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Roles of Glycosphingolipids in Metabolism
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Roles of Glycosphingolipids in Metabolism

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 December 2020) | Viewed by 23645

Special Issue Editor

Prof. Dr. Kazunori Hamamura

E-Mail Website
Guest Editor
Department of Pharmacology, School of Dentistry, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan
Interests: glycosylation; glycosphingolipids; bone metabolism; malignant properties
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glycosphingolipids are essential in maintenance of the integrity of nervous tissues and homeostasis of organisms. Furthermore, glycosphingolipids play important roles in malignant properties in cancer cells. As one of the mechanisms, localization of glycosphingolipids in lipid rafts regulates interaction of membrane molecules to control cellular signaling.
Recently, it has been reported that glycosphingolipids regulate bone metabolism and endocrine metabolism. However, the involvement of glycosphingolipids in metabolism is not well understood. The special issue “Roles of Glycosphingolipids in Metabolism” will cover research topics and current review articles in this field.

Dr. Kazunori Hamamura
Guest Editor

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Keywords

  • Glycosylation
  • Glycosphingolipids
  • Gangliosides
  • Globo-series
  • Osteoblast proliferation
  • Osteoblast differentiation
  • Osteoclast differentiation
  • Bone metabolism
  • Endocrine metabolism
  • Cancer cells
  • Malignant properties

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Published Papers (5 papers)

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Research

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10 pages, 1811 KiB  
Communication
Isolation and Characterization of Antibodies Induced by Immunization with TNF-α Inducible Globotetraosylceramide
by Tetsuya Okuda
Int. J. Mol. Sci. 2020, 21(10), 3632; https://doi.org/10.3390/ijms21103632 - 21 May 2020
Cited by 8 | Viewed by 3001
Abstract
Glycosphingolipids containing very-long-chain fatty acids (VLCFAs) regulate several immune responses, such as cytokine production, immune signaling, and antibody induction. We previously reported that stimulation with an inflammatory mediator, TNF-α, promotes the expression of glycosphingolipids in vascular endothelial cells. The major component is globotetraosylceramide [...] Read more.
Glycosphingolipids containing very-long-chain fatty acids (VLCFAs) regulate several immune responses, such as cytokine production, immune signaling, and antibody induction. We previously reported that stimulation with an inflammatory mediator, TNF-α, promotes the expression of glycosphingolipids in vascular endothelial cells. The major component is globotetraosylceramide containing VLCFAs (Gb4Cer-VLCFAs), but its role in inflammatory responses has not been fully investigated. In this study, the antibody-inducing properties of Gb4Cer-VLCFAs were analyzed using serum and hybridoma cells generated from Gb4Cer-VLCFA-immunized mice. The reactivity of serum antibodies against Gb4Cer indicated that immunization with Gb4Cer-VLCFAs immediately induced the production of anti-Gb4Cer antibodies. Over 81% of hybridomas generated from the splenocytes of an immunized mouse produced anti-Gb4Cer antibodies, a subset of which recognized an epitope shared by Gb4Cer and its precursor globotriaosylceramide (Gb3Cer). Further biochemical analyses of established monoclonal antibodies revealed that these antibodies included IgM and IgG3, which specifically react with Gb4Cer and Gb3Cer. These results indicate that immunization with Gb4Cer-VLCFAs can efficiently induce the production of anti-Gb4Cer and -Gb3Cer antibodies by B cells. Full article
(This article belongs to the Special Issue Roles of Glycosphingolipids in Metabolism)
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13 pages, 3259 KiB  
Article
Deletion of Gb3 Synthase in Mice Resulted in the Attenuation of Bone Formation via Decrease in Osteoblasts
by Kazunori Hamamura, Kosuke Hamajima, Shoyoku Yo, Yoshitaka Mishima, Koichi Furukawa, Makoto Uchikawa, Yuji Kondo, Hironori Mori, Hisataka Kondo, Kenjiro Tanaka, Ken Miyazawa, Shigemi Goto and Akifumi Togari
Int. J. Mol. Sci. 2019, 20(18), 4619; https://doi.org/10.3390/ijms20184619 - 18 Sep 2019
Cited by 6 | Viewed by 3718
Abstract
Glycosphingolipids are known to play a role in developing and maintaining the integrity of various organs and tissues. Among glycosphingolipids, there are several reports on the involvement of gangliosides in bone metabolism. However, there have been no reports on the presence or absence [...] Read more.
Glycosphingolipids are known to play a role in developing and maintaining the integrity of various organs and tissues. Among glycosphingolipids, there are several reports on the involvement of gangliosides in bone metabolism. However, there have been no reports on the presence or absence of expression of globo-series glycosphingolipids in osteoblasts and osteoclasts, and the involvement of their glycosphingolipids in bone metabolism. In the present study, we investigated the presence or absence of globo-series glycosphingolipids such as Gb3 (globotriaosylceramide), Gb4 (globoside), and Gb5 (galactosyl globoside) in osteoblasts and osteoclasts, and the effects of genetic deletion of Gb3 synthase, which initiates the synthesis of globo-series glycosphingolipids on bone metabolism. Among Gb3, Gb4, and Gb5, only Gb4 was expressed in osteoblasts. However, these glycosphingolipids were not expressed in pre-osteoclasts and osteoclasts. Three-dimensional micro-computed tomography (3D-μCT) analysis revealed that femoral cancellous bone mass in Gb3 synthase-knockout (Gb3S KO) mice was lower than that in wild type (WT) mice. Calcein double labeling also revealed that bone formation in Gb3S KO mice was significantly lower than that in WT mice. Consistent with these results, the deficiency of Gb3 synthase in mice decreased the number of osteoblasts on the bone surface, and suppressed mRNA levels of osteogenic differentiation markers. On the other hand, osteoclast numbers on the bone surface and mRNA levels of osteoclast differentiation markers in Gb3S KO mice did not differ from WT mice. This study demonstrated that deletion of Gb3 synthase in mice decreases bone mass via attenuation of bone formation. Full article
(This article belongs to the Special Issue Roles of Glycosphingolipids in Metabolism)
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Review

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25 pages, 1579 KiB  
Review
Convergence: Lactosylceramide-Centric Signaling Pathways Induce Inflammation, Oxidative Stress, and Other Phenotypic Outcomes
by Subroto Chatterjee, Amrita Balram and Wendy Li
Int. J. Mol. Sci. 2021, 22(4), 1816; https://doi.org/10.3390/ijms22041816 - 12 Feb 2021
Cited by 54 | Viewed by 6362
Abstract
Lactosylceramide (LacCer), also known as CD17/CDw17, is a member of a large family of small molecular weight compounds known as glycosphingolipids. It plays a pivotal role in the biosynthesis of glycosphingolipids, primarily by way of serving as a precursor to the majority of [...] Read more.
Lactosylceramide (LacCer), also known as CD17/CDw17, is a member of a large family of small molecular weight compounds known as glycosphingolipids. It plays a pivotal role in the biosynthesis of glycosphingolipids, primarily by way of serving as a precursor to the majority of its higher homolog sub-families such as gangliosides, sulfatides, fucosylated-glycosphingolipids and complex neutral glycosphingolipids—some of which confer “second-messenger” and receptor functions. LacCer is an integral component of the “lipid rafts,” serving as a conduit to transduce external stimuli into multiple phenotypes, which may contribute to mortality and morbidity in man and in mouse models of human disease. LacCer is synthesized by the action of LacCer synthase (β-1,4 galactosyltransferase), which transfers galactose from uridine diphosphate galactose (UDP-galactose) to glucosylceramide (GlcCer). The convergence of multiple physiologically relevant external stimuli/agonists—platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), stress, cigarette smoke/nicotine, tumor necrosis factor-α (TNF-α), and in particular, oxidized low-density lipoprotein (ox-LDL)—on β-1,4 galactosyltransferase results in its phosphorylation or activation, via a “turn-key” reaction, generating LacCer. This newly synthesized LacCer activates NADPH (nicotinamide adenine dihydrogen phosphate) oxidase to generate reactive oxygen species (ROS) and a highly “oxidative stress” environment, which trigger a cascade of signaling molecules and pathways and initiate diverse phenotypes like inflammation and atherosclerosis. For instance, LacCer activates an enzyme, cytosolic phospholipase A2 (cPLA2), which cleaves arachidonic acid from phosphatidylcholine. In turn, arachidonic acid serves as a precursor to eicosanoids and prostaglandin, which transduce a cascade of reactions leading to inflammation—a major phenotype underscoring the initiation and progression of several debilitating diseases such as atherosclerosis and cancer. Our aim here is to present an updated account of studies made in the field of LacCer metabolism and signaling using multiple animal models of human disease, human tissue, and cell-based studies. These advancements have led us to propose that previously unrelated phenotypes converge in a LacCer-centric manner. This LacCer synthase/LacCer-induced “oxidative stress” environment contributes to inflammation, atherosclerosis, skin conditions, hair greying, cardiovascular disease, and diabetes due to mitochondrial dysfunction. Thus, targeting LacCer synthase may well be the answer to remedy these pathologies. Full article
(This article belongs to the Special Issue Roles of Glycosphingolipids in Metabolism)
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18 pages, 1568 KiB  
Review
Function of Platelet Glycosphingolipid Microdomains/Lipid Rafts
by Keisuke Komatsuya, Kei Kaneko and Kohji Kasahara
Int. J. Mol. Sci. 2020, 21(15), 5539; https://doi.org/10.3390/ijms21155539 - 2 Aug 2020
Cited by 27 | Viewed by 6022
Abstract
Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the regulation of vital cellular processes. The rafts at the cell surface play important functions in signal transduction. Recent reports have demonstrated that lipid [...] Read more.
Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the regulation of vital cellular processes. The rafts at the cell surface play important functions in signal transduction. Recent reports have demonstrated that lipid rafts are spatially and compositionally heterogeneous in the single-cell membrane. In this review, we summarize our recent data on living platelets using two specific probes of raft components: lysenin as a probe of sphingomyelin-rich rafts and BCθ as a probe of cholesterol-rich rafts. Sphingomyelin-rich rafts that are spatially and functionally distinct from the cholesterol-rich rafts were found at spreading platelets. Fibrin is translocated to sphingomyelin-rich rafts and platelet sphingomyelin-rich rafts act as platforms where extracellular fibrin and intracellular actomyosin join to promote clot retraction. On the other hand, the collagen receptor glycoprotein VI is known to be translocated to cholesterol-rich rafts during platelet adhesion to collagen. Furthermore, the functional roles of platelet glycosphingolipids and platelet raft-binding proteins including G protein-coupled receptors, stomatin, prohibitin, flotillin, and HflK/C-domain protein family, tetraspanin family, and calcium channels are discussed. Full article
(This article belongs to the Special Issue Roles of Glycosphingolipids in Metabolism)
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18 pages, 2035 KiB  
Review
Gangliosides and Neuroblastomas
by Cara-Lynne Schengrund
Int. J. Mol. Sci. 2020, 21(15), 5313; https://doi.org/10.3390/ijms21155313 - 27 Jul 2020
Cited by 20 | Viewed by 3816
Abstract
The focus of this review is the ganglio-series of glycosphingolipids found in neuroblastoma (NB) and the myriad of unanswered questions associated with their possible role(s) in this cancer. NB is one of the more common solid malignancies of children. Five-year survival for those [...] Read more.
The focus of this review is the ganglio-series of glycosphingolipids found in neuroblastoma (NB) and the myriad of unanswered questions associated with their possible role(s) in this cancer. NB is one of the more common solid malignancies of children. Five-year survival for those diagnosed with low risk NB is 90–95%, while that for children with high-risk NB is around 40–50%. Much of the survival rate reflects age of diagnosis with children under a year having a much better prognosis than those over two. Identification of expression of GD2 on the surface of most NB cells led to studies of the effectiveness and subsequent approval of anti-GD2 antibodies as a treatment modality. Despite much success, a subset of patients, possibly those whose tumors fail to express concentrations of gangliosides such as GD1b and GT1b found in tumors from patients with a good prognosis, have tumors refractory to treatment. These observations support discussion of what is known about control of ganglioside synthesis, and their actual functions in NB, as well as their possible relationship to treatment response. Full article
(This article belongs to the Special Issue Roles of Glycosphingolipids in Metabolism)
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