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Open AccessEditorial

Special Issue on “Sphingolipids: From Pathology to Therapeutic Perspectives”

by Gerhild van Echten-Deckert

Cells 2020, 9(11), 2404; https://doi.org/10.3390/cells9112404 - 3 Nov 2020

Viewed by 1590

Abstract

It is an honor for us to dedicate this Special Issue to our dearest friend Lina Obeid, who was not only a pioneer in the field of sphingolipids, but also a remarkable personality [...] Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

Research

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17 pages, 3410 KiB

Open AccessArticle

Dissecting G_q/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1

by Kira Vanessa Blankenbach, Ralf Frederik Claas, Natalie Judith Aster, Anna Katharina Spohner, Sandra Trautmann, Nerea Ferreirós, Justin L. Black, John J. G. Tesmer, Stefan Offermanns, Thomas Wieland and Dagmar Meyer zu Heringdorf

Cells 2020, 9(10), 2201; https://doi.org/10.3390/cells9102201 - 29 Sep 2020

Cited by 5 | Viewed by 2602

Abstract

Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that G_q-coupled receptors and constitutively active Gα_q/11 specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical G [...] Read more.

Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that G_q-coupled receptors and constitutively active Gα_q/11 specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical G_q/phospholipase C (PLC) signaling. Here, we further characterized G_q/11 regulation of SphK1. SphK1 translocation by the M₃ receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLCβ₃, but accelerated by wild-type PLCβ₃ and the PLCδ PH domain. Both wild-type SphK1 and catalytically inactive SphK1-G82D reduced M₃ receptor-stimulated inositol phosphate production, suggesting competition at Gα_q. Embryonic fibroblasts from Gα_q/11 double-deficient mice were used to show that amino acids W263 and T257 of Gα_q, which interact directly with PLCβ₃ and p63RhoGEF, were important for bradykinin B₂ receptor-induced SphK1 translocation. Finally, an AIXXPL motif was identified in vertebrate SphK1 (positions 100–105 in human SphK1a), which resembles the Gα_q binding motif, ALXXPI, in PLCβ and p63RhoGEF. After M₃ receptor stimulation, SphK1-A100E-I101E and SphK1-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLCβ/PLCδ(PH) expression are important for regulation of SphK1 by G_q/11. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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13 pages, 2595 KiB

Open AccessArticle

Neurodegeneration Caused by S1P-Lyase Deficiency Involves Calcium-Dependent Tau Pathology and Abnormal Histone Acetylation

by Shah Alam, Antonia Piazzesi, Mariam Abd El Fatah, Maren Raucamp and Gerhild van Echten-Deckert

Cells 2020, 9(10), 2189; https://doi.org/10.3390/cells9102189 - 28 Sep 2020

Cited by 17 | Viewed by 3146

Abstract

We have shown that sphingosine 1-phosphate (S1P) generated by sphingosine kinase 2 (SK2) is toxic in neurons lacking S1P-lyase (SGPL1), the enzyme that catalyzes its irreversible cleavage. Interestingly, patients harboring mutations in the gene encoding this enzyme (SGPL1) often present with [...] Read more.

We have shown that sphingosine 1-phosphate (S1P) generated by sphingosine kinase 2 (SK2) is toxic in neurons lacking S1P-lyase (SGPL1), the enzyme that catalyzes its irreversible cleavage. Interestingly, patients harboring mutations in the gene encoding this enzyme (SGPL1) often present with neurological pathologies. Studies in a mouse model with a developmental neural-specific ablation of SGPL1 (SGPL1^fl/fl/Nes) confirmed the importance of S1P metabolism for the presynaptic architecture and neuronal autophagy, known to be essential for brain health. We now investigated in SGPL1-deficient murine brains two other factors involved in neurodegenerative processes, namely tau phosphorylation and histone acetylation. In hippocampal and cortical slices SGPL1 deficiency and hence S1P accumulation are accompanied by hyperphosphorylation of tau and an elevated acetylation of histone3 (H3) and histone4 (H4). Calcium chelation with BAPTA-AM rescued both tau hyperphosphorylation and histone acetylation, designating calcium as an essential mediator of these (patho)physiological functions of S1P in the brain. Studies in primary cultured neurons and astrocytes derived from SGPL1^fl/fl/Nes mice revealed hyperphosphorylated tau only in SGPL1-deficient neurons and increased histone acetylation only in SGPL1-deficient astrocytes. Both could be reversed to control values with BAPTA-AM, indicating the close interdependence of S1P metabolism, calcium homeostasis, and brain health. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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18 pages, 4575 KiB

Open AccessArticle

Exogenous Flupirtine as Potential Treatment for CLN3 Disease

by Katia Maalouf, Joelle Makoukji, Sara Saab, Nadine J. Makhoul, Angelica V. Carmona, Nihar Kinarivala, Noël Ghanem, Paul C. Trippier and Rose-Mary Boustany

Cells 2020, 9(8), 1872; https://doi.org/10.3390/cells9081872 - 11 Aug 2020

Cited by 5 | Viewed by 3158

Abstract

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in [...] Read more.

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3^Δex7/8 mice. WT/Cln3^Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in Cln3^Δex7/8 mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in Cln3^Δex7/8 mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female Cln3^Δex7/8 mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in Cln3^Δex7/8 mice, paving the way for potential therapies for CLN3 disease. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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22 pages, 5045 KiB

Open AccessArticle

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

by Alessandra Mingione, Emerenziana Ottaviano, Matteo Barcella, Ivan Merelli, Lorenzo Rosso, Tatiana Armeni, Natalia Cirilli, Riccardo Ghidoni, Elisa Borghi and Paola Signorelli

Cells 2020, 9(8), 1845; https://doi.org/10.3390/cells9081845 - 6 Aug 2020

Cited by 10 | Viewed by 3083

Abstract

Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and [...] Read more.

Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients’ derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients’ monocytes killing of A. fumigatus. CF patients’ monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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17 pages, 1867 KiB

Open AccessArticle

Opposing Roles of S1P₃ Receptors in Myocardial Function

by Dina Wafa, Nóra Koch, Janka Kovács, Margit Kerék, Richard L. Proia, Gábor J. Tigyi, Zoltán Benyó and Zsuzsanna Miklós

Cells 2020, 9(8), 1770; https://doi.org/10.3390/cells9081770 - 24 Jul 2020

Cited by 5 | Viewed by 2732

Abstract

Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator with diverse biological function mediated by S1P_1–5 receptors. Whereas S1P was shown to protect the heart against ischemia/reperfusion (I/R) injury, other studies highlighted its vasoconstrictor effects. We aimed to separate the beneficial and potentially deleterious cardiac [...] Read more.

Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator with diverse biological function mediated by S1P_1–5 receptors. Whereas S1P was shown to protect the heart against ischemia/reperfusion (I/R) injury, other studies highlighted its vasoconstrictor effects. We aimed to separate the beneficial and potentially deleterious cardiac effects of S1P during I/R and identify the signaling pathways involved. Wild type (WT), S1P₂-KO and S1P₃-KO Langendorff-perfused murine hearts were exposed to intravascular S1P, I/R, or both. S1P induced a 45% decrease of coronary flow (CF) in WT-hearts. The presence of S1P-chaperon albumin did not modify this effect. CF reduction diminished in S1P₃-KO but not in S1P₂-KO hearts, indicating that in our model S1P₃ mediates coronary vasoconstriction. In I/R experiments, S1P₃ deficiency had no influence on postischemic CF but diminished functional recovery and increased infarct size, indicating a cardioprotective effect of S1P₃. Preischemic S1P exposure resulted in a substantial reduction of postischemic CF and cardiac performance and increased the infarcted area. Although S1P₃ deficiency increased postischemic CF, this failed to improve cardiac performance. These results indicate a dual role of S1P₃ involving a direct protective action on the myocardium and a cardiosuppressive effect due to coronary vasoconstriction. In acute coronary syndrome when S1P may be released abundantly, intravascular and myocardial S1P production might have competing influences on myocardial function via activation of S1P₃ receptors. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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12 pages, 1272 KiB

Open AccessArticle

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice

by Iulia Zoicas, Fabian Schumacher, Burkhard Kleuser, Martin Reichel, Erich Gulbins, Anna Fejtova, Johannes Kornhuber and Cosima Rhein

Cells 2020, 9(5), 1244; https://doi.org/10.3390/cells9051244 - 18 May 2020

Cited by 15 | Viewed by 2983

Abstract

Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg^fb) that [...] Read more.

Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg^fb) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg^fb mice than in female Asm-tg^fb mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg^fb mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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11 pages, 901 KiB

Open AccessArticle

Anxiety and Depression Are Related to Higher Activity of Sphingolipid Metabolizing Enzymes in the Rat Brain

by Iulia Zoicas, Christiane Mühle, Anna K. Schmidtner, Erich Gulbins, Inga D. Neumann and Johannes Kornhuber

Cells 2020, 9(5), 1239; https://doi.org/10.3390/cells9051239 - 17 May 2020

Cited by 16 | Viewed by 3352

Abstract

Changes in sphingolipid metabolism have been suggested to contribute to the pathophysiology of major depression. In this study, we investigated the activity of acid and neutral sphingomyelinases (ASM, NSM) and ceramidases (AC, NC), respectively, in twelve brain regions of female rats selectively bred [...] Read more.

Changes in sphingolipid metabolism have been suggested to contribute to the pathophysiology of major depression. In this study, we investigated the activity of acid and neutral sphingomyelinases (ASM, NSM) and ceramidases (AC, NC), respectively, in twelve brain regions of female rats selectively bred for high (HAB) versus low (LAB) anxiety-like behavior. Concomitant with their highly anxious and depressive-like phenotype, HAB rats showed increased activity of ASM and NSM as well as of AC and NC in multiple brain regions associated with anxiety- and depressive-like behavior, including the lateral septum, hypothalamus, ventral hippocampus, ventral and dorsal mesencephalon. Strong correlations between anxiety-like behavior and ASM activity were found in female HAB rats in the amygdala, ventral hippocampus and dorsal mesencephalon, whereas NSM activity correlated with anxiety levels in the dorsal mesencephalon. These results provide novel information about the sphingolipid metabolism, especially about the sphingomyelinases and ceramidases, in major depression and comorbid anxiety. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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16 pages, 3603 KiB

Open AccessArticle

Inflammatory Conditions Disrupt Constitutive Endothelial Cell Barrier Stabilization by Alleviating Autonomous Secretion of Sphingosine 1-Phosphate

by Jefri Jeya Paul, Cynthia Weigel, Tina Müller, Regine Heller, Sarah Spiegel and Markus H. Gräler

Cells 2020, 9(4), 928; https://doi.org/10.3390/cells9040928 - 10 Apr 2020

Cited by 20 | Viewed by 4484

Abstract

The breakdown of the endothelial cell (EC) barrier contributes significantly to sepsis mortality. Sphingosine 1-phosphate (S1P) is one of the most effective EC barrier-stabilizing signaling molecules. Stabilization is mainly transduced via the S1P receptor type 1 (S1PR1). Here, we demonstrate that S1P was [...] Read more.

The breakdown of the endothelial cell (EC) barrier contributes significantly to sepsis mortality. Sphingosine 1-phosphate (S1P) is one of the most effective EC barrier-stabilizing signaling molecules. Stabilization is mainly transduced via the S1P receptor type 1 (S1PR1). Here, we demonstrate that S1P was autonomously produced by ECs. S1P secretion was significantly higher in primary human umbilical vein endothelial cells (HUVEC) compared to the endothelial cell line EA.hy926. Constitutive barrier stability of HUVEC, but not EA.hy926, was significantly compromised by the S1PR1 antagonist W146 and by the anti-S1P antibody Sphingomab. HUVEC and EA.hy926 differed in the expression of the S1P-transporter Spns2, which allowed HUVEC, but not EA.hy926, to secrete S1P into the extracellular space. Spns2 deficient mice showed increased serum albumin leakage in bronchoalveolar lavage fluid (BALF). Lung ECs isolated from Spns2 deficient mice revealed increased leakage of fluorescein isothiocyanate (FITC) labeled dextran and decreased resistance in electric cell-substrate impedance sensing (ECIS) measurements. Spns2 was down-regulated in HUVEC after stimulation with pro-inflammatory cytokines and lipopolysaccharides (LPS), which contributed to destabilization of the EC barrier. Our work suggests a new mechanism for barrier integrity maintenance. Secretion of S1P by EC via Spns2 contributed to constitutive EC barrier maintenance, which was disrupted under inflammatory conditions via the down-regulation of the S1P-transporter Spns2. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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Review

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12 pages, 402 KiB

Open AccessReview

Transcriptional Regulation of Sphingosine Kinase 1

by Joseph Bonica, Cungui Mao, Lina M. Obeid and Yusuf A. Hannun

Cells 2020, 9(11), 2437; https://doi.org/10.3390/cells9112437 - 8 Nov 2020

Cited by 12 | Viewed by 2818

Abstract

Once thought to be primarily structural in nature, sphingolipids have become increasingly appreciated as second messengers in a wide array of signaling pathways. Sphingosine kinase 1, or SK1, is one of two sphingosine kinases that phosphorylate sphingosine into sphingosine-1-phosphate (S1P). S1P is generally [...] Read more.

Once thought to be primarily structural in nature, sphingolipids have become increasingly appreciated as second messengers in a wide array of signaling pathways. Sphingosine kinase 1, or SK1, is one of two sphingosine kinases that phosphorylate sphingosine into sphingosine-1-phosphate (S1P). S1P is generally pro-inflammatory, pro-angiogenic, immunomodulatory, and pro-survival; therefore, high SK1 expression and activity have been associated with certain inflammatory diseases and cancer. It is thus important to develop an understanding of the regulation of SK1 expression and activity. In this review, we explore the current literature on SK1 transcriptional regulation, illustrating a complex system of transcription factors, cytokines, and even micro-RNAs (miRNAs) on the post transcriptional level. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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29 pages, 2169 KiB

Open AccessReview

New Insights into the Role of Sphingolipid Metabolism in Melanoma

by Lorry Carrié, Mathieu Virazels, Carine Dufau, Anne Montfort, Thierry Levade, Bruno Ségui and Nathalie Andrieu-Abadie

Cells 2020, 9(9), 1967; https://doi.org/10.3390/cells9091967 - 26 Aug 2020

Cited by 15 | Viewed by 3998

Abstract

Cutaneous melanoma is a deadly skin cancer whose aggressiveness is directly linked to its metastatic potency. Despite remarkable breakthroughs in term of treatments with the emergence of targeted therapy and immunotherapy, the prognosis for metastatic patients remains uncertain mainly because of resistances. Better [...] Read more.

Cutaneous melanoma is a deadly skin cancer whose aggressiveness is directly linked to its metastatic potency. Despite remarkable breakthroughs in term of treatments with the emergence of targeted therapy and immunotherapy, the prognosis for metastatic patients remains uncertain mainly because of resistances. Better understanding the mechanisms responsible for melanoma progression is therefore essential to uncover new therapeutic targets. Interestingly, the sphingolipid metabolism is dysregulated in melanoma and is associated with melanoma progression and resistance to treatment. This review summarises the impact of the sphingolipid metabolism on melanoma from the initiation to metastatic dissemination with emphasis on melanoma plasticity, immune responses and resistance to treatments. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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31 pages, 1725 KiB

Open AccessReview

Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells

by Ewa Gurgul-Convey

Cells 2020, 9(8), 1835; https://doi.org/10.3390/cells9081835 - 4 Aug 2020

Cited by 9 | Viewed by 4241

Abstract

Type 1 diabetes (T1DM) is a chronic autoimmune disease, with a strong genetic background, leading to a gradual loss of pancreatic beta-cells, which secrete insulin and control glucose homeostasis. Patients with T1DM require life-long substitution with insulin and are at high risk for [...] Read more.

Type 1 diabetes (T1DM) is a chronic autoimmune disease, with a strong genetic background, leading to a gradual loss of pancreatic beta-cells, which secrete insulin and control glucose homeostasis. Patients with T1DM require life-long substitution with insulin and are at high risk for development of severe secondary complications. The incidence of T1DM has been continuously growing in the last decades, indicating an important contribution of environmental factors. Accumulating data indicates that sphingolipids may be crucially involved in T1DM development. The serum lipidome of T1DM patients is characterized by significantly altered sphingolipid composition compared to nondiabetic, healthy probands. Recently, several polymorphisms in the genes encoding the enzymatic machinery for sphingolipid production have been identified in T1DM individuals. Evidence gained from studies in rodent islets and beta-cells exposed to cytokines indicates dysregulation of the sphingolipid biosynthetic pathway and impaired function of several sphingolipids. Moreover, a number of glycosphingolipids have been suggested to act as beta-cell autoantigens. Studies in animal models of autoimmune diabetes, such as the Non Obese Diabetic (NOD) mouse and the LEW.1AR1-iddm (IDDM) rat, indicate a crucial role of sphingolipids in immune cell trafficking, islet infiltration and diabetes development. In this review, the up-to-date status on the findings about sphingolipids in T1DM will be provided, the under-investigated research areas will be identified and perspectives for future studies will be given. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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19 pages, 2310 KiB

Open AccessReview

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

by Jeanne Guitton, Cécile L. Bandet, Mohamed L. Mariko, Sophie Tan-Chen, Olivier Bourron, Yacir Benomar, Eric Hajduch and Hervé Le Stunff

Cells 2020, 9(7), 1682; https://doi.org/10.3390/cells9071682 - 13 Jul 2020

Cited by 40 | Viewed by 4560

Abstract

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). [...] Read more.

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic β cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic β cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic β cells, which depends on its origin or its degradation pathway. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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34 pages, 2981 KiB

Open AccessReview

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

by Alexandra Lucaciu, Robert Brunkhorst, Josef M. Pfeilschifter, Waltraud Pfeilschifter and Julien Subburayalu

Cells 2020, 9(6), 1515; https://doi.org/10.3390/cells9061515 - 22 Jun 2020

Cited by 34 | Viewed by 9648

Abstract

Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, [...] Read more.

Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P–S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P–S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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20 pages, 2124 KiB

Open AccessReview

Elusive Roles of the Different Ceramidases in Human Health, Pathophysiology, and Tissue Regeneration

by Carolina Duarte, Juliet Akkaoui, Chiaki Yamada, Anny Ho, Cungui Mao and Alexandru Movila

Cells 2020, 9(6), 1379; https://doi.org/10.3390/cells9061379 - 2 Jun 2020

Cited by 18 | Viewed by 4722

Abstract

Ceramide and sphingosine are important interconvertible sphingolipid metabolites which govern various signaling pathways related to different aspects of cell survival and senescence. The conversion of ceramide into sphingosine is mediated by ceramidases. Altogether, five human ceramidases—named acid ceramidase, neutral ceramidase, alkaline ceramidase 1, [...] Read more.

Ceramide and sphingosine are important interconvertible sphingolipid metabolites which govern various signaling pathways related to different aspects of cell survival and senescence. The conversion of ceramide into sphingosine is mediated by ceramidases. Altogether, five human ceramidases—named acid ceramidase, neutral ceramidase, alkaline ceramidase 1, alkaline ceramidase 2, and alkaline ceramidase 3—have been identified as having maximal activities in acidic, neutral, and alkaline environments, respectively. All five ceramidases have received increased attention for their implications in various diseases, including cancer, Alzheimer’s disease, and Farber disease. Furthermore, the potential anti-inflammatory and anti-apoptotic effects of ceramidases in host cells exposed to pathogenic bacteria and viruses have also been demonstrated. While ceramidases have been a subject of study in recent decades, our knowledge of their pathophysiology remains limited. Thus, this review provides a critical evaluation and interpretive analysis of existing literature on the role of acid, neutral, and alkaline ceramidases in relation to human health and various diseases, including cancer, neurodegenerative diseases, and infectious diseases. In addition, the essential impact of ceramidases on tissue regeneration, as well as their usefulness in enzyme replacement therapy, is also discussed. Full article

(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives - A Themed Honorary Issue to Prof. Lina Obeid)

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