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Sphingolipid Metabolism and Signaling in Diseases 3.0

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

Deadline for manuscript submissions: closed (16 March 2023) | Viewed by 22703

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Dr. Paola Giussani

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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
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Dear Colleagues,

It is now well known that sphingolipids are not only ubiquitous components of cell membranes but also have emerged as bioactive molecules involved in the control of cell fate. Sphingolipids have been shown to be involved in signal transduction and, consequently, in the regulation of a huge number of physiological and pathophysiological processes such as cell proliferation, survival, death, differentiation, migration, and invasiveness. The dysregulation of sphingolipid metabolism and signaling is associated with and contributes to the pathogenesis of numerous pathologies, including inflammation, cancer, diabetes, neurodegenerative diseases, and cystic fibrosis. The control of sphingolipid levels can be achieved through the regulation of specific enzymes of their metabolism as well as of the specific transporters or receptors involved in their transport within or outside the cells. The exact molecular mechanisms mediated by sphingolipids to modulate the cellular effects are still not completely understood, and new knowledge on the metabolism and signaling of sphingolipids will help in further understanding the role of sphingolipids in a variety of physiopathological conditions.

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

Dr. Paola Giussani
Guest Editor

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Keywords

sphingolipids
sphingosine-1-phosphate
ceramide
sphingolipid-mediated signaling
cancer
neurodegenerative diseases
inflammatory diseases
diabetes
cystic fibrosis

Published Papers (12 papers)

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Research

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18 pages, 2555 KiB

Open AccessArticle

A Sphingolipidomic Profiling Approach for Comparing X-ray-Exposed and Unexposed HepG2 Cells

by Martina Moggio, Bahar Faramarzi, Marianna Portaccio, Lorenzo Manti, Maria Lepore and Nadia Diano

Int. J. Mol. Sci. 2023, 24(15), 12364; https://doi.org/10.3390/ijms241512364 - 02 Aug 2023

Viewed by 921

Abstract

An analytical method based on tandem mass spectrometry-shotgun is presently proposed to obtain sphingolipidomic profiles useful for the characterization of lipid extract from X-ray-exposed and unexposed hepatocellular carcinoma cells (HepG2). To obtain a targeted lipidic profile from a specific biological system, the best extraction method must be identified before instrumental analysis. Accordingly, four different classic lipid extraction protocols were compared in terms of efficiency, specificity, and reproducibility. The performance of each procedure was evaluated using the Fourier-transform infrared spectroscopic technique; subsequently, the quality of extracts was estimated using electrospray ionization tandem mass spectrometry. The selected procedure based on chloroform/methanol/water was successfully used in mass spectrometry-based shotgun sphingolipidomics, allowing for evaluation of the response of cells to X-ray irradiation, the most common anticancer therapy. Using a relative quantitative approach, the changes in the sphingolipid profiles of irradiated cell extracts were demonstrated, confirming that lipidomic technologies are also useful tools for studying the key sphingolipid role in regulating cancer growth during radiotherapy. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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13 pages, 3069 KiB

Open AccessArticle

Adult-Onset CNS Sulfatide Deficiency Causes Sex-Dependent Metabolic Disruption in Aging

by Shulan Qiu, Sijia He, Jianing Wang, Hu Wang, Anindita Bhattacharjee, Xin Li, Moawiz Saeed, Jeffrey L. Dupree and Xianlin Han

Int. J. Mol. Sci. 2023, 24(13), 10483; https://doi.org/10.3390/ijms241310483 - 22 Jun 2023

Cited by 1 | Viewed by 1219

Abstract

The interconnection between obesity and central nervous system (CNS) neurological dysfunction has been widely appreciated. Accumulating evidence demonstrates that obesity is a risk factor for CNS neuroinflammation and cognitive impairment. However, the extent to which CNS disruption influences peripheral metabolism remains to be elucidated. We previously reported that myelin-enriched sulfatide loss leads to CNS neuroinflammation and cognitive decline. In this study, we further investigated the impact of CNS sulfatide deficiency on peripheral metabolism while considering sex- and age-specific effects. We found that female sulfatide-deficient mice gained significantly more body weight, exhibited higher basal glucose levels, and were glucose-intolerant during glucose-tolerance test (GTT) compared to age-matched controls under a normal diet, whereas male sulfatide-deficient mice only displayed glucose intolerance at a much older age compared to female sulfatide-deficient mice. Mechanistically, we found that increased body weight was associated with increased food intake and elevated neuroinflammation, especially in the hypothalamus, in a sex-specific manner. Our results suggest that CNS sulfatide deficiency leads to sex-specific alterations in energy homeostasis via dysregulated hypothalamic control of food intake. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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23 pages, 5241 KiB

Open AccessArticle

Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation

by Khalifa El Malki, Pia Wehling, Francesca Alt, Roger Sandhoff, Sebastian Zahnreich, Arsenij Ustjanzew, Carolin Wilzius, Marc A. Brockmann, Arthur Wingerter, Alexandra Russo, Olaf Beck, Clemens Sommer, Malte Ottenhausen, Katrin B. M. Frauenknecht, Claudia Paret and Jörg Faber

Int. J. Mol. Sci. 2023, 24(12), 9905; https://doi.org/10.3390/ijms24129905 - 08 Jun 2023

Cited by 3 | Viewed by 2271

Abstract

H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann–Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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17 pages, 4397 KiB

Open AccessArticle

Sphingosine Kinases at the Intersection of Pro-Inflammatory LPS and Anti-Inflammatory Endocannabinoid Signaling in BV2 Mouse Microglia Cells

by Sara Standoli, Cinzia Rapino, Camilla Di Meo, Agnes Rudowski, Nicole Kämpfer-Kolb, Luisa Michelle Volk, Dominique Thomas, Sandra Trautmann, Yannick Schreiber, Dagmar Meyer zu Heringdorf and Mauro Maccarrone

Int. J. Mol. Sci. 2023, 24(10), 8508; https://doi.org/10.3390/ijms24108508 - 09 May 2023

Cited by 1 | Viewed by 1784

Abstract

Microglia, the resident immune cells of the central nervous system, play important roles in brain homeostasis as well as in neuroinflammation, neurodegeneration, neurovascular diseases, and traumatic brain injury. In this context, components of the endocannabinoid (eCB) system have been shown to shift microglia towards an anti-inflammatory activation state. Instead, much less is known about the functional role of the sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) system in microglia biology. In the present study, we addressed potential crosstalk of the eCB and the S1P systems in BV2 mouse microglia cells challenged with lipopolysaccharide (LPS). We show that URB597, the selective inhibitor of fatty acid amide hydrolase (FAAH)—the main degradative enzyme of the eCB anandamide—prevented LPS-induced production of tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), and caused the accumulation of anandamide itself and eCB-like molecules such as oleic acid and cis-vaccenic acid ethanolamide, palmitoylethanolamide, and docosahexaenoyl ethanolamide. Furthermore, treatment with JWH133, a selective agonist of the eCB-binding cannabinoid 2 (CB₂) receptor, mimicked the anti-inflammatory effects of URB597. Interestingly, LPS induced transcription of both SphK1 and SphK2, and the selective inhibitors of SphK1 (SLP7111228) and SphK2 (SLM6031434) strongly reduced LPS-induced TNFα and IL-1β production. Thus, the two SphKs were pro-inflammatory in BV2 cells in a non-redundant manner. Most importantly, the inhibition of FAAH by URB597, as well as the activation of CB₂ by JWH133, prevented LPS-stimulated transcription of SphK1 and SphK2. These results present SphK1 and SphK2 at the intersection of pro-inflammatory LPS and anti-inflammatory eCB signaling, and suggest the further development of inhibitors of FAAH or SphKs for the treatment of neuroinflammatory diseases. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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9 pages, 3813 KiB

Open AccessCommunication

Azido-Ceramides, a Tool to Analyse SARS-CoV-2 Replication and Inhibition—SARS-CoV-2 Is Inhibited by Ceramides

by Daniela Brenner, Nina Geiger, Jan Schlegel, Viktoria Diesendorf, Louise Kersting, Julian Fink, Linda Stelz, Sibylle Schneider-Schaulies, Markus Sauer, Jochen Bodem and Jürgen Seibel

Int. J. Mol. Sci. 2023, 24(8), 7281; https://doi.org/10.3390/ijms24087281 - 14 Apr 2023

Cited by 1 | Viewed by 1094

Abstract

Recently, we have shown that C6-ceramides efficiently suppress viral replication by trapping the virus in lysosomes. Here, we use antiviral assays to evaluate a synthetic ceramide derivative α-NH2-ω-N3-C6-ceramide (AKS461) and to confirm the biological activity of C6-ceramides inhibiting SARS-CoV-2. Click-labeling with a fluorophore demonstrated that AKS461 accumulates in lysosomes. Previously, it has been shown that suppression of SARS-CoV-2 replication can be cell-type specific. Thus, AKS461 inhibited SARS-CoV-2 replication in Huh-7, Vero, and Calu-3 cells up to 2.5 orders of magnitude. The results were confirmed by CoronaFISH, indicating that AKS461 acts comparable to the unmodified C6-ceramide. Thus, AKS461 serves as a tool to study ceramide-associated cellular and viral pathways, such as SARS-CoV-2 infections, and it helped to identify lysosomes as the central organelle of C6-ceramides to inhibit viral replication. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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15 pages, 2221 KiB

Open AccessArticle

S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR_2,4, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health

by Shah Alam, Sumaiya Yasmeen Afsar and Gerhild Van Echten-Deckert

Int. J. Mol. Sci. 2023, 24(5), 4581; https://doi.org/10.3390/ijms24054581 - 26 Feb 2023

Cited by 3 | Viewed by 2241

Abstract

Astrocytes are critical players in brain health and disease. Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival, and migration. It was shown to be crucial for brain development. Its absence is embryonically lethal, affecting, inter alia, the anterior neural tube closure. However, an excess of S1P due to mutations in S1P-lyase (SGPL1), the enzyme responsible for its constitutive removal, is also harmful. Of note, the gene SGPL1 maps to a region prone to mutations in several human cancers and also in S1P-lyase insufficiency syndrome (SPLIS) characterized by several symptoms, including peripheral and central neurological defects. Here, we investigated the impact of S1P on astrocytes in a mouse model with the neural−targeted ablation of SGPL1. We found that SGPL1 deficiency, and hence the accumulation of its substrate, S1P, causes the elevated expression of glycolytic enzymes and preferentially directs pyruvate into the tricarboxylic acid (TCA) cycle through its receptors (S1PR_2,4). In addition, the activity of TCA regulatory enzymes was increased, and consequently, so was the cellular ATP content. The high energy load activates the mammalian target of rapamycin (mTOR), thus keeping astrocytic autophagy in check. Possible consequences for the viability of neurons are discussed. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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16 pages, 10956 KiB

Open AccessArticle

Sphingolipid Long-Chain Base Signaling in Compatible and Non-Compatible Plant–Pathogen Interactions in Arabidopsis

by Mariana Saucedo-García, Ariadna González-Solís, Priscila Rodríguez-Mejía, Guadalupe Lozano-Rosas, Teresa de Jesús Olivera-Flores, Laura Carmona-Salazar, A. Arturo Guevara-García, Edgar B. Cahoon and Marina Gavilanes-Ruíz

Int. J. Mol. Sci. 2023, 24(5), 4384; https://doi.org/10.3390/ijms24054384 - 23 Feb 2023

Cited by 4 | Viewed by 1552

Abstract

The chemical diversity of sphingolipids in plants allows the assignment of specific roles to special molecular species. These roles include NaCl receptors for glycosylinositolphosphoceramides or second messengers for long-chain bases (LCBs), free or in their acylated forms. Such signaling function has been associated with plant immunity, with an apparent connection to mitogen-activated protein kinase 6 (MPK6) and reactive oxygen species (ROS). This work used in planta assays with mutants and fumonisin B1 (FB1) to generate varying levels of endogenous sphingolipids. This was complemented with in planta pathogenicity tests using virulent and avirulent Pseudomonas syringae strains. Our results indicate that the surge of specific free LCBs and ceramides induced by FB1 or an avirulent strain trigger a biphasic ROS production. The first transient phase is partially produced by NADPH oxidase, and the second is sustained and is related to programmed cell death. MPK6 acts downstream of LCB buildup and upstream of late ROS and is required to selectively inhibit the growth of the avirulent but not the virulent strain. Altogether, these results provide evidence that a LCB– MPK6– ROS signaling pathway contributes differentially to the two forms of immunity described in plants, upregulating the defense scheme of a non-compatible interaction. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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16 pages, 4294 KiB

Open AccessArticle

Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury

by Si Hyun Lee, A Ra Kho, Song Hee Lee, Dae Ki Hong, Beom Seok Kang, Min Kyu Park, Chang Juhn Lee, Hyun Wook Yang, Seo Young Woo, Se Wan Park, Dong Yeon Kim, Bo Young Choi and Sang Won Suh

Int. J. Mol. Sci. 2022, 23(23), 14749; https://doi.org/10.3390/ijms232314749 - 25 Nov 2022

Cited by 5 | Viewed by 1573

Abstract

Traumatic brain injury (TBI) broadly degrades the normal function of the brain after a bump, blow, or jolt to the head. TBI leads to the aggravation of pre-existing brain dysfunction and promotes neurotoxic cascades that involve processes such as oxidative stress, loss of dendritic arborization, and zinc accumulation. Acid sphingomyelinase (ASMase) is an enzyme that hydrolyzes sphingomyelin to ceramide in cells. Under normal conditions, ceramide plays an important role in various physiological functions, such as differentiation and apoptosis. However, under pathological conditions, excessive ceramide production is toxic and activates the neuronal-death pathway. Therefore, we hypothesized that the inhibition of ASMase activity by imipramine would reduce ceramide formation and thus prevent TBI-induced neuronal death. To test our hypothesis, an ASMase inhibitor, imipramine (10 mg/kg, i.p.), was administrated to rats immediately after TBI. Based on the results of this study, we confirmed that imipramine significantly reduced ceramide formation, dendritic loss, oxidative stress, and neuronal death in the TBI-imipramine group compared with the TBI-vehicle group. Additionally, we validated that imipramine prevented TBI-induced cognitive dysfunction and the modified neurological severity score. Consequently, we suggest that ASMase inhibition may be a promising therapeutic strategy to reduce hippocampal neuronal death after TBI. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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Review

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21 pages, 1124 KiB

Open AccessReview

Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration

by Iga Wieczorek and Robert Piotr Strosznajder

Int. J. Mol. Sci. 2023, 24(7), 6180; https://doi.org/10.3390/ijms24076180 - 24 Mar 2023

Viewed by 1685

Abstract

Sphingosine-1-phosphate lyase (SPL) is a pyridoxal 5′-phosphate-dependent enzyme involved in the irreversible degradation of sphingosine-1-phosphate (S1P)—a bioactive sphingolipid that modulates a broad range of biological processes (cell proliferation, migration, differentiation and survival; mitochondrial functioning; and gene expression). Although SPL activity leads to a decrease in the available pool of S1P in the cell, at the same time, hexadecenal and phosphoethanolamine, compounds with potential biological activity, are generated. The increased expression and/or activity of SPL, and hence the imbalance between S1P and the end products of its cleavage, were demonstrated in several pathological states. On the other hand, loss-of-function mutations in the SPL encoding gene are a cause of severe developmental impairments. Recently, special attention has been paid to neurodegenerative diseases as the most common pathologies of the nervous system. This review summarizes the current findings concerning the role of SPL in the nervous system with an emphasis on neurodegeneration. Moreover, it briefly discusses pharmacological compounds directed to inhibit its activity. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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19 pages, 1922 KiB

Open AccessReview

Fatty Acid 2-Hydroxylase and 2-Hydroxylated Sphingolipids: Metabolism and Function in Health and Diseases

by Matthias Eckhardt

Int. J. Mol. Sci. 2023, 24(5), 4908; https://doi.org/10.3390/ijms24054908 - 03 Mar 2023

Cited by 6 | Viewed by 2429

Abstract

Sphingolipids containing acyl residues that are hydroxylated at C-2 are found in most, if not all, eukaryotes and certain bacteria. 2-hydroxylated sphingolipids are present in many organs and cell types, though they are especially abundant in myelin and skin. The enzyme fatty acid 2-hydroxylase (FA2H) is involved in the synthesis of many but not all 2-hydroxylated sphingolipids. Deficiency in FA2H causes a neurodegenerative disease known as hereditary spastic paraplegia 35 (HSP35/SPG35) or fatty acid hydroxylase-associated neurodegeneration (FAHN). FA2H likely also plays a role in other diseases. A low expression level of FA2H correlates with a poor prognosis in many cancers. This review presents an updated overview of the metabolism and function of 2-hydroxylated sphingolipids and the FA2H enzyme under physiological conditions and in diseases. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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24 pages, 755 KiB

Open AccessReview

Gene Therapy of Sphingolipid Metabolic Disorders

by Alisa A. Shaimardanova, Valeriya V. Solovyeva, Shaza S. Issa and Albert A. Rizvanov

Int. J. Mol. Sci. 2023, 24(4), 3627; https://doi.org/10.3390/ijms24043627 - 11 Feb 2023

Cited by 4 | Viewed by 3974

Abstract

Sphingolipidoses are defined as a group of rare hereditary diseases resulting from mutations in the genes encoding lysosomal enzymes. This group of lysosomal storage diseases includes more than 10 genetic disorders, including GM1-gangliosidosis, Tay–Sachs disease, Sandhoff disease, the AB variant of GM2-gangliosidosis, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann–Pick disease, Farber disease, etc. Enzyme deficiency results in accumulation of sphingolipids in various cell types, and the nervous system is also usually affected. There are currently no known effective methods for the treatment of sphingolipidoses; however, gene therapy seems to be a promising therapeutic variant for this group of diseases. In this review, we discuss gene therapy approaches for sphingolipidoses that are currently being investigated in clinical trials, among which adeno-associated viral vector-based approaches and transplantation of hematopoietic stem cells genetically modified with lentiviral vectors seem to be the most effective. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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Other

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14 pages, 467 KiB

Open AccessHypothesis

Sphingosine-1-Phosphate as Lung and Cardiac Vasculature Protecting Agent in SARS-CoV-2 Infection

by Manale Karam and Christian Auclair

Int. J. Mol. Sci. 2023, 24(17), 13088; https://doi.org/10.3390/ijms241713088 - 23 Aug 2023

Cited by 1 | Viewed by 1040

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause severe respiratory illness with high mortality. SARS-CoV-2 infection results in a massive inflammatory cell infiltration into the infected lungs accompanied by excessive pro-inflammatory cytokine production. The lung histology of dead patients shows that some areas are severely emphysematous, with enormously dilated blood vessels and micro-thromboses. The inappropriate inflammatory response damaging the pulmonary interstitial arteriolar walls suggests that the respiratory distress may come in a large part from lung vasculature injuries. It has been recently observed that low plasmatic sphingosine-1-phosphate (S1P) is a marker of a worse prognosis of clinical outcome in severe coronavirus disease (COVID) patients. S1P is an angiogenic molecule displaying anti-inflammatory and anti-apoptotic properties, that promote intercellular interactions between endothelial cells and pericytes resulting in the stabilization of arteries and capillaries. In this context, it can be hypothesized that the benefit of a normal S1P level is due to its protective effect on lung vasculature functionality. This paper provides evidence supporting this concept, opening the way for the design of a pharmacological approach involving the use of an S1P lyase inhibitor to increase the S1P level that in turn will rescue the lung vasculature functionality. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 3.0)

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