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Johannes M F G Aerts - One of the best experts on this subject based on the ideXlab platform.
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Glycosphingolipids and infection potential new therapeutic avenues
Frontiers in Cell and Developmental Biology, 2019Co-Authors: Johannes M F G Aerts, Maria J. Ferraz, Marta Artola, M Van Eijk, Rolf G. BootAbstract:Glycosphingolipids (GSLs), the main topic of this review, are a subclass of sphingolipids. With their glycans exposed to the extracellular space, Glycosphingolipids are ubiquitous components of the plasma membrane of cells. GSLs are implicated in a variety of biological processes including specific infections. Several pathogens use GSLs at the surface of host cells as binding receptors. In addition, lipid-rafts in the plasma membrane of host cells may act as platform for signaling the presence of pathogens. Relatively common in man are inherited deficiencies in lysosomal glycosidases involved in the turnover of GSLs. The associated storage disorders (glycosphingolipidoses) show lysosomal accumulation of substrate(s) of the deficient enzyme. In recent years compounds have been identified that allow modulation of GSLs levels in cells. Some of these agents are well tolerated and already used to treat lysosomal glycosphingolipidoses. This review summarizes present knowledge on the role of GSLs in infection and subsequent immune response. It concludes with the thought to apply glycosphingolipid-lowering agents to prevent and/or combat infections.
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Iminosugar-based inhibitors of glucosylceramide synthase increase brain Glycosphingolipids and survival in a mouse model of Sandhoff disease
PLOS ONE, 2011Co-Authors: Kathleen M Ashe, Jennifer B Nietupski, Mario A. Cabrera-salazar, Christopher G.f. Cooper, Dinesh S Bangari, Lingyun Li, Johannes M F G Aerts, Scott D Bercury, Diane P CopelandAbstract:The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related Glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in Glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.
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Glycosphingolipids and insulin resistance.
Advances in experimental medicine and biology, 2011Co-Authors: Johannes M F G Aerts, Marco Van Eijk, Rolf G. Boot, Johanna E. M. Groener, Nora Bijl, Elisa Lombardo, Florence Bietrix, Nick Dekker, Albert K. Groen, Roelof OttenhoffAbstract:Glycosphingolipids are structural membrane components, residing largely in the plasma membrane with their sugar-moieties exposed at the cell's surface. In recent times a crucial role for Glycosphingolipids in insulin resistance has been proposed. A chronic state of insulin resistance is a rapidly increasing disease condition in Western and developing countries. It is considered to be the major underlying cause of the metabolic syndrome, a combination of metabolic abnormalities that increases the risk for an individual to develop Type 2 diabetes, obesity, cardiovascular disease, polycystic ovary syndrome and nonalcoholic fatty liver disease. As discussed in this chapter, the evidence for a direct regulatory interaction of Glycosphingolipids with insulin signaling is still largely indirect. However, the recent finding in animal models that pharmacological reduction of glycosphingolipid biosynthesis ameliorates insulin resistance and prevents some manifestations of metabolic syndrome, supports the view that somehow Glycosphingolipids act as critical regulators, Importantly, since reductions in glycosphingolipid biosynthesis have been found to be well tolerated, such approaches may have a therapeutic potential.
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Glycosphingolipids nature function and pharmacological modulation
ChemInform, 2010Co-Authors: Tom Wennekes, Rolf G. Boot, Richard J B H N Van Den Berg, Gijsbert A Van Der Marel, Herman S Overkleeft, Johannes M F G AertsAbstract:The discovery of the Glycosphingolipids is generally attributed to Johan L. W. Thudichum, who in 1884 published on the chemical composition of the brain. In his studies he isolated several compounds from ethanolic brain extracts which he coined cerebrosides. He subjected one of these, phrenosin (now known as galactosylceramide), to acid hydrolysis, and this produced three distinct components. One he identified as a fatty acid and another proved to be an isomer of D-glucose, which is now known as D-galactose. The third component, with an "alkaloidal nature", presented "many enigmas" to Thudichum, and therefore he named it sphingosine, after the mythological riddle of the Sphinx. Today, sphingolipids and their glycosidated derivatives are the subjects of intense study aimed at elucidating their role in the structural integrity of the cell membrane, their participation in recognition and signaling events, and in particular their involvement in pathological processes that are at the basis of human disease (for example, sphingolipidoses and diabetes type 2). This Review details some of the recent findings on the biosynthesis, function, and degradation of Glycosphingolipids in man, with a focus on the glycosphingolipid glucosylceramide. Special attention is paid to the clinical relevance of compounds directed at interfering with the factors responsible for glycosphingolipid metabolism.
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Glycosphingolipids and insulin resistance.
Progress in lipid research, 2009Co-Authors: Mirjam Langeveld, Johannes M F G AertsAbstract:Obesity is associated with an increased risk for insulin resistance, a state characterized by impaired responsiveness of liver, muscle and adipose tissue to insulin. One class of lipids involved in the development of insulin resistance are the (glyco)sphingolipids. Ceramide, the most simple sphingolipid, directly inhibits phosphorylation of the insulin signaling mediator Akt/Protein Kinase B. More complex Glycosphingolipids, so-called gangliosides, block phosphorylation of the insulin receptor and down-stream signaling, possibly by exclusion of the insulin receptor from specific membrane domains. Pharmacological inhibition of glycosphingolipid synthesis is found to markedly improve insulin sensitivity in rodent models of insulin resistance. Partial glycosphingolipid reduction is well tolerated and may thus offer an attractive new treatment modality for obesity-induced insulin resistance and type II diabetes.
Robin H. Lachmann - One of the best experts on this subject based on the ideXlab platform.
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miglustat substrate reduction therapy for glycosphingolipid storage disorders
Therapy, 2005Co-Authors: Robin H. LachmannAbstract:Miglustat (N-butyldeoxynojirimycin) is a potent inhibitor of ceramide-specific glucosyltransferase, the enzyme that catalyses the first committed step in glycosphingolipid biosynthesis. Inhibition of glycosphingolipid synthesis is a potential strategy for the treatment of a number of lysosomal storage disorders that result in the accumulation of Glycosphingolipids within cells, an approach which has been termed substrate-reduction therapy. This article discusses the studies that led to the licensing of miglustat as a treatment for Type 1 Gaucher disease and its current and potential use in this, and other, glycosphingolipid storage disorders.
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treatment with miglustat reverses the lipid trafficking defect in niemann pick disease type c
Neurobiology of Disease, 2004Co-Authors: Robin H. Lachmann, Daniel J. Sillence, Gabriele Reinkensmeier, Raymond A Dwek, Terry D Butters, Timothy M. Cox, Danielle Te Vruchte, Emyr Lloydevans, Luisa Fernandezguillen, Frances M. PlattAbstract:Niemann-Pick disease type C (NP-C) is a hereditary neurovisceral lipid storage disorder. Although traditionally considered a primary cholesterol storage disorder, a variety of glycolipids accumulate in NP-C cells, which resemble those from glycosphingolipidosis patients. Substrate reduction therapy (SRT) with miglustat, an inhibitor of glycosphingolipid biosynthesis, is a novel therapy for the glycosphingolipidoses. We report the use of SRT in a patient with NP-C. We show that depletion of Glycosphingolipids by miglustat treatment reduces pathological lipid storage, improves endosomal uptake and normalises lipid trafficking in peripheral blood B lymphocytes. The demonstration that treatment with miglustat, which has no direct effect on cholesterol metabolism, corrects the abnormal lipid trafficking seen in B lymphocytes in NP-C indicates that glycosphingolipid accumulation is the primary pathogenetic event in NP-C. These observations support the use of SRT in patients with this devastating neurodegenerative disease.
Roelof Ottenhoff - One of the best experts on this subject based on the ideXlab platform.
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lyso glycosphingolipid abnormalities in different murine models of lysosomal storage disorders
Molecular Genetics and Metabolism, 2016Co-Authors: Maria J. Ferraz, Roelof Ottenhoff, Andre Marques, Paulo Gaspar, Mina Mirzaian, Cindy P A A Van Roomen, Pilar Alfonso, Pilar Irun, Pilar Giraldo, Patrick WisseAbstract:In lysosomal glycosphingolipid storage disorders, marked elevations in corresponding glycosphingoid bases (lyso-Glycosphingolipids) have been reported, such as galactosylsphingosine in Krabbe disease, glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease. Using LC–MS/MS, we comparatively investigated the occurrence of abnormal lyso-Glycosphingolipids in tissues and plasma of mice with deficiencies in lysosomal α-galactosidase A, glucocerebrosidase and galactocerebrosidase. The nature and specificity of lyso-glycosphingolipid abnormalities are reported and compared to that in correspondingly more abundant N-acylated Glycosphingolipids. Specific elevations in tissue and plasma globotriaosylsphingosine were detected in α-galactosidase A-deficient mice; glucosylsphingosine in glucocerebrosidase-deficient mice and galactosylsphingosine in galactocerebrosidase-deficient animals. A similar investigation was conducted for two mouse models of Niemann Pick type C (Npc1nih and Npc1nmf164), revealing significant tissue elevation of several neutral Glycosphingolipids and concomitant increased plasma glucosylsphingosine. This latter finding was recapitulated by analysis of plasma of NPC patients. The value of plasma glucosylsphingosine in biochemical confirmation of the diagnosis of NPC is discussed.
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Glycosphingolipids and insulin resistance.
Advances in experimental medicine and biology, 2011Co-Authors: Johannes M F G Aerts, Marco Van Eijk, Rolf G. Boot, Johanna E. M. Groener, Nora Bijl, Elisa Lombardo, Florence Bietrix, Nick Dekker, Albert K. Groen, Roelof OttenhoffAbstract:Glycosphingolipids are structural membrane components, residing largely in the plasma membrane with their sugar-moieties exposed at the cell's surface. In recent times a crucial role for Glycosphingolipids in insulin resistance has been proposed. A chronic state of insulin resistance is a rapidly increasing disease condition in Western and developing countries. It is considered to be the major underlying cause of the metabolic syndrome, a combination of metabolic abnormalities that increases the risk for an individual to develop Type 2 diabetes, obesity, cardiovascular disease, polycystic ovary syndrome and nonalcoholic fatty liver disease. As discussed in this chapter, the evidence for a direct regulatory interaction of Glycosphingolipids with insulin signaling is still largely indirect. However, the recent finding in animal models that pharmacological reduction of glycosphingolipid biosynthesis ameliorates insulin resistance and prevents some manifestations of metabolic syndrome, supports the view that somehow Glycosphingolipids act as critical regulators, Importantly, since reductions in glycosphingolipid biosynthesis have been found to be well tolerated, such approaches may have a therapeutic potential.
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dual action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral Glycosphingolipids and buffering of carbohydrate assimilation
Journal of Medicinal Chemistry, 2010Co-Authors: Tom Wennekes, Marco Van Eijk, Rolf G. Boot, Johanna E. M. Groener, Nora Bijl, Albert K. Groen, Roelof Ottenhoff, Alfred J Meijer, Karen Ghauharali, Hang SongAbstract:The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral Glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the l-ido derivative of 2, l-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral Glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of...
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reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity adipogenesis and reduces inflammation
PLOS ONE, 2009Co-Authors: Marco Van Eijk, Nora Bijl, Roelof Ottenhoff, Cindy P A A Van Roomen, Jan Aten, Peter F Dubbelhuis, Ingar Seeman, Karen Ghauharalivan Der Vlugt, Hermen S Overkleeft, Cynthia ArbeenyAbstract:Adipose tissue is a critical mediator in obesity-induced insulin resistance. Previously we have demonstrated that pharmacological lowering of Glycosphingolipids and subsequently GM3 by using the iminosugar AMP-DNM, strikingly improves glycemic control. Here we studied the effects of AMP-DNM on adipose tissue function and inflammation in detail to provide an explanation for the observed improved glucose homeostasis. Leptin-deficient obese (LepOb) mice were fed AMP-DNM and its effects on insulin signalling, adipogenesis and inflammation were monitored in fat tissue. We show that reduction of glycosphingolipid biosynthesis in adipose tissue of LepOb mice restores insulin signalling in isolated ex vivo insulin-stimulated adipocytes. We observed improved adipogenesis as the number of larger adipocytes was reduced and expression of genes like peroxisome proliferator-activated receptor (PPAR) γ, insulin responsive glucose transporter (GLUT)-4 and adipsin increased. In addition, we found that adiponectin gene expression and protein were increased by AMP-DNM. As a consequence of this improved function of fat tissue we observed less inflammation, which was characterized by reduced numbers of adipose tissue macrophages (crown-like structures) and reduced levels of the macrophage chemo attractants monocyte-chemoattractant protein-1 (Mcp-1/Ccl2) and osteopontin (OPN). In conclusion, pharmacological lowering of Glycosphingolipids by inhibition of glucosylceramide biosynthesis improves adipocyte function and as a consequence reduces inflammation in adipose tissue of obese animals.
Rolf G. Boot - One of the best experts on this subject based on the ideXlab platform.
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Glycosphingolipids and infection potential new therapeutic avenues
Frontiers in Cell and Developmental Biology, 2019Co-Authors: Johannes M F G Aerts, Maria J. Ferraz, Marta Artola, M Van Eijk, Rolf G. BootAbstract:Glycosphingolipids (GSLs), the main topic of this review, are a subclass of sphingolipids. With their glycans exposed to the extracellular space, Glycosphingolipids are ubiquitous components of the plasma membrane of cells. GSLs are implicated in a variety of biological processes including specific infections. Several pathogens use GSLs at the surface of host cells as binding receptors. In addition, lipid-rafts in the plasma membrane of host cells may act as platform for signaling the presence of pathogens. Relatively common in man are inherited deficiencies in lysosomal glycosidases involved in the turnover of GSLs. The associated storage disorders (glycosphingolipidoses) show lysosomal accumulation of substrate(s) of the deficient enzyme. In recent years compounds have been identified that allow modulation of GSLs levels in cells. Some of these agents are well tolerated and already used to treat lysosomal glycosphingolipidoses. This review summarizes present knowledge on the role of GSLs in infection and subsequent immune response. It concludes with the thought to apply glycosphingolipid-lowering agents to prevent and/or combat infections.
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Glycosphingolipids and insulin resistance.
Advances in experimental medicine and biology, 2011Co-Authors: Johannes M F G Aerts, Marco Van Eijk, Rolf G. Boot, Johanna E. M. Groener, Nora Bijl, Elisa Lombardo, Florence Bietrix, Nick Dekker, Albert K. Groen, Roelof OttenhoffAbstract:Glycosphingolipids are structural membrane components, residing largely in the plasma membrane with their sugar-moieties exposed at the cell's surface. In recent times a crucial role for Glycosphingolipids in insulin resistance has been proposed. A chronic state of insulin resistance is a rapidly increasing disease condition in Western and developing countries. It is considered to be the major underlying cause of the metabolic syndrome, a combination of metabolic abnormalities that increases the risk for an individual to develop Type 2 diabetes, obesity, cardiovascular disease, polycystic ovary syndrome and nonalcoholic fatty liver disease. As discussed in this chapter, the evidence for a direct regulatory interaction of Glycosphingolipids with insulin signaling is still largely indirect. However, the recent finding in animal models that pharmacological reduction of glycosphingolipid biosynthesis ameliorates insulin resistance and prevents some manifestations of metabolic syndrome, supports the view that somehow Glycosphingolipids act as critical regulators, Importantly, since reductions in glycosphingolipid biosynthesis have been found to be well tolerated, such approaches may have a therapeutic potential.
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Glycosphingolipids nature function and pharmacological modulation
ChemInform, 2010Co-Authors: Tom Wennekes, Rolf G. Boot, Richard J B H N Van Den Berg, Gijsbert A Van Der Marel, Herman S Overkleeft, Johannes M F G AertsAbstract:The discovery of the Glycosphingolipids is generally attributed to Johan L. W. Thudichum, who in 1884 published on the chemical composition of the brain. In his studies he isolated several compounds from ethanolic brain extracts which he coined cerebrosides. He subjected one of these, phrenosin (now known as galactosylceramide), to acid hydrolysis, and this produced three distinct components. One he identified as a fatty acid and another proved to be an isomer of D-glucose, which is now known as D-galactose. The third component, with an "alkaloidal nature", presented "many enigmas" to Thudichum, and therefore he named it sphingosine, after the mythological riddle of the Sphinx. Today, sphingolipids and their glycosidated derivatives are the subjects of intense study aimed at elucidating their role in the structural integrity of the cell membrane, their participation in recognition and signaling events, and in particular their involvement in pathological processes that are at the basis of human disease (for example, sphingolipidoses and diabetes type 2). This Review details some of the recent findings on the biosynthesis, function, and degradation of Glycosphingolipids in man, with a focus on the glycosphingolipid glucosylceramide. Special attention is paid to the clinical relevance of compounds directed at interfering with the factors responsible for glycosphingolipid metabolism.
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dual action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral Glycosphingolipids and buffering of carbohydrate assimilation
Journal of Medicinal Chemistry, 2010Co-Authors: Tom Wennekes, Marco Van Eijk, Rolf G. Boot, Johanna E. M. Groener, Nora Bijl, Albert K. Groen, Roelof Ottenhoff, Alfred J Meijer, Karen Ghauharali, Hang SongAbstract:The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral Glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the l-ido derivative of 2, l-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral Glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of...
Andre M Deelder - One of the best experts on this subject based on the ideXlab platform.
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Investigations on Aberrant Glycosylation of Glycosphingolipids in Colorectal Cancer Tissues Using Liquid Chromatography and Matrix-Assisted Laser Desorption Time-of-Flight Mass Spectrometry (MALDI-TOF-MS)
Molecular & Cellular Proteomics, 2013Co-Authors: Stephanie Holst, Aswin Verhoeven, Liam M. Mcdonnell, Oleg A. Mayboroda, Wilma E. Mesker, Crina I.a. Balog, Kathrin Stavenhagen, Rob A. E. M. Tollenaar, Andre M DeelderAbstract:Cancer is a leading cause of death and alterations of glycosylation are characteristic features of malignant cells. Colorectal cancer is one of the most common cancers and its exact causes and biology are not yet well understood. Here, we compared glycosylation profiles of colorectal tumor tissues and corresponding control tissues of 13 colorectal cancer patients to contribute to the understanding of this cancer. Using MALDI-TOF(/TOF)-MS and 2-dimensional LC-MS/MS we characterized enzymatically released and 2-aminobenzoic acid labeled glycans from Glycosphingolipids. Multivariate data analysis revealed significant differences between tumor and corresponding control tissues. Main discriminators were obtained, which represent the overall alteration in glycosylation of Glycosphingolipids during colorectal cancer progression, and these were found to be characterized by (1) increased fucosylation, (2) decreased acetylation, (3) decreased sulfation, (4) reduced expression of globo-type glycans, as well as (5) disialyl gangliosides. The findings of our current research confirm former reports, and in addition expand the knowledge of glycosphingolipid glycosylation in colorectal cancer by revealing new glycans with discriminative power and characteristic, cancer-associated glycosylation alterations. The obtained discriminating glycans can contribute to progress the discovery of biomarkers to improve diagnostics and patient treatment.