammatory processes reduce the transdifferentiation capacity and thus diminish peripheral nerve repair. It was recently described that the sphingosine-1-phosphate receptor (S1PR) agonist Fingolimod enhances the Schwann cell repair phenotype by activation of dedifferentiation markers and concomitant release of trophic factors resulting in enhanced neurite growth. Since Fingolimod targets four out of five S1PRs (S1P1, S1P3-5) possibly leading to non-specific adverse effects, identification of the main receptor(s) responsible for the observed phenotypic changes is mandatory for future specific treatment approaches. Our experiments revealed that S1P3 dominates and that along with S1P1 acts as the responsible receptor for Schwann cell transdifferentiation as revealed by the combinatory application of specific agonists and antagonists. Targeting both receptors reduced the expression of myelin-associated genes, increased PDGF-BB representing enhanced trophic factor expression likely to result from c-Jun induction. Furthermore, we demonstrated that S1P4 and S1P5 play only a minor role in the adaptation of the repair phenotype. In conclusion, modulation of S1P1 and S1P3 could be effective to enhance the Schwann cell repair phenotype and thus stimulate proper nerve repair. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Sphingolipids)

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12 pages, 1355 KiB

Open AccessArticle

Differential Ganglioside and Cholesterol Depletion by Various Cyclodextrin Derivatives and Their Effect on Synaptosomal Glutamate Release

by Orsolya Geda, Tamás Tábi, Péter P. Lakatos and Éva Szökő

Int. J. Mol. Sci. 2022, 23(16), 9460; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169460 - 21 Aug 2022

Cited by 2 | Viewed by 2221

Abstract

Gangliosides are glycosphingolipids of the plasma membrane and are highly enriched in the nervous system where they play a vital role in normal cell functions. Furthermore, several studies suggest their potential involvement in the pathogenesis of neurological conditions. Since cyclodextrins (CDs) can form inclusion complexes with various lipids, methylated beta-CDs are widely used in biomedical research to extract cholesterol from the membrane and study its cellular role. Despite CDs being known to interact with other membrane lipid components, their effect on gangliosides is poorly characterized. The aim of this research was to investigate the effect of dimethyl-beta-cyclodextrin (DIMEB), hydroxypropyl-beta-cyclodextrin (HPBCD), randomly methylated-alpha-cyclodextrin (RAMEA), and hydroxypropyl-alpha-cyclodextrin (HPACD) on ganglioside and cholesterol levels in rat brain synaptosomes. Their effect on membrane integrity and viability was also assessed. We examined the role of lipid depletion by CDs on the release of the major excitatory neurotransmitter, glutamate. Selective concentration range for cholesterol depletion was only found with HPBCD, but not with DIMEB. Selective depletion of gangliosides was achieved by both RAMEA and HPACD. The inhibition of stimulated glutamate release upon ganglioside depletion was found, suggesting their potential role in neurotransmission. Our study highlights the importance of the characterization of the lipid depleting capability of different CDs. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Sphingolipids)

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17 pages, 2977 KiB

Open AccessArticle

Involvement of a Cluster of Basic Amino Acids in Phosphorylation-Dependent Functional Repression of the Ceramide Transport Protein CERT

by Asako Goto, Daichi Egawa, Nario Tomishige, Toshiyuki Yamaji, Kentaro Shimasaki, Keigo Kumagai and Kentaro Hanada

Int. J. Mol. Sci. 2022, 23(15), 8576; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158576 - 02 Aug 2022

Cited by 3 | Viewed by 2098

Abstract

Ceramide transport protein (CERT) mediates ceramide transfer from the endoplasmic reticulum to the Golgi for sphingomyelin (SM) biosynthesis. CERT is inactivated by multiple phosphorylation at the serine-repeat motif (SRM), and mutations that impair the SRM phosphorylation are associated with a group of inherited intellectual disorders in humans. It has been suggested that the N-terminal phosphatidylinositol 4-monophosphate [PtdIns(4)P] binding domain and the C-terminal ceramide-transfer domain of CERT physically interfere with each other in the SRM phosphorylated state, thereby repressing the function of CERT; however, it remains unclear which regions in CERT are involved in the SRM phosphorylation-dependent repression of CERT. Here, we identified a previously uncharacterized cluster of lysine/arginine residues that were predicted to be located on the outer surface of a probable coiled-coil fold in CERT. Substitutions of the basic amino acids in the cluster with alanine released the SRM-dependent repression of CERT activities, i.e., the synthesis of SM, PtdIns(4)P-binding, vesicle-associated membrane protein-associated protein (VAP) binding, ceramide-transfer activity, and localization to the Golgi, although the effect on SM synthesis activity was only partially compromised by the alanine substitutions, which moderately destabilized the trimeric status of CERT. These results suggest that the basic amino acid cluster in the coiled-coil region is involved in the regulation of CERT function. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Sphingolipids)

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Review

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22 pages, 952 KiB

Open AccessReview

Sphingolipids in Atherosclerosis: Chimeras in Structure and Function

by Lisa Peters, Wolfgang M. Kuebler and Szandor Simmons

Int. J. Mol. Sci. 2022, 23(19), 11948; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911948 - 08 Oct 2022

Cited by 7 | Viewed by 2251

Abstract

Atherosclerosis—a systemic inflammatory disease—is the number one cause of mortality and morbidity worldwide. As such, the prevention of disease progression is of global interest in order to reduce annual deaths at a significant scale. Atherosclerosis is characterized by plaque formation in the arteries, resulting in vascular events such as ischemic stroke or myocardial infarction. A better understanding of the underlying pathophysiological processes at the cellular and molecular level is indispensable to identify novel therapeutic targets that may alleviate disease initiation or progression. Sphingolipids—a lipid class named after the chimeric creature sphinx—are considered to play a critical and, metaphorically, equally chimeric regulatory role in atherogenesis. Previous studies identified six common sphingolipids, namely dihydroceramide (DhCer), ceramide (Cer), sphingosine-1-phosphate (S1P), sphingomyelin (SM), lactosylceramide (LacCer), and glucosylceramide (GluCer) in carotid plaques, and demonstrated their potential as inducers of plaque inflammation. In this review, we point out their specific roles in atherosclerosis by focusing on different cell types, carrier molecules, enzymes, and receptors involved in atherogenesis. Whereas we assume mainly atheroprotective effects for GluCer and LacCer, the sphingolipids DhCer, Cer, SM and S1P mediate chimeric functions. Initial studies demonstrate the successful use of interventions in the sphingolipid pathway to prevent atherosclerosis. However, as atherosclerosis is a multifactorial disease with a variety of underlying cellular processes, it is imperative for future research to emphasize the circumstances in which sphingolipids exert protective or progressive functions and to evaluate their therapeutic benefits in a spatiotemporal manner. Full article

(This article belongs to the Special Issue Advances in Biological Functions of Sphingolipids)

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