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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 (31 March 2019) | Viewed by 53005

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Dr. Jean-Pierre Jaffrézou

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CNRS UMR5549, CerCo, TMBI, CHU Purpan, Pavillon Baudot, 31059 Toulouse, France
Interests: cancer therapies; chemoresistance; microdomains; cell signaling
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Dear Colleagues,

The emergence of ceramide as an important mediator in a variety of cellular processes and diseases has stimulated extensive and all-encompassing research.

Ceramide originates from three sources. Increases in sphingomyelin hydrolysis by activation of sphingomyelinases; increased de novo synthesis to activation of serine palmitoyl transferase and/or ceramide synthase; and increased sphingosine-1-phosphate hydrolysis by sphingosine-1-phosphatase to produce sphingosine followed by ceramide synthesis by ceramide synthase.

Ceramide generation in response, for example, to cellular stress is known to mediate cell death through various mechanisms, including induction of apoptosis, necroptosis, autophagy and ER stress. However, the role of ceramide varies widely depending on cell and tissue type, its subcellular localization, and the availability of downstream targets.

This Special Issue will discuss the recent advances in the field of ceramide mediated cell signaling. Thereby contributing to our knowledge on how the rapid metabolic conversions, trafficking, and signaling roles of ceramide come into play in both physiological and pathological conditions.

Dr. Jean-Pierre Jaffrézou
Guest Editor

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Keywords

ceramide
ceramide synthase
sphingolipids
sphingosine 1-phosphate
signaling
mitochondria
stress
cell death
necroptosis
inflammation
autophagy
cancer
metabolic disorder

Published Papers (10 papers)

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Research

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14 pages, 6197 KiB

Open AccessArticle

C₂-Ceramide-Induced Rb-Dominant Senescence-Like Phenotype Leads to Human Breast Cancer MCF-7 Escape from p53-Dependent Cell Death

by Wen-Tsan Chang, Chang-Yi Wu, Yin-Chieh Lin, Min-Tsui Wu, Kai-Li Su, Shyng-Shiou Yuan, Hui-Min David Wang, Yao Fong, Yi-Hsiung Lin and Chien-Chih Chiu

Int. J. Mol. Sci. 2019, 20(17), 4292; https://doi.org/10.3390/ijms20174292 - 02 Sep 2019

Cited by 12 | Viewed by 3727

Abstract

Ceramide is a sphingolipid which regulates a variety of signaling pathways in eukaryotic cells. Exogenous ceramide has been shown to induce cellular apoptosis. In this study, we observed that exogenous ceramide induced two distinct morphologies of cell fate following C₂-ceramide treatment between the two breast cancer cell lines MCF-7 (wild type p53) and MDA-MB-231 (mutant p53) cells. The growth assessment showed that C₂-ceramide caused significant growth inhibition and apoptosis in MDA-MB-231 cells through down-regulating the expression of mutant p53 whereas up-regulating the expression of pro-apoptotic Bad, and the proteolytic activation of caspase-3. However, senescence-associated (SA)-β-galactosidase (β-gal) was regulated in MCF-7 cells after C₂-ceramide treatment. The results of proliferation and apoptosis assays showed that MCF-7 cells were more resistant to C₂-ceramide treatment compared to MDA-MB-231 cells. Furthermore, C₂-ceramide treatment induced a time-responsive increase in Rb protein, a key regulator of senescence accompanied with the upregulation of both mRNA level and protein level of SA-genes PAI-1 and TGaseII in MCF-7 but not in MDA-MB-231 cells, suggesting that some cancer cells escape apoptosis through modulating senescence-like phenotype. The results of our present study depicted the mechanism of C₂-ceramide-resistant breast cancer cells, which might benefit the strategic development of ceramide-based chemotherapeutics against cancer in the future. Full article

(This article belongs to the Special Issue Ceramide)

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16 pages, 2112 KiB

Open AccessArticle

Neurite Outgrowth and Morphological Changes Induced by 8-trans Unsaturation of Sphingadienine in kCer Molecular Species

by Seigo Usuki, Noriko Tamura, Tomohiro Tamura, Kunikazu Tanji, Daisuke Mikami, Katsuyuki Mukai and Yasuyuki Igarashi

Int. J. Mol. Sci. 2019, 20(9), 2116; https://doi.org/10.3390/ijms20092116 - 29 Apr 2019

Cited by 4 | Viewed by 5397

Abstract

Konjac ceramide (kCer), which consists of plant-type molecular species of characteristic shingoid bases and fatty acids, is prepared from konjac glucosylceramide GlcCer by chemoenzymatical deglucosylation. kCer activates the semaphorin 3A (Sema3A) signaling pathway, inducing collapsin response mediator protein 2 (CRMP2) phosphorylation. This results in neurite outgrowth inhibition and morphological changes in remaining long neurites in PC12 cells. Whether a specific molecular species of kCer can bind to the Sema3A receptor (Neuropilin1, Nrp1) and activate the Sema3A signaling pathway remains unknown. Here, we prepared kCer molecular species using endoglycoceramidase I-mediated deglucosylation and examined neurite outgrowth and phosphorylation of collapsin response mediator protein 2 in nerve growth factor (NGF)-primed cells. The 8-trans unsaturation of sphingadienine of kCer was essential for Sema3A-like signaling pathway activation. Conversely, 8-cis unsaturation of kCer molecular species had no effect on Sema3A-like activation, and neurite outgrowth inhibition resulted in remaining short neurites. In addition, α-hydroxylation of fatty acids was not associated with the Sema3A-like activity of the kCer molecular species. These results suggest that 8-trans or 8-cis isomerization of sphingadienine determines the specific interactions at the ligand-binding site of Nrp1. Full article

(This article belongs to the Special Issue Ceramide)

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12 pages, 1601 KiB

Open AccessArticle

Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model

by Kerstin Kiefer, Josefina Casas, Roberto García-López and Rubén Vicente

Int. J. Mol. Sci. 2019, 20(6), 1391; https://doi.org/10.3390/ijms20061391 - 20 Mar 2019

Cited by 16 | Viewed by 5246

Abstract

Increased orosomucoid-like 3 (ORMDL3) expression levels, due to single nucleotide polymorphisms (SNPs), have been associated with several inflammatory diseases, including asthma and inflammatory bowel diseases. ORMDL proteins inhibit serine palmitoyltransferase (SPT), the first rate-limiting enzyme in de novo sphingolipid synthesis and alter cellular calcium homeostasis. Both processes are essential for immune response. The present study addresses ORMDL3 protein involvement in macrophage physiology using an overexpressing knock-in mouse model. Ceramide content was notably different in the bone-marrow-derived macrophages (BMDM) from the transgenic mouse model compared with the wild type (WT) macrophages. Our data revealed an alteration of de novo production of sphinganine upon BMDM activation in the transgenic mouse. Gene-expression analysis showed that alteration in ORMDL3 expression levels did not affect activation or macrophage polarization. Nevertheless, we studied phagocytosis and autophagy—crucial processes that are dependent on lipid membrane composition. Phagocytosis in transgenic macrophages was not affected by ORMDL3 overexpression, but we did find a reduction in toll-like receptor 4 (TLR-4)-mediated autophagy. Both genetic and functional studies have pointed to autophagy as an essential pathway involved in inflammation. We believe that our work provides new insights into the functional link between ORMDL3 expression and inflammatory diseases. Full article

(This article belongs to the Special Issue Ceramide)

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14 pages, 1201 KiB

Open AccessArticle

Muscle-Saturated Bioactive Lipids Are Increased with Aging and Influenced by High-Intensity Interval Training

by Ditte Søgaard, Marcin Baranowski, Steen Larsen, Michael Taulo Lund, Cathrine Munk Scheuer, Carina Vestergaard Abildskov, Sofie Greve Dideriksen, Flemming Dela and Jørn Wulff Helge

Int. J. Mol. Sci. 2019, 20(5), 1240; https://doi.org/10.3390/ijms20051240 - 12 Mar 2019

Cited by 22 | Viewed by 4637

Abstract

Ceramide and diacylglycerol are linked to insulin resistance in rodents, but in humans the data are inconsistent. Insulin resistance is frequently observed with aging, but the role of ceramide and diacylglycerol is not clarified. Training improves metabolic health and, therefore, we aimed to elucidate the influence of age and high-intensity interval training (HIIT) on ceramide and diacylglycerol content in muscle. Fourteen young (33 ± 1) and 22 older (63 ± 1) overweight to obese subjects performed 6 weeks HIIT three times a week. Maximal oxygen uptake and body composition were measured and muscle biopsies and fasting blood samples were obtained. Muscle ceramide and diacylglycerol were measured by gas-liquid chromatography and proteins in insulin signaling, lipid and glucose metabolism were measured by Western blotting. Content of ceramide and diacylglycerol total, saturated, C16:0 and C18:0 fatty acids and C18:1 ceramide were higher in older compared to young. HIIT reduced saturated and C18:0 ceramides, while the content of the proteins involved in glucose (GLUT4, glycogen synthase, hexokinase II, AKT) and lipid metabolism (adipose triglyceride lipase, fatty acid binding protein) were increased after HIIT. We demonstrate a higher content of saturated ceramide and diacylglycerol fatty acids in the muscle of older subjects compared to young. Moreover, the content of saturated ceramides was reduced and muscle glucose metabolism improved at protein level after HIIT. This study highlights an increased content of saturated ceramides in aging which could be speculated to influence insulin sensitivity. Full article

(This article belongs to the Special Issue Ceramide)

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14 pages, 2060 KiB

Open AccessArticle

Inhibition of Ceramide De Novo Synthesis Affects Adipocytokine Secretion and Improves Systemic and Adipose Tissue Insulin Sensitivity

by Agnieszka U. Blachnio-Zabielska, Hady Razak Hady, Adam R. Markowski, Adam Kurianiuk, Alicja Karwowska, Jan Górski and Piotr Zabielski

Int. J. Mol. Sci. 2018, 19(12), 3995; https://doi.org/10.3390/ijms19123995 - 11 Dec 2018

Cited by 28 | Viewed by 3284

Abstract

Ceramide accumulation in muscle and in liver is implicated in the induction of insulin resistance. Much less in known about the role of ceramide in adipose tissue. The aim of the present study was to elucidate the role of ceramide in adipose tissue and to clarify whether lipids participate in the regulation of adipocytokine secretion. The experiments were performed on male Wistar rats divided into three groups: 1. Control, 2. fed high fat diet (HFD), and 3. fed HFD and treated with myriocin. Ceramide (Cer) and diacylglycerol (DAG) content were analyzed by LC/MS/MS. Hormone sensitive lipase (HSL) phosphorylation was analyzed by Western Blot. Plasma adiponectin and tumor necrosis factor alpha (TNF-α) concentration were measured by enzyme-linked immunosorbent assay. An oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) was also performed. In HFD group, total DAG and Cer content was elevated in both subcutaneous and visceral adipose tissue, which was accompanied by increased glucose, insulin, and HOMA-IR value. Myriocin treatment restored HOMA-IR as well as glucose and insulin concentration to control values. Moreover, myriocin decreased not only Cer, but also DAG levels in both fat depots. Furthermore, we observed a strong correlation between adiponectin (negative) and TNF-α (positive) and Cer in both fat tissues, which suggests that Cer is involved in the regulation of adipocytokine secretion. Full article

(This article belongs to the Special Issue Ceramide)

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17 pages, 7044 KiB

Open AccessArticle

Acid Sphingomyelinase Inhibition Stabilizes Hepatic Ceramide Content and Improves Hepatic Biotransformation Capacity in a Murine Model of Polymicrobial Sepsis

by Ha-Yeun Chung, C. Julius Witt, Jorge Hurtado-Oliveros, Jonathan Wickel, Markus H. Gräler, Amelie Lupp and Ralf A. Claus

Int. J. Mol. Sci. 2018, 19(10), 3163; https://doi.org/10.3390/ijms19103163 - 15 Oct 2018

Cited by 7 | Viewed by 3124

Abstract

Liver dysfunction during sepsis is an independent risk factor leading to increased mortality rates. Specifically, dysregulation of hepatic biotransformation capacity, especially of the cytochrome P450 (CYP) system, represents an important distress factor during host response. The activity of the conserved stress enzyme sphingomyelin phosphodiesterase 1 (SMPD1) has been shown to be elevated in sepsis patients, allowing for risk stratification. Therefore, the aim of the present study was to investigate whether SMPD1 activity has an impact on expression and activity of different hepatic CYP enzymes using an animal model of polymicrobial sepsis. Polymicrobial sepsis was induced in SMPD1 wild-type and heterozygous mice and hepatic ceramide content as well as CYP mRNA, protein expression and enzyme activities were assessed at two different time points, at 24 h, representing the acute phase, and at 28 days, representing the post-acute phase of host response. In the acute phase of sepsis, SMPD1^+/+ mice showed an increased hepatic C16- as well as C18-ceramide content. In addition, a downregulation of CYP expression and activities was detected. In SMPD1^+/− mice, however, no noticeable changes of ceramide content and CYP expression and activities during sepsis could be observed. After 28 days, CYP expression and activities were normalized again in all study groups, whereas mRNA expression remained downregulated in SMPD^+/+ animals. In conclusion, partial genetic inhibition of SMPD1 stabilizes hepatic ceramide content and improves hepatic monooxygenase function in the acute phase of polymicrobial sepsis. Since we were also able to show that the functional inhibitor of SMPD1, desipramine, ameliorates downregulation of CYP mRNA expression and activities in the acute phase of sepsis in wild-type mice, SMPD1 might be an interesting pharmacological target, which should be further investigated. Full article

(This article belongs to the Special Issue Ceramide)

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13 pages, 2096 KiB

Open AccessArticle

Exogenous C₈-Ceramide Induces Apoptosis by Overproduction of ROS and the Switch of Superoxide Dismutases SOD1 to SOD2 in Human Lung Cancer Cells

by Yuli C. Chang, Yao Fong, Eing-Mei Tsai, Ya-Gin Chang, Han Lin Chou, Chang-Yi Wu, Yen-Ni Teng, Ta-Chih Liu, Shyng-Shiou Yuan and Chien-Chih Chiu

Int. J. Mol. Sci. 2018, 19(10), 3010; https://doi.org/10.3390/ijms19103010 - 02 Oct 2018

Cited by 25 | Viewed by 4158

Abstract

Ceramides, abundant sphingolipids on the cell membrane, can act as signaling molecules to regulate cellular functions including cell viability. Exogenous ceramide has been shown to exert potent anti-proliferative effects against cancer cells, but little is known about how it affects reactive oxygen species (ROS) in lung cancer cells. In this study, we investigated the effect of N-octanoyl-D-erythro-sphingosine (C₈-ceramide) on human non-small-cell lung cancer H1299 cells. Flow cytometry-based assays indicated that C₈-ceramide increased the level of endogenous ROS in H1299 cells. Interestingly, the ratio of superoxide dismutases (SODs) SOD1 and SOD2 seem to be regulated by C₈-ceramide treatment. Furthermore, the accumulation of cell cycle G1 phase and apoptotic populations in C₈-ceramide-treated H1299 cells was observed. The results of the Western blot showed that C₈-ceramide causes a dramatically increased protein level of cyclin D1, a critical regulator of cell cycle G1/S transition. These results suggest that C₈-ceramide acts as a potent chemotherapeutic agent and may increase the endogenous ROS level by regulating the switch of SOD1 and SOD2, causing the anti-proliferation, and consequently triggering the apoptosis of NSCLC H1299 cells. Accordingly, our works may give a promising strategy for lung cancer treatment in the future. Full article

(This article belongs to the Special Issue Ceramide)

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Review

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26 pages, 1415 KiB

Open AccessReview

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

by Cécile L. Bandet, Sophie Tan-Chen, Olivier Bourron, Hervé Le Stunff and Eric Hajduch

Int. J. Mol. Sci. 2019, 20(3), 479; https://doi.org/10.3390/ijms20030479 - 23 Jan 2019

Cited by 69 | Viewed by 8557

Abstract

Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance. In healthy individuals, excess FA are stored as lipid droplets in adipocytes. In situations like obesity and T2D, FA from lipolysis and food are in excess and eventually accumulate in peripheral tissues. High plasma concentrations of FA are generally associated with increased risk of developing diabetes. Indeed, ectopic fat accumulation is associated with insulin-resistance; this is called lipotoxicity. However, FA themselves are not involved in insulin-resistance, but rather some of their metabolic derivatives, such as ceramides. Ceramides, which are synthetized de novo from saturated FA like palmitate, have been demonstrated to play a critical role in the deterioration of insulin sensitivity in muscle cells. This review describes the latest progress involving ceramides as major players in the development of muscle insulin-resistance through the targeting of selective actors of the insulin signaling pathway. Full article

(This article belongs to the Special Issue Ceramide)

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23 pages, 1184 KiB

Open AccessReview

Ceramide and Regulation of Vascular Tone

by Angel Cogolludo, Eduardo Villamor, Francisco Perez-Vizcaino and Laura Moreno

Int. J. Mol. Sci. 2019, 20(2), 411; https://doi.org/10.3390/ijms20020411 - 18 Jan 2019

Cited by 53 | Viewed by 6904

Abstract

In addition to playing a role as a structural component of cellular membranes, ceramide is now clearly recognized as a bioactive lipid implicated in a variety of physiological functions. This review aims to provide updated information on the role of ceramide in the regulation of vascular tone. Ceramide may induce vasodilator or vasoconstrictor effects by interacting with several signaling pathways in endothelial and smooth muscle cells. There is a clear, albeit complex, interaction between ceramide and redox signaling. In fact, reactive oxygen species (ROS) activate different ceramide generating pathways and, conversely, ceramide is known to increase ROS production. In recent years, ceramide has emerged as a novel key player in oxygen sensing in vascular cells and mediating vascular responses of crucial physiological relevance such as hypoxic pulmonary vasoconstriction (HPV) or normoxic ductus arteriosus constriction. Likewise, a growing body of evidence over the last years suggests that exaggerated production of vascular ceramide may have detrimental effects in a number of pathological processes including cardiovascular and lung diseases. Full article

(This article belongs to the Special Issue Ceramide)

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24 pages, 1490 KiB

Open AccessReview

Ceramide Metabolism Balance, a Multifaceted Factor in Critical Steps of Breast Cancer Development

by Victor García-González, José Fernando Díaz-Villanueva, Octavio Galindo-Hernández, Israel Martínez-Navarro, Gustavo Hurtado-Ureta and Abril Alicia Pérez-Arias

Int. J. Mol. Sci. 2018, 19(9), 2527; https://doi.org/10.3390/ijms19092527 - 26 Aug 2018

Cited by 27 | Viewed by 7144

Abstract

Ceramides are key lipids in energetic-metabolic pathways and signaling cascades, modulating critical physiological functions in cells. While synthesis of ceramides is performed in endoplasmic reticulum (ER), which is altered under overnutrition conditions, proteins associated with ceramide metabolism are located on membrane arrangement of mitochondria and ER (MAMs). However, ceramide accumulation in meta-inflammation, condition that associates obesity with a chronic low-grade inflammatory state, favors the deregulation of pathways such as insulin signaling, and induces structural rearrangements on mitochondrial membrane, modifying its permeability and altering the flux of ions and other molecules. Considering the wide biological processes in which sphingolipids are implicated, they have been associated with diseases that present abnormalities in their energetic metabolism, such as breast cancer. In this sense, sphingolipids could modulate various cell features, such as growth, proliferation, survival, senescence, and apoptosis in cancer progression; moreover, ceramide metabolism is associated to chemotherapy resistance, and regulation of metastasis. Cell–cell communication mediated by exosomes and lipoproteins has become relevant in the transport of several sphingolipids. Therefore, in this work we performed a comprehensive analysis of the state of the art about the multifaceted roles of ceramides, specifically the deregulation of ceramide metabolism pathways, being a key factor that could modulate neoplastic processes development. Under specific conditions, sphingolipids perform important functions in several cellular processes, and depending on the preponderant species and cellular and/or tissue status can inhibit or promote the development of metabolic and potentially breast cancer disease. Full article

(This article belongs to the Special Issue Ceramide)

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