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Cells
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Sphingolipid Signaling and Human Disease
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Sphingolipid Signaling and Human Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (10 January 2022) | Viewed by 39240

Special Issue Editors

Dr. Nawajes Mandal

E-Mail Website
Guest Editor
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
Interests: sphingolipids; ceramides; S1P; sphingolipid metabolism; sphingolipid signaling; retina; cornea; meibomian glands; eye diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Kazuyuki Kitatani

E-Mail Website
Guest Editor
Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata 573‐0101, Japan
Interests: sphingolipids; ceramides; sphingotherapy; cancer therapy; cancer biology; cancer metastasis; cellular signaling; cell death; necroptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sphingolipids are a family of membrane lipids and many of their members are biologically active (acting as signaling molecules) and play crucial roles in the regulation of cellular events such as cell survival, proliferation, differentiation, growth, and inflammatory and apoptotic responses. The scope of sphingolipid system’s impact on mammalian biology has been factually demonstrated to be impressive, and its roles in many human diseases associated with inflammation, neurodegeneration, neovascularization, tumorigenesis, and diabetes have just begun to be understood. Current advancements in sphingolipid research are contributing greatly toward our understanding of the pathobiology of complex human diseases and developing of novel therapies. Among several bioactive sphingolipids, the key metabolites, ceramide and sphingosine-1-phosphate (S1P), are found to be pivotal in the pathophysiology of various human diseases, such as Alzheimer’s disease, insulin resistance and diabetes, cancer, and cardiovascular diseases, and imbalance in the homeostasis of these bioactive lipids is found to be linked to the key components of the pathogenesis. Sphingolipid metabolism is complex, with several isoenzymes having been discovered for a single metabolic step; for example, there are six different ceramide synthases and five different ceramidases for anabolism and catabolism of ceramide, respectively. These enzymes are diverse in their structure, substrate specificity, and subcellular localization. Sphingolipid signaling is also complex, as exemplified in signaling mediated by S1P, that binds to five different cell surface receptors and activates a myriad of cellular pathways. This Special Issue aims to improve our knowledge with regards to the intricate mechanisms of sphingolipid metabolism and signaling in human diseases and update our understanding based on recent advancements in the field. We invite original research articles, reviews, shorter perspective articles, or expert opinions on any topics of controversy in the area of sphingolipid signaling and human diseases.

Relevant topics include but are not limited to:

  • Sphingolipid signaling
  • Ceramide metabolism and signaling
  • S1P signaling and receptors
  • Sphingolipids in human diseases (inflammatory, metabolic, neovascular, neurodegenerative, neoplastic, age-related diseases)
  • Targeting the sphingolipid pathway for therapeutic development

Dr. Nawajes Mandal
Dr. Kazuyuki Kitatani
Guest Editors

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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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
  • ceramides
  • S1P
  • sphingolipid metabolism
  • sphingolipid signaling
  • sphingolipid association with human diseases

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Related Special Issue

Published Papers (7 papers)

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Research

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21 pages, 3279 KiB  
Article
Serine Palmitoyltransferase Gene Silencing Prevents Ceramide Accumulation and Insulin Resistance in Muscles in Mice Fed a High-Fat Diet
by Monika Imierska, Piotr Zabielski, Kamila Roszczyc-Owsiejczuk, Emilia Sokołowska, Karolina Pogodzińska, Iwona Kojta and Agnieszka Błachnio-Zabielska
Cells 2022, 11(7), 1123; https://doi.org/10.3390/cells11071123 - 26 Mar 2022
Cited by 6 | Viewed by 2506
Abstract
Skeletal muscles account for ~80% of insulin-stimulated glucose uptake and play a key role in lipid metabolism. Consumption of a high-fat diet (HFD) contributes to metabolic changes in muscles, including the development of insulin resistance. The studies carried out to date indicate that [...] Read more.
Skeletal muscles account for ~80% of insulin-stimulated glucose uptake and play a key role in lipid metabolism. Consumption of a high-fat diet (HFD) contributes to metabolic changes in muscles, including the development of insulin resistance. The studies carried out to date indicate that the accumulation of biologically active lipids, such as long-chain acyl-CoA, diacylglycerols and ceramides, play an important role in the development of insulin resistance in skeletal muscles. Unfortunately, it has not yet been clarified which of these lipid groups plays the dominant role in inducing these disorders. In order to explore this topic further, we locally silenced the gene encoding serine palmitoyltransferase (SPT) in the gastrocnemius muscle of animals with HFD-induced insulin resistance. This enzyme is primarily responsible for the first step of de novo ceramide biosynthesis. The obtained results confirm that the HFD induces the development of whole-body insulin resistance, which results in inhibition of the insulin pathway. This is associated with an increased level of biologically active lipids in the muscles. Our results also demonstrate that silencing the SPT gene with the shRNA plasmid reduces the accumulation of ceramides in gastrocnemius muscle, which, in turn, boosts the activity of the insulin signaling pathway. Furthermore, inhibition of ceramide synthesis does not significantly affect the content of other lipids, which suggests the leading role of ceramide in the lipid-related induction of skeletal muscle insulin resistance. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease)
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20 pages, 6291 KiB  
Article
Administration of an Acidic Sphingomyelinase (ASMase) Inhibitor, Imipramine, Reduces Hypoglycemia-Induced Hippocampal Neuronal Death
by A Ra Kho, Bo Young Choi, Song Hee Lee, Dae Ki Hong, Beom Seok Kang, Si Hyun Lee and Sang Won Suh
Cells 2022, 11(4), 667; https://doi.org/10.3390/cells11040667 - 14 Feb 2022
Cited by 10 | Viewed by 2857
Abstract
Severe hypoglycemia (below 35 mg/dL) appears most often in diabetes patients who continuously inject insulin. To rapidly cease the hypoglycemic state in this study, glucose reperfusion was conducted, which can induce a secondary neuronal death cascade following hypoglycemia. Acid sphingomyelinase (ASMase) hydrolyzes sphingomyelin [...] Read more.
Severe hypoglycemia (below 35 mg/dL) appears most often in diabetes patients who continuously inject insulin. To rapidly cease the hypoglycemic state in this study, glucose reperfusion was conducted, which can induce a secondary neuronal death cascade following hypoglycemia. Acid sphingomyelinase (ASMase) hydrolyzes sphingomyelin into ceramide and phosphorylcholine. ASMase activity can be influenced by cations, pH, redox, lipids, and other proteins in the cells, and there are many changes in these factors in hypoglycemia. Thus, we expect that ASMase is activated excessively after hypoglycemia. Ceramide is known to cause free radical production, excessive inflammation, calcium dysregulation, and lysosomal injury, resulting in apoptosis and the necrosis of neurons. Imipramine is mainly used in the treatment of depression and certain anxiety disorders, and it is particularly known as an ASMase inhibitor. We hypothesized that imipramine could decrease hippocampal neuronal death by reducing ceramide via the inhibition of ASMase after hypoglycemia. In the present study, we confirmed that the administration of imipramine significantly reduced hypoglycemia-induced neuronal death and improved cognitive function. Therefore, we suggest that imipramine may be a promising therapeutic tool for preventing hypoglycemia-induced neuronal death. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease)
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17 pages, 5074 KiB  
Article
Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane
by Gergana Deevska, Patrick P. Dotson 2nd, Mihail Mitov, D. Allan Butterfield and Mariana Nikolova-Karakashian
Cells 2021, 10(6), 1278; https://doi.org/10.3390/cells10061278 - 21 May 2021
Cited by 4 | Viewed by 3652
Abstract
Ceramide and diacylglycerol (DAG) are bioactive lipids and mediate many cellular signaling pathways. Sphingomyelin synthase (SMS) is the single metabolic link between the two, while SMS2 is the only SMS form located at the plasma membrane. SMS2 functions were investigated in HepG2 cell [...] Read more.
Ceramide and diacylglycerol (DAG) are bioactive lipids and mediate many cellular signaling pathways. Sphingomyelin synthase (SMS) is the single metabolic link between the two, while SMS2 is the only SMS form located at the plasma membrane. SMS2 functions were investigated in HepG2 cell lines stably expressing SMS2. SMS2 overexpression did not alter sphingomyelin (SM), phosphatidylcholine (PC), or ceramide levels. DAG content increased by approx. 40% and led to downregulation of DAG-dependent protein kinase C (PKC). SMS2 overexpression also induced senescence, characterized by positivity for β-galactosidase activity and heterochromatin foci. HepG2-SMS2 cells exhibited protruded mitochondria and suppressed mitochondrial respiration rates. ATP production and the abundance of Complex V were substantially lower in HepG2-SMS2 cells as compared to controls. SMS2 overexpression was associated with inflammasome activation based on increases in IL-1β and nlpr3 mRNA levels. HepG2-SMS2 cells exhibited lipid droplet accumulation, constitutive activation of AMPK based on elevated 172Thr phosphorylation, increased AMPK abundance, and insensitivity to insulin suppression of AMPK. Thus, our results show that SMS2 regulates DAG homeostasis and signaling in hepatocytes and also provide proof of principle for the concept that offset in bioactive lipids’ production at the plasma membrane can drive the senescence program in association with steatosis and, seemingly, by cell-autonomous mechanisms. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease)
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Review

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16 pages, 2351 KiB  
Review
A Comprehensive Review on the Interplay between Neisseria spp. and Host Sphingolipid Metabolites
by Simon Peters, Ingo Fohmann, Thomas Rudel and Alexandra Schubert-Unkmeir
Cells 2021, 10(11), 3201; https://doi.org/10.3390/cells10113201 - 17 Nov 2021
Cited by 5 | Viewed by 2998
Abstract
Sphingolipids represent a class of structural related lipids involved in membrane biology and various cellular processes including cell growth, apoptosis, inflammation and migration. Over the past decade, sphingolipids have become the focus of intensive studies regarding their involvement in infectious diseases. Pathogens can [...] Read more.
Sphingolipids represent a class of structural related lipids involved in membrane biology and various cellular processes including cell growth, apoptosis, inflammation and migration. Over the past decade, sphingolipids have become the focus of intensive studies regarding their involvement in infectious diseases. Pathogens can manipulate the sphingolipid metabolism resulting in cell membrane reorganization and receptor recruitment to facilitate their entry. They may recruit specific host sphingolipid metabolites to establish a favorable niche for intracellular survival and proliferation. In contrast, some sphingolipid metabolites can also act as a first line defense against bacteria based on their antimicrobial activity. In this review, we will focus on the strategies employed by pathogenic Neisseria spp. to modulate the sphingolipid metabolism and hijack the sphingolipid balance in the host to promote cellular colonization, invasion and intracellular survival. Novel techniques and innovative approaches will be highlighted that allow imaging of sphingolipid derivatives in the host cell as well as in the pathogen. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease)
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23 pages, 3597 KiB  
Review
Sphingolipids in Hematopoiesis: Exploring Their Role in Lineage Commitment
by Yasharah Raza, Huda Salman and Chiara Luberto
Cells 2021, 10(10), 2507; https://doi.org/10.3390/cells10102507 - 22 Sep 2021
Cited by 7 | Viewed by 13042
Abstract
Sphingolipids, associated enzymes, and the sphingolipid pathway are implicated in complex, multifaceted roles impacting several cell functions, such as cellular homeostasis, apoptosis, cell differentiation, and more through intrinsic and autocrine/paracrine mechanisms. Given this broad range of functions, it comes as no surprise that [...] Read more.
Sphingolipids, associated enzymes, and the sphingolipid pathway are implicated in complex, multifaceted roles impacting several cell functions, such as cellular homeostasis, apoptosis, cell differentiation, and more through intrinsic and autocrine/paracrine mechanisms. Given this broad range of functions, it comes as no surprise that a large body of evidence points to important functions of sphingolipids in hematopoiesis. As the understanding of the processes that regulate hematopoiesis and of the specific characteristics that define each type of hematopoietic cells is being continuously refined, the understanding of the roles of sphingolipid metabolism in hematopoietic lineage commitment is also evolving. Recent findings indicate that sphingolipid alterations can modulate lineage commitment from stem cells all the way to megakaryocytic, erythroid, myeloid, and lymphoid cells. For instance, recent evidence points to the ability of de novo sphingolipids to regulate the stemness of hematopoietic stem cells while a substantial body of literature implicates various sphingolipids in specialized terminal differentiation, such as thrombopoiesis. This review provides a comprehensive discussion focused on the mechanisms that link sphingolipids to the commitment of hematopoietic cells to the different lineages, also highlighting yet to be resolved questions. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease)
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17 pages, 1583 KiB  
Review
The Pathogenic and Therapeutic Implications of Ceramide Abnormalities in Atopic Dermatitis
by Masanori Fujii
Cells 2021, 10(9), 2386; https://doi.org/10.3390/cells10092386 - 10 Sep 2021
Cited by 38 | Viewed by 8944
Abstract
Ceramides play an essential role in forming a permeability barrier in the skin. Atopic dermatitis (AD) is a common chronic skin disease associated with skin barrier dysfunction and immunological abnormalities. In patients with AD, the amount and composition of ceramides in the stratum [...] Read more.
Ceramides play an essential role in forming a permeability barrier in the skin. Atopic dermatitis (AD) is a common chronic skin disease associated with skin barrier dysfunction and immunological abnormalities. In patients with AD, the amount and composition of ceramides in the stratum corneum are altered. This suggests that ceramide abnormalities are involved in the pathogenesis of AD. The mechanism underlying lipid abnormalities in AD has not yet been fully elucidated, but the involvement of Th2 and Th1 cytokines is implicated. Ceramide-dominant emollients have beneficial effects on skin barrier function; thus, they have been approved as an adjunctive barrier repair agent for AD. This review summarizes the current understanding of the mechanisms of ceramide abnormalities in AD. Furthermore, the potential therapeutic approaches for correcting ceramide abnormalities in AD are discussed. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease)
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21 pages, 2217 KiB  
Review
Sphingolipids: Effectors and Achilles Heals in Viral Infections?
by Sibylle Schneider-Schaulies, Fabian Schumacher, Dominik Wigger, Marie Schöl, Trushnal Waghmare, Jan Schlegel, Jürgen Seibel and Burkhard Kleuser
Cells 2021, 10(9), 2175; https://doi.org/10.3390/cells10092175 - 24 Aug 2021
Cited by 14 | Viewed by 3887
Abstract
As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions [...] Read more.
As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention. Full article
(This article belongs to the Special Issue Sphingolipid Signaling and Human Disease)
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