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Wilkerson JL, Tatum SM, Holland WL, Summers SA. Ceramides are fuel gauges on the drive to cardiometabolic disease. Physiol Rev 2024; 104:1061-1119. [PMID: 38300524 PMCID: PMC11381030 DOI: 10.1152/physrev.00008.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 01/23/2024] [Accepted: 01/25/2024] [Indexed: 02/02/2024] Open
Abstract
Ceramides are signals of fatty acid excess that accumulate when a cell's energetic needs have been met and its nutrient storage has reached capacity. As these sphingolipids accrue, they alter the metabolism and survival of cells throughout the body including in the heart, liver, blood vessels, skeletal muscle, brain, and kidney. These ceramide actions elicit the tissue dysfunction that underlies cardiometabolic diseases such as diabetes, coronary artery disease, metabolic-associated steatohepatitis, and heart failure. Here, we review the biosynthesis and degradation pathways that maintain ceramide levels in normal physiology and discuss how the loss of ceramide homeostasis drives cardiometabolic pathologies. We highlight signaling nodes that sense small changes in ceramides and in turn reprogram cellular metabolism and stimulate apoptosis. Finally, we evaluate the emerging therapeutic utility of these unique lipids as biomarkers that forecast disease risk and as targets of ceramide-lowering interventions that ameliorate disease.
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Affiliation(s)
- Joseph L Wilkerson
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
| | - Sean M Tatum
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
| | - William L Holland
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
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2
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Slieker RC, Donnelly LA, Akalestou E, Lopez-Noriega L, Melhem R, Güneş A, Abou Azar F, Efanov A, Georgiadou E, Muniangi-Muhitu H, Sheikh M, Giordano GN, Åkerlund M, Ahlqvist E, Ali A, Banasik K, Brunak S, Barovic M, Bouland GA, Burdet F, Canouil M, Dragan I, Elders PJM, Fernandez C, Festa A, Fitipaldi H, Froguel P, Gudmundsdottir V, Gudnason V, Gerl MJ, van der Heijden AA, Jennings LL, Hansen MK, Kim M, Leclerc I, Klose C, Kuznetsov D, Mansour Aly D, Mehl F, Marek D, Melander O, Niknejad A, Ottosson F, Pavo I, Duffin K, Syed SK, Shaw JL, Cabrera O, Pullen TJ, Simons K, Solimena M, Suvitaival T, Wretlind A, Rossing P, Lyssenko V, Legido Quigley C, Groop L, Thorens B, Franks PW, Lim GE, Estall J, Ibberson M, Beulens JWJ, 't Hart LM, Pearson ER, Rutter GA. Identification of biomarkers for glycaemic deterioration in type 2 diabetes. Nat Commun 2023; 14:2533. [PMID: 37137910 PMCID: PMC10156700 DOI: 10.1038/s41467-023-38148-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 04/18/2023] [Indexed: 05/05/2023] Open
Abstract
We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
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Affiliation(s)
- Roderick C Slieker
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC, Amsterdam, the Netherlands
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Louise A Donnelly
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK
| | - Elina Akalestou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Livia Lopez-Noriega
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Rana Melhem
- CHUM Research Centre and University of Montreal, Montreal, QC, Canada
| | - Ayşim Güneş
- IRCM and University of Montreal, Montreal, QC, Canada
| | | | - Alexander Efanov
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, US
| | - Eleni Georgiadou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Hermine Muniangi-Muhitu
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Mahsa Sheikh
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | | | - Mikael Åkerlund
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Emma Ahlqvist
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Ashfaq Ali
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Copenhagen, Denmark
| | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Copenhagen, Denmark
| | - Marko Barovic
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Medical Faculty, Dresden, Germany
| | - Gerard A Bouland
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Frédéric Burdet
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Mickaël Canouil
- INSERM U1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital, Lille, F-59000, France
| | - Iulian Dragan
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Petra J M Elders
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC-location VUmc, Amsterdam, the Netherlands
| | | | - Andreas Festa
- Eli Lilly Regional Operations GmbH, Vienna, Austria
- 1st Medical Department, LK Stockerau, Niederösterreich, Austria
| | - Hugo Fitipaldi
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Phillippe Froguel
- INSERM U1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille University Hospital, Lille, F-59000, France
- Division of Systems Biology, Department of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Valborg Gudmundsdottir
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
- Icelandic Heart Association, Kopavogur, Iceland
| | - Vilmundur Gudnason
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
- Icelandic Heart Association, Kopavogur, Iceland
| | | | - Amber A van der Heijden
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, Amsterdam UMC-location VUmc, Amsterdam, the Netherlands
| | - Lori L Jennings
- Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA
| | - Michael K Hansen
- Cardiovascular and Metabolic Disease Research, Janssen Research & Development, Spring House, PA, USA
| | - Min Kim
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicines, King's College London, London, UK
| | - Isabelle Leclerc
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- CHUM Research Centre and University of Montreal, Montreal, QC, Canada
| | | | - Dmitry Kuznetsov
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | | | - Florence Mehl
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Diana Marek
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Olle Melander
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Anne Niknejad
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Filip Ottosson
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Section for Clinical Mass Spectrometry, Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Imre Pavo
- Eli Lilly Regional Operations GmbH, Vienna, Austria
| | - Kevin Duffin
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, US
| | - Samreen K Syed
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, US
| | - Janice L Shaw
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, US
| | - Over Cabrera
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, US
| | - Timothy J Pullen
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Department of Diabetes, Guy's Campus King's College London, London, UK
| | | | - Michele Solimena
- Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Medical Faculty, Dresden, Germany
- Molecular Diabetology, University Hospital and Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany
| | | | | | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Valeriya Lyssenko
- Department of Clinical Science, Center for Diabetes Research, University of Bergen, Bergen, Norway
- Genomics, Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden
| | - Cristina Legido Quigley
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicines, King's College London, London, UK
| | - Leif Groop
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Finnish Institute of Molecular Medicine, Helsinki University, Helsinki, Finland
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, CH-1015, Lausanne, Switzerland
| | - Paul W Franks
- Department of Clinical Sciences, Lund University, Malmö, Sweden
- Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
| | - Gareth E Lim
- CHUM Research Centre and University of Montreal, Montreal, QC, Canada
| | | | - Mark Ibberson
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Joline W J Beulens
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC, Amsterdam, the Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Leen M 't Hart
- Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUMC, Amsterdam, the Netherlands.
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
| | - Ewan R Pearson
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK.
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
- CHUM Research Centre and University of Montreal, Montreal, QC, Canada.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
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Zhu L, Ma M, Zhang L, Wang S, Guo Y, Ling X, Lin H, Lai N, Lin S, Du L, Dong Q. System Analysis Based on Lipid-Metabolism-Related Genes Identifies AGT as a Novel Therapy Target for Gastric Cancer with Neoadjuvant Chemotherapy. Pharmaceutics 2023; 15:810. [PMID: 36986671 PMCID: PMC10051152 DOI: 10.3390/pharmaceutics15030810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common causes of cancer-related deaths worldwide, and chemotherapy is still a standard strategy for treating patients with advanced GC. Lipid metabolism has been reported to play an important role in the carcinogenesis and development of GC. However, the potential values of lipid-metabolism-related genes (LMRGs) concerning prognostic value and the prediction of chemotherapy responsiveness in GC remains unclear. A total of 714 stomach adenocarcinoma patients were enrolled from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Using univariate Cox and LASSO regression analyses, we developed a risk signature based on LMRGs that can distinguish high-GC-risk patients from low-risk patients with significant differences in overall survival. We further validated this signature prognostic value using the GEO database. The R package "pRRophetic" was applied to calculate the sensitivity of each sample from high- and low-risk groups to chemotherapy drugs. The expression of two LMRGs, AGT and ENPP7, can predict the prognosis and response to chemotherapy in GC. Furthermore, AGT significantly promoted GC growth and migration, and the downregulation of AGT enhanced the chemotherapy response of GC both in vitro and in vivo. Mechanistically, AGT induced significant levels of epithelial-mesenchymal transition (EMT) through the PI3K/AKT pathway. The PI3K/AKT pathway agonist 740 Y-P can restore the EMT of GC cells impaired by AGT knockdown and treatment with 5-fluorouracil. Our findings suggest that AGT plays a key role in the development of GC, and targeting AGT may help to improve the chemotherapy response of GC patients.
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Affiliation(s)
- Le Zhu
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Ming Ma
- Gastroenterology Department of Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Lumin Zhang
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Shun Wang
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Yu Guo
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Xinxin Ling
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Hanchao Lin
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Nannan Lai
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Shengli Lin
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University & Shanghai Collaborative Innovation Center of Endoscopy, Shanghai 200032, China
| | - Ling Du
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
| | - Qiongzhu Dong
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Shanghai Municipal Health Commission (SMHC), Minhang Hospital, Fudan University, Shanghai 201199, China
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4
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Zhu J, Wang L, Guo Z, Zhang T, Zhang P. Transcriptome analysis of intestine from alk-SMase knockout mice reveals the effect of alk-SMase. Cancer Cell Int 2022; 22:344. [DOI: 10.1186/s12935-022-02764-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 10/11/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Objective
Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor associated with digestion and inhibition of cancer. There is few study to analyze the correlated function and characterize the genes related to alk-SMase comprehensively. We characterised transcriptome landscapes of intestine tissues from alk-SMase knockout (KO) mice aiming to identify novel associated genes and research targets.
Methods
We performed the high-resolution RNA sequencing of alk-SMase KO mice and compared them to wild type (WT) mice. Differentially expressed genes (DEGs) for the training group were screened. Functional enrichment analysis of the DEGs between KO mice and WT mice was implemented using the Database for Annotation, Visualization and Integrated Discovery (DAVID). An integrated protein–protein interaction (PPI) and Kyoto Encyclopedia of Genes and Genomes (KEGG) network was chose to study the relationship of differentially expressed gene. Moreover, quantitative real-time polymerase chain reaction (qPCR) was further used to validate the accuracy of RNA-seq technology.
Results
Our RNA-seq data found 97 differentially expressed mRNAs between the WT mice and alk-SMase gene NPP7 KO mice, in which 32 were significantly up-regulated and 65 were down-regulated, including protein coding genes, non-coding RNAs. Notably, the results of gene ontology functional enrichment analysis indicated that DEGs were functionally associated with the immune response, regulation of cell proliferation and development related terms. Additionally, an integrated network analysis was shown that some modules was significantly related to alk-SMase and with accordance of previously results. We chose 6 of these genes randomly were validated the accuracy of RNA-seq technology using qPCR and 2 genes showed difference significantly (P < 0.05).
Conclusions
We investigated the potential biological significant of alk-SMase with high resolution genome-wide transcriptome of alk-SMase knockout mice. The results revealed new insight into the functional modules related to alk-SMase was involved in the intestinal related diseases.
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McCluskey G, Donaghy C, Morrison KE, McConville J, Duddy W, Duguez S. The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases. J Pers Med 2022; 12:jpm12091418. [PMID: 36143200 PMCID: PMC9501626 DOI: 10.3390/jpm12091418] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/26/2022] [Accepted: 08/27/2022] [Indexed: 11/16/2022] Open
Abstract
Amyotrophic Lateral Sclerosis (ALS), Spinal Bulbar Muscular Atrophy (SBMA), and Spinal Muscular Atrophy (SMA) are motor neuron diseases (MNDs) characterised by progressive motor neuron degeneration, weakness and muscular atrophy. Lipid dysregulation is well recognised in each of these conditions and occurs prior to neurodegeneration. Several lipid markers have been shown to predict prognosis in ALS. Sphingolipids are complex lipids enriched in the central nervous system and are integral to key cellular functions including membrane stability and signalling pathways, as well as being mediators of neuroinflammation and neurodegeneration. This review highlights the metabolism of sphingomyelin (SM), the most abundant sphingolipid, and of its metabolite ceramide, and its role in the pathophysiology of neurodegeneration, focusing on MNDs. We also review published lipidomic studies in MNDs. In the 13 studies of patients with ALS, 12 demonstrated upregulation of multiple SM species and 6 demonstrated upregulation of ceramides. SM species also correlated with markers of clinical progression in five of six studies. These data highlight the potential use of SM and ceramide as biomarkers in ALS. Finally, we review potential therapeutic strategies for targeting sphingolipid metabolism in neurodegeneration.
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Affiliation(s)
- Gavin McCluskey
- Personalised Medicine Center, School of Medicine, Ulster University, Derry BT47 6SB, UK
- Department of Neurology, Altnagelvin Hospital, Derry, BT47 6SB, UK
- Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK
| | - Colette Donaghy
- Department of Neurology, Altnagelvin Hospital, Derry, BT47 6SB, UK
| | - Karen E. Morrison
- Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK
- Faculty of Medicine, Health & Life Sciences, Queen’s University, Belfast BT9 6AG, UK
| | - John McConville
- Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK
- Department of Neurology, Ulster Hospital, Dundonald, Belfast BT16 1RH, UK
| | - William Duddy
- Personalised Medicine Center, School of Medicine, Ulster University, Derry BT47 6SB, UK
| | - Stephanie Duguez
- Personalised Medicine Center, School of Medicine, Ulster University, Derry BT47 6SB, UK
- Correspondence:
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Zhu J, Wang L, Li X, Lan D, Song L, Li Y, Cheng Y, Zhang P. Transcriptome analysis alk-SMase knockout mice reveals the effect of alkaline sphingomyelinase on liver. Biochem Biophys Rep 2022; 30:101240. [PMID: 35360085 PMCID: PMC8961189 DOI: 10.1016/j.bbrep.2022.101240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/21/2022] [Accepted: 02/26/2022] [Indexed: 11/25/2022] Open
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Li Y, Nicholson RJ, Summers SA. Ceramide signaling in the gut. Mol Cell Endocrinol 2022; 544:111554. [PMID: 34998898 PMCID: PMC8828712 DOI: 10.1016/j.mce.2022.111554] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 12/29/2021] [Accepted: 01/03/2022] [Indexed: 11/16/2022]
Abstract
Sphingolipids are essential lipid components in the intestinal epithelial cells (IEC) along the intestinal tract. They play crucial roles in maintaining barrier integrity, regulating nutrient absorption, and acting as signaling molecules to regulate regeneration and differentiation of intestinal mucosa (Kurek et al., 2012). Ceramide is the central sphingolipid species and the precursor of all complex sphingolipids and other downstream simple intermediates like sphingosine (SPH), ceramide-1-phosphate (C-1-P), and sphingosine-1-phosphate (S-1-P). It is also a critical signaling molecule regulating numerous physiologic and pathologic processes. This review will summarize the metabolism of ceramides in the gut and their regulation in inflammatory bowel diseases and colorectal cancer.
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Affiliation(s)
- Ying Li
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, 15 North 2030 East, UT, 84112, Salt Lake City, USA.
| | - Rebekah J Nicholson
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, 15 North 2030 East, UT, 84112, Salt Lake City, USA
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, 15 North 2030 East, UT, 84112, Salt Lake City, USA
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8
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Chung LH, Liu D, Liu XT, Qi Y. Ceramide Transfer Protein (CERT): An Overlooked Molecular Player in Cancer. Int J Mol Sci 2021; 22:13184. [PMID: 34947980 PMCID: PMC8705978 DOI: 10.3390/ijms222413184] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/02/2021] [Accepted: 12/05/2021] [Indexed: 12/26/2022] Open
Abstract
Sphingolipids are a class of essential lipids implicated in constructing cellular membranes and regulating nearly all cellular functions. Sphingolipid metabolic network is centered with the ceramide-sphingomyelin axis. Ceramide is well-recognized as a pro-apoptotic signal; while sphingomyelin, as the most abundant type of sphingolipids, is required for cell growth. Therefore, the balance between these two sphingolipids can be critical for cancer cell survival and functioning. Ceramide transfer protein (CERT) dictates the ratio of ceramide to sphingomyelin within the cell. It is the only lipid transfer protein that specifically delivers ceramide from the endoplasmic reticulum to the Golgi apparatus, where ceramide serves as the substrate for sphingomyelin synthesis. In the past two decades, an increasing body of evidence has suggested a critical role of CERT in cancer, but much more intensive efforts are required to draw a definite conclusion. Herein, we review all research findings of CERT, focusing on its molecular structure, cellular functions and implications in cancer. This comprehensive review of CERT will help to better understand the molecular mechanism of cancer and inspire to identify novel druggable targets.
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Affiliation(s)
- Long Hoa Chung
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW 2050, Australia; (D.L.); (X.T.L.)
| | | | | | - Yanfei Qi
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW 2050, Australia; (D.L.); (X.T.L.)
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Cholesterol-phospholipid interactions resist the detergent effect of bovine bile. Colloids Surf B Biointerfaces 2021; 205:111842. [PMID: 34022699 DOI: 10.1016/j.colsurfb.2021.111842] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/02/2021] [Accepted: 05/08/2021] [Indexed: 12/29/2022]
Abstract
Sphingomyelin (SM) and cholesterol complexation gives rise to detergent-resistant liquid-ordered domains. The persistence of these domains and subsequent mixed micelle formation was examined in the presence of bile under physiological digestive in vitro conditions for vesicles comprising either SM/cholesterol, porcine brain phosphatidylcholine (BPC)/cholesterol, or soy phosphatidylcholine (SPC)/cholesterol bilayers, the latter two systems having no liquid-ordered domains. Micellization of these digested phospholipid multilamellar vesicle systems was confirmed by transmission electron microscopy. Bovine bile was found to consist of large multilamellar sheets which subsumed phospholipid vesicles to form aggregated superstructures. Budding off from these superstructures were vesicle-to-micelle transition intermediates: unilamellar vesicles and cylindrical micelles. The presence of cholesterol (60/40 phospholipid/cholesterol mol/mol) delayed the initial rapid onset of digestion, but not for BPC and SPC vesicle systems. Acyl chain order/disorder before and after vesicle-to-micelle transition of all three phospholipid/cholesterol systems was examined using Raman spectroscopy. The addition of bovine bile to both PC/cholesterol vesicle systems reduced the overall ratio of acyl chain disorder to order. In SM/cholesterol vesicles with ≤ 20% mol cholesterol, only the lateral inter-acyl chain packing was reduced, whereas for SM/cholesterol vesicles with ≥ 30% mol cholesterol, a higher proportion of gauche-to-trans isomerization was apparent, demonstrating that SM/cholesterol complexes modify the acyl chain structure of micelles.
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10
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Abed Rabbo M, Khodour Y, Kaguni LS, Stiban J. Sphingolipid lysosomal storage diseases: from bench to bedside. Lipids Health Dis 2021; 20:44. [PMID: 33941173 PMCID: PMC8094529 DOI: 10.1186/s12944-021-01466-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/14/2021] [Indexed: 01/13/2023] Open
Abstract
Johann Ludwig Wilhelm Thudicum described sphingolipids (SLs) in the late nineteenth century, but it was only in the past fifty years that SL research surged in importance and applicability. Currently, sphingolipids and their metabolism are hotly debated topics in various biochemical fields. Similar to other macromolecular reactions, SL metabolism has important implications in health and disease in most cells. A plethora of SL-related genetic ailments has been described. Defects in SL catabolism can cause the accumulation of SLs, leading to many types of lysosomal storage diseases (LSDs) collectively called sphingolipidoses. These diseases mainly impact the neuronal and immune systems, but other systems can be affected as well. This review aims to present a comprehensive, up-to-date picture of the rapidly growing field of sphingolipid LSDs, their etiology, pathology, and potential therapeutic strategies. We first describe LSDs biochemically and briefly discuss their catabolism, followed by general aspects of the major diseases such as Gaucher, Krabbe, Fabry, and Farber among others. We conclude with an overview of the available and potential future therapies for many of the diseases. We strive to present the most important and recent findings from basic research and clinical applications, and to provide a valuable source for understanding these disorders.
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Affiliation(s)
- Muna Abed Rabbo
- Department of Biology and Biochemistry, Birzeit University, P.O. Box 14, Ramallah, West Bank, 627, Palestine
| | - Yara Khodour
- Department of Biology and Biochemistry, Birzeit University, P.O. Box 14, Ramallah, West Bank, 627, Palestine
| | - Laurie S Kaguni
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
| | - Johnny Stiban
- Department of Biology and Biochemistry, Birzeit University, P.O. Box 14, Ramallah, West Bank, 627, Palestine.
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11
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Sphingomyelinases and Liver Diseases. Biomolecules 2020; 10:biom10111497. [PMID: 33143193 PMCID: PMC7692672 DOI: 10.3390/biom10111497] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most studied SL due to its role as a second messenger in the regulation of multiple signaling pathways and cellular processes. Ceramide is a heterogeneous lipid entity determined by the length of the fatty acyl chain linked to its carbon backbone sphingosine, which can be generated either by de novo synthesis from serine and palmitoyl-CoA in the endoplasmic reticulum or via sphingomyelin (SM) hydrolysis by sphingomyelinases (SMases). Unlike de novo synthesis, SMase-induced SM hydrolysis represents a rapid and transient mechanism of ceramide generation in specific intracellular sites that accounts for the diverse biological effects of ceramide. Several SMases have been described at the molecular level, which exhibit different pH requirements for activity: neutral, acid or alkaline. Among the SMases, the neutral (NSMase) and acid (ASMase) are the best characterized for their contribution to signaling pathways and role in diverse pathologies, including liver diseases. As part of a Special Issue (Phospholipases: From Structure to Biological Function), the present invited review summarizes the physiological functions of NSMase and ASMase and their role in chronic and metabolic liver diseases, of which the most relevant is nonalcoholic steatohepatitis and its progression to hepatocellular carcinoma, due to the association with the obesity and type 2 diabetes epidemic. A better understanding of the regulation and role of SMases in liver pathology may offer the opportunity for novel treatments of liver diseases.
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12
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Bassaganyas L, Popa SJ, Horlbeck M, Puri C, Stewart SE, Campelo F, Ashok A, Butnaru CM, Brouwers N, Heydari K, Ripoche J, Weissman J, Rubinsztein DC, Schekman R, Malhotra V, Moreau K, Villeneuve J. New factors for protein transport identified by a genome-wide CRISPRi screen in mammalian cells. J Cell Biol 2019; 218:3861-3879. [PMID: 31488582 PMCID: PMC6829651 DOI: 10.1083/jcb.201902028] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/16/2019] [Accepted: 08/12/2019] [Indexed: 12/11/2022] Open
Abstract
Protein and membrane trafficking pathways are critical for cell and tissue homeostasis. Traditional genetic and biochemical approaches have shed light on basic principles underlying these processes. However, the list of factors required for secretory pathway function remains incomplete, and mechanisms involved in their adaptation poorly understood. Here, we present a powerful strategy based on a pooled genome-wide CRISPRi screen that allowed the identification of new factors involved in protein transport. Two newly identified factors, TTC17 and CCDC157, localized along the secretory pathway and were found to interact with resident proteins of ER-Golgi membranes. In addition, we uncovered that upon TTC17 knockdown, the polarized organization of Golgi cisternae was altered, creating glycosylation defects, and that CCDC157 is an important factor for the fusion of transport carriers to Golgi membranes. In conclusion, our work identified and characterized new actors in the mechanisms of protein transport and secretion and opens stimulating perspectives for the use of our platform in physiological and pathological contexts.
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Affiliation(s)
- Laia Bassaganyas
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, UK
| | - Stephanie J Popa
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Max Horlbeck
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA
| | - Claudia Puri
- Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
| | - Sarah E Stewart
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Felix Campelo
- Institut de Ciencies Fotoniques, Barcelona Institute of Science and Technology, Castelldefels, Spain
| | - Anupama Ashok
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Cristian M Butnaru
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
- Department of Photonic Investigations, Center of Advanced Laser Technologies, National Institute for Laser, Plasma and Radiation Physics, Magurele, Romania
| | - Nathalie Brouwers
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | | | - Jean Ripoche
- Institut National de la Sante et de la Recherche Medicale U1026, Université de Bordeaux, Bordeaux, France
| | - Jonathan Weissman
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
- UK Dementia Research Institute, Cambridge, UK
| | - Randy Schekman
- Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA
| | - Vivek Malhotra
- Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Kevin Moreau
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Julien Villeneuve
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK
- Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
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13
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Nilsson Å, Duan RD. Pancreatic and mucosal enzymes in choline phospholipid digestion. Am J Physiol Gastrointest Liver Physiol 2019; 316:G425-G445. [PMID: 30576217 DOI: 10.1152/ajpgi.00320.2018] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The digestion of choline phospholipids is important for choline homeostasis, lipid signaling, postprandial lipid and energy metabolism, and interaction with intestinal bacteria. The digestion is mediated by the combined action of pancreatic and mucosal enzymes. In the proximal small intestine, hydrolysis of phosphatidylcholine (PC) to 1-lyso-PC and free fatty acid (FFA) by the pancreatic phospholipase A2 IB coincides with the digestion of the dietary triacylglycerols by lipases, but part of the PC digestion is extended and must be mediated by other enzymes as the jejunoileal brush-border phospholipase B/lipase and mucosal secreted phospholipase A2 X. Absorbed 1-lyso-PC is partitioned in the mucosal cells between degradation and reacylation into chyle PC. Reutilization of choline for hepatic bile PC synthesis, and the reacylation of 1-lyso-PC into chylomicron PC by the lyso-PC-acyl-CoA-acyltransferase 3 are important features of choline recycling and postprandial lipid metabolism. The role of mucosal enzymes is emphasized by sphingomyelin (SM) being sequentially hydrolyzed by brush-border alkaline sphingomyelinase (alk-SMase) and neutral ceramidase to sphingosine and FFA, which are well absorbed. Ceramide and sphingosine-1-phosphate are generated and are both metabolic intermediates and important lipid messengers. Alk-SMase has anti-inflammatory effects that counteract gut inflammation and tumorigenesis. These may be mediated by multiple mechanisms including generation of sphingolipid metabolites and suppression of autotaxin induction and lyso-phosphatidic acid formation. Here we summarize current knowledge on the roles of pancreatic and mucosal enzymes in PC and SM digestion, and its implications in intestinal and liver diseases, bacterial choline metabolism in the gut, and cholesterol absorption.
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Affiliation(s)
- Åke Nilsson
- Department of Clow-linical Sciences Lund, Division of Medicine, Gastroenterology, Lund University , Lund , Sweden
| | - Rui-Dong Duan
- Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences, Lund University , Lund , Sweden
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14
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Bhat OM, Yuan X, Li G, Lee R, Li PL. Sphingolipids and Redox Signaling in Renal Regulation and Chronic Kidney Diseases. Antioxid Redox Signal 2018; 28:1008-1026. [PMID: 29121774 PMCID: PMC5849286 DOI: 10.1089/ars.2017.7129] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 10/30/2017] [Accepted: 11/04/2017] [Indexed: 01/04/2023]
Abstract
Significance: Sphingolipids play critical roles in the membrane biology and intracellular signaling events that influence cellular behavior and function. Our review focuses on the cellular mechanisms and functional relevance of the cross talk between sphingolipids and redox signaling, which may be critically implicated in the pathogenesis of different renal diseases. Recent Advances: Reactive oxygen species (ROS) and sphingolipids can regulate cellular redox homeostasis through the regulation of NADPH oxidase, mitochondrial integrity, nitric oxide synthase (NOS), and antioxidant enzymes. Over the last two decades, there have been significant advancements in the field of sphingolipid research, and it was in 2010 for the first time that sphingolipid receptor modulator was exploited as a therapeutic in humans. The cross talk of sphingolipids with redox signaling pathways becomes an important mechanism in the development of many different diseases such as renal diseases. Critical Issues: The critical issues to be addressed in this review are how sphingolipids interact with the redox signaling pathway to regulate renal function and even result in chronic kidney diseases. Ceramide, sphingosine, and sphingosine-1-phosphate (S1P) as main signaling sphingolipids are discussed in more detail. Future Directions: Although sphingolipids and ROS may mediate or modulate cellular responses to physiological and pathological stimuli, more translational studies and mechanistic pursuit in a tissue- or cell-specific way are needed to enhance our understanding of this important topic and to develop effective therapeutic strategies to treat diseases associated with redox signaling and sphingolipid cross talk. Antioxid. Redox Signal. 28, 1008-1026.
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Affiliation(s)
- Owais M Bhat
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Xinxu Yuan
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Guangbi Li
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - RaMi Lee
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
| | - Pin-Lan Li
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
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15
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Duan RD. Alkaline sphingomyelinase (NPP7) in hepatobiliary diseases: A field that needs to be closely studied. World J Hepatol 2018; 10:246-253. [PMID: 29527260 PMCID: PMC5838443 DOI: 10.4254/wjh.v10.i2.246] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 01/13/2018] [Accepted: 01/24/2018] [Indexed: 02/06/2023] Open
Abstract
Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidylcholine. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ecto-nucleotide pyrophosphatase/phosphodiesterase (NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.
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Affiliation(s)
- Rui-Dong Duan
- Gastroenterology and Nutrition Lab, Department of Clinical Sciences, Lund University, Lund S-22184, Sweden
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16
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Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation. Nutrients 2017; 9:nu9111180. [PMID: 29143791 PMCID: PMC5707652 DOI: 10.3390/nu9111180] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 10/21/2017] [Accepted: 10/25/2017] [Indexed: 12/13/2022] Open
Abstract
Chronic inflammation is a common underlying factor in many major metabolic diseases afflicting Western societies. Sphingolipid metabolism is pivotal in the regulation of inflammatory signaling pathways. The regulation of sphingolipid metabolism is in turn influenced by inflammatory pathways. In this review, we provide an overview of sphingolipid metabolism in mammalian cells, including a description of sphingolipid structure, biosynthesis, turnover, and role in inflammatory signaling. Sphingolipid metabolites play distinct and complex roles in inflammatory signaling and will be discussed. We also review studies examining dietary sphingolipids and inflammation, derived from in vitro and rodent models, as well as human clinical trials. Dietary sphingolipids appear to influence inflammation-related chronic diseases through inhibiting intestinal lipid absorption, altering gut microbiota, activation of anti-inflammatory nuclear receptors, and neutralizing responses to inflammatory stimuli. The anti-inflammatory effects observed with consuming dietary sphingolipids are in contrast to the observation that most cellular sphingolipids play roles in augmenting inflammatory signaling. The relationship between dietary sphingolipids and low-grade chronic inflammation in metabolic disorders is complex and appears to depend on sphingolipid structure, digestion, and metabolic state of the organism. Further research is necessary to confirm the reported anti-inflammatory effects of dietary sphingolipids and delineate their impacts on endogenous sphingolipid metabolism.
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17
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Suh JH, Makarova AM, Gomez JM, Paul LA, Saba JD. An LC/MS/MS method for quantitation of chemopreventive sphingadienes in food products and biological samples. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1061-1062:292-299. [PMID: 28772225 DOI: 10.1016/j.jchromb.2017.07.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 07/15/2017] [Accepted: 07/21/2017] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer mortality. Diet has a significant influence on colon cancer risk. Identifying chemopreventive agents, dietary constituents, practices and/or diet supplements that promote gut health and reduce the incidence of intestinal neoplasias and CRC could significantly impact public health. Sphingadienes (SDs) are dietary sphingolipids found in plant-based food products. SDs are cytotoxic to colon cancer cells and exhibit chemopreventive properties. The aim of the present study was to develop a sensitive and robust ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for quantifying SDs in food products and biological samples. The assay was linear over a concentration range of 80nM to 50μM and was sensitive to a detection limit of 3.3nM. Post-extraction stability was 100% at 24h. SD content in soy oils was approximately 10nM. SDs were detected transiently in the plasma of adult mice 10min after gavage delivery of a 25mg/kg bolus and declined to baseline by 1h. SD uptake in the gut was maximal in the duodenum and peaked 1h after gavage delivery. Disappearance of SDs in the lower gastrointestinal tract suggests either rapid metabolism to yet unidentified products or potentially luminal export.
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Affiliation(s)
- J H Suh
- Children's Hospital Oakland Research Institute, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA
| | - A M Makarova
- Children's Hospital Oakland Research Institute, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA
| | - J M Gomez
- Children's Hospital Oakland Research Institute, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA
| | - L A Paul
- Children's Hospital Oakland Research Institute, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA
| | - J D Saba
- Children's Hospital Oakland Research Institute, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.
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18
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Gorelik A, Liu F, Illes K, Nagar B. Crystal structure of the human alkaline sphingomyelinase provides insights into substrate recognition. J Biol Chem 2017; 292:7087-7094. [PMID: 28292932 DOI: 10.1074/jbc.m116.769273] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 03/08/2017] [Indexed: 01/02/2023] Open
Abstract
Absorption of dietary sphingomyelin (SM) requires its initial degradation into ceramide, a process catalyzed by the intestinal enzyme alkaline sphingomyelinase (alk-SMase, NPP7, ENPP7). alk-SMase belongs to the nucleotide pyrophosphatase/phosphodiesterase (NPP) family, the members of which hydrolyze nucleoside phosphates, phospholipids, and other related molecules. NPP7 is the only paralog that can cleave SM, and its activity requires the presence of bile salts, a class of physiological anionic detergents. To elucidate the mechanism of substrate recognition, we determined the crystal structure of human alk-SMase in complex with phosphocholine, a reaction product. Although the overall fold and catalytic center are conserved relative to other NPPs, alk-SMase recognizes the choline moiety of its substrates via an NPP7-specific aromatic box composed of tyrosine residues. Mutational analysis and enzymatic activity assays identified features on the surface of the protein-a cationic patch and a unique hydrophobic loop-that are essential for accessing SM in bile salt micelles. These results shed new light on substrate specificity determinants within the NPP enzyme family.
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Affiliation(s)
- Alexei Gorelik
- From the Department of Biochemistry and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec H3G 0B1, Canada
| | - Fangyu Liu
- From the Department of Biochemistry and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec H3G 0B1, Canada
| | - Katalin Illes
- From the Department of Biochemistry and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec H3G 0B1, Canada
| | - Bhushan Nagar
- From the Department of Biochemistry and Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec H3G 0B1, Canada
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19
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Cheng M, Bhujwalla ZM, Glunde K. Targeting Phospholipid Metabolism in Cancer. Front Oncol 2016; 6:266. [PMID: 28083512 PMCID: PMC5187387 DOI: 10.3389/fonc.2016.00266] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 12/14/2016] [Indexed: 12/14/2022] Open
Abstract
All cancers tested so far display abnormal choline and ethanolamine phospholipid metabolism, which has been detected with numerous magnetic resonance spectroscopy (MRS) approaches in cells, animal models of cancer, as well as the tumors of cancer patients. Since the discovery of this metabolic hallmark of cancer, many studies have been performed to elucidate the molecular origins of deregulated choline metabolism, to identify targets for cancer treatment, and to develop MRS approaches that detect choline and ethanolamine compounds for clinical use in diagnosis and treatment monitoring. Several enzymes in choline, and recently also ethanolamine, phospholipid metabolism have been identified, and their evaluation has shown that they are involved in carcinogenesis and tumor progression. Several already established enzymes as well as a number of emerging enzymes in phospholipid metabolism can be used as treatment targets for anticancer therapy, either alone or in combination with other chemotherapeutic approaches. This review summarizes the current knowledge of established and relatively novel targets in phospholipid metabolism of cancer, covering choline kinase α, phosphatidylcholine-specific phospholipase D1, phosphatidylcholine-specific phospholipase C, sphingomyelinases, choline transporters, glycerophosphodiesterases, phosphatidylethanolamine N-methyltransferase, and ethanolamine kinase. These enzymes are discussed in terms of their roles in oncogenic transformation, tumor progression, and crucial cancer cell properties such as fast proliferation, migration, and invasion. Their potential as treatment targets are evaluated based on the current literature.
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Affiliation(s)
- Menglin Cheng
- Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine , Baltimore, MD , USA
| | - Zaver M Bhujwalla
- Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kristine Glunde
- Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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20
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Turroni S, Fiori J, Rampelli S, Schnorr SL, Consolandi C, Barone M, Biagi E, Fanelli F, Mezzullo M, Crittenden AN, Henry AG, Brigidi P, Candela M. Fecal metabolome of the Hadza hunter-gatherers: a host-microbiome integrative view. Sci Rep 2016; 6:32826. [PMID: 27624970 PMCID: PMC5021991 DOI: 10.1038/srep32826] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 08/15/2016] [Indexed: 12/28/2022] Open
Abstract
The recent characterization of the gut microbiome of traditional rural and foraging societies allowed us to appreciate the essential co-adaptive role of the microbiome in complementing our physiology, opening up significant questions on how the microbiota changes that have occurred in industrialized urban populations may have altered the microbiota-host co-metabolic network, contributing to the growing list of Western diseases. Here, we applied a targeted metabolomics approach to profile the fecal metabolome of the Hadza of Tanzania, one of the world's few remaining foraging populations, and compared them to the profiles of urban living Italians, as representative of people in the post-industrialized West. Data analysis shows that during the rainy season, when the diet is primarily plant-based, Hadza are characterized by a distinctive enrichment in hexoses, glycerophospholipids, sphingolipids, and acylcarnitines, while deplete in the most common natural amino acids and derivatives. Complementary to the documented unique metagenomic features of their gut microbiome, our findings on the Hadza metabolome lend support to the notion of an alternate microbiome configuration befitting of a nomadic forager lifestyle, which helps maintain metabolic homeostasis through an overall scarcity of inflammatory factors, which are instead highly represented in the Italian metabolome.
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Affiliation(s)
- Silvia Turroni
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Jessica Fiori
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Simone Rampelli
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Stephanie L. Schnorr
- Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, OK 73019, USA
| | - Clarissa Consolandi
- Institute of Biomedical Technologies, Italian National Research Council, Segrate, Milan 20090, Italy
| | - Monica Barone
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Elena Biagi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Flaminia Fanelli
- Endocrinology Unit, Department of Medical and Surgical Sciences and Center for Applied Biomedical Research, University of Bologna – S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - Marco Mezzullo
- Endocrinology Unit, Department of Medical and Surgical Sciences and Center for Applied Biomedical Research, University of Bologna – S. Orsola-Malpighi Hospital, Bologna 40138, Italy
| | - Alyssa N. Crittenden
- Metabolism, Anthropometry, and Nutrition Laboratory, Department of Anthropology, University of Nevada, Las Vegas, NV 89154-5003, USA
| | - Amanda G. Henry
- Plant Foods in Hominin Dietary Ecology Research Group, Max Planck Institute for Evolutionary Anthropology, Leipzig 04103, Germany
| | - Patrizia Brigidi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Marco Candela
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
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21
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Sphingolipids as Mediators in the Crosstalk between Microbiota and Intestinal Cells: Implications for Inflammatory Bowel Disease. Mediators Inflamm 2016; 2016:9890141. [PMID: 27656050 PMCID: PMC5021499 DOI: 10.1155/2016/9890141] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/10/2016] [Accepted: 07/14/2016] [Indexed: 12/21/2022] Open
Abstract
Inflammatory bowel disease (IBD) describes different illnesses characterized by chronic inflammation of the gastrointestinal tract. Although the pathogenic mechanisms leading to IBD are poorly understood, immune system disturbances likely underlie its development. Sphingolipids (SLs) have been identified as important players and promising therapeutic targets to control inflammation in IBD. Interestingly, it seems that microorganisms of the normal gut microbiota and probiotics are involved in sphingolipid function. However, there is a great need to investigate the role of SLs as intermediates in the crosstalk between intestinal immunity and microorganisms. This review focuses on recent investigations that describe some mechanisms involved in the regulation of cytokine profiles by SLs. We also describe the importance of gut microbiota in providing signaling molecules that favor the communication between resident bacteria and intestinal cells. This, in turn, modulates the immune response in the bowel and likely in other peripheral organs. The potential of SLs and gut microbiota as targets or therapeutic agents for IBD is also discussed.
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22
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Zhou K, Blom T. Trafficking and Functions of Bioactive Sphingolipids: Lessons from Cells and Model Membranes. Lipid Insights 2015; 8:11-20. [PMID: 26715852 PMCID: PMC4685176 DOI: 10.4137/lpi.s31615] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 11/08/2015] [Accepted: 11/10/2015] [Indexed: 12/15/2022] Open
Abstract
Ceramide and sphingosine and their phosphorylated counterparts are recognized as "bioactive sphingolipids" and modulate membrane integrity, the activity of enzymes, or act as ligands of G protein-coupled receptors. The subcellular distribution of the bioactive sphingolipids is central to their function as the same lipid can mediate diametrically opposite effects depending on its location. To ensure that these lipids are present in the right amount and in the appropriate organelles, cells employ selective lipid transport and compartmentalize sphingolipid-metabolizing enzymes to characteristic subcellular sites. Our knowledge of key mechanisms involved in sphingolipid signaling and trafficking has increased substantially in the past decades-thanks to advances in biochemical and cell biological methods. In this review, we focus on the bioactive sphingolipids and discuss how the combination of studies in cells and in model membranes have contributed to our understanding of how they behave and function in living organisms.
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Affiliation(s)
- Kecheng Zhou
- Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tomas Blom
- Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Chen Y, Zhang P, Xu SC, Yang L, Voss U, Ekblad E, Wu Y, Min Y, Hertervig E, Nilsson Å, Duan RD. Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice. Mol Cancer Ther 2014; 14:259-67. [PMID: 25381265 DOI: 10.1158/1535-7163.mct-14-0468-t] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor (PAF) and was previously suggested to have anticancer properties. The direct evidence is still lacking. We studied colonic tumorigenesis in alk-SMase knockout (KO) mice. Formation of aberrant crypt foci (ACF) was examined after azoxymethane (AOM) injection. Tumor was induced by AOM alone, a conventional AOM/dextran sulfate sodium (DSS) treatment, and an enhanced AOM/DSS method. β-Catenin was determined by immunohistochemistry, PAF levels by ELISA, and sphingomyelin metabolites by mass spectrometry. Without treatment, spontaneous tumorigenesis was not identified but the intestinal mucosa appeared thicker in KO than in wild-type (WT) littermates. AOM alone induced more ACF in KO mice but no tumors 28 weeks after injection. However, combination of AOM/DSS treatments induced colonic tumors and the incidence was significantly higher in KO than in WT mice. By the enhanced AOM/DSS method, tumor number per mouse increased 4.5 times and tumor size 1.8 times in KO compared with WT mice. Although all tumors were adenomas in WT mice, 32% were adenocarcinomas in KO mice. Compared with WT mice, cytosol expression of β-catenin was significantly increased and nuclear translocation in tumors was more pronounced in KO mice. Lipid analysis showed decreased ceramide in small intestine and increased sphingosine-1-phosphate (S1P) in both small intestine and colon in nontreated KO mice. PAF levels in feces were significantly higher in the KO mice after AOM/DSS treatment. In conclusion, lack of alk-SMase markedly increases AOM/DSS-induced colonic tumorigenesis associated with decreased ceramide and increased S1P and PAF levels.
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Affiliation(s)
- Ying Chen
- Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden. Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ping Zhang
- Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden
| | - Shu-Chang Xu
- Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Liping Yang
- Cancer Research Center, Tumor Hospital of Nantong University, Nantong, China
| | - Ulrikke Voss
- Neurogastroenterology, Department of Experimental Medical Science, University of Lund, Lund, Sweden
| | - Eva Ekblad
- Neurogastroenterology, Department of Experimental Medical Science, University of Lund, Lund, Sweden
| | - Yunjin Wu
- Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yalan Min
- Cancer Research Center, Tumor Hospital of Nantong University, Nantong, China
| | - Erik Hertervig
- Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden. Gastroenterology, Skåne University Hospital, Lund, Sweden
| | - Åke Nilsson
- Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden. Gastroenterology, Skåne University Hospital, Lund, Sweden
| | - Rui-Dong Duan
- Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden.
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Metabolism, physiological role, and clinical implications of sphingolipids in gastrointestinal tract. BIOMED RESEARCH INTERNATIONAL 2013; 2013:908907. [PMID: 24083248 PMCID: PMC3780527 DOI: 10.1155/2013/908907] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 06/30/2013] [Accepted: 08/02/2013] [Indexed: 01/21/2023]
Abstract
Sphingolipids in digestive system are responsible for numerous important physiological and pathological processes. In the membrane of gut epithelial cells, sphingolipids provide structural integrity, regulate absorption of some nutrients, and act as receptors for many microbial antigens and their toxins. Moreover, bioactive sphingolipids such as ceramide or sphingosine-1-phosphate regulate cellular growth, differentiation, and programmed cell death-apoptosis. Although it is well established that sphingolipids have clinical implications in gastrointestinal tumorigenesis or inflammation, further studies are needed to fully explore the role of sphingolipids in neoplastic and inflammatory diseases in gastrointestinal tract. Pharmacological agents which regulate metabolism of sphingolipids can be potentially used in the management of colorectal cancer or inflammatory bowel diseases. The aim of this work is to critically the review physiological and pathological roles of sphingolipids in the gastrointestinal tract.
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25
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Nilsson Å. Sphingolipids. PHOSPHOLIPID TECHNOLOGY AND APPLICATIONS 2012:169-194. [DOI: 10.1533/9780857097880.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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26
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The effect of milk polar lipids separated from butter serum on the lipid levels in the liver and the plasma of obese-model mouse (KK-A ). J Funct Foods 2011. [DOI: 10.1016/j.jff.2011.06.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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COMPOSITION, PROPERTIES AND NUTRITIONAL ASPECTS OF MILK FAT GLOBULE MEMBRANE – A REVIEW. POL J FOOD NUTR SCI 2011. [DOI: 10.2478/v10222-011-0001-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Suresh PS, Olubiyi O, Thirunavukkarasu C, Strodel B, Kumar MS. Molecular modeling of human alkaline sphingomyelinase. Bioinformation 2011; 6:78-82. [PMID: 21544170 PMCID: PMC3082857 DOI: 10.6026/97320630006078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Accepted: 03/16/2011] [Indexed: 11/23/2022] Open
Abstract
Alkaline sphingomyelinase, which is expressed in the human intestine and hydrolyses sphingomyelin, is a component of the plasma and the lysosomal membranes. Hydrolase of sphingomyelin generates ceramide, sphingosine, and sphingosine 1-phosphate that have regulatory effects on vital cellular functions such as proliferation, differentiation, and apoptosis. The enzyme belongs to the Nucleotide Pyrophosphatase/Phosphodiesterase family and it differs in structural similarity with acidic and neutral sphingomyelinase. In the present study we modeled alkaline sphingomyelinase using homology modeling based on the structure of Nucleotide Pyrophosphatase/Phosphodiesterase from Xanthomonas axonopodis with which it shares 34% identity. Homology modeling was performed using Modeller9v7. We found that Cys78 and Cys394 form a disulphide bond. Further analysis shows that Ser76 may be important for the function of this enzyme, which is supported by the findings of Wu et al. (2005), that S76F abolishes the activity completely. We found that the residues bound to Zn(2+) are conserved and geometrically similar with the template. Molecular Dynamics simulations were carried out for the modeled protein to observe the effect of Zinc metal ions. It was observed that the metal ion has little effect with regard to the stability but induces increased fluctuations in the protein. These analyses showed that Zinc ions play an important role in stabilizing the secondary structure and in maintaining the compactness of the active site.
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Affiliation(s)
- Panneer Selvam Suresh
- Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry, India
| | - Olujide Olubiyi
- Institute of Structural Biology and Biophysics / ISB-3, Research Centre Julich, 52425 Julich, Germany
| | - Chinnasamy Thirunavukkarasu
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry, India
| | - Birgit Strodel
- Institute of Structural Biology and Biophysics / ISB-3, Research Centre Julich, 52425 Julich, Germany
| | - Muthuvel Suresh Kumar
- Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry, India
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Zhang Y, Cheng Y, Hansen GH, Niels-Christiansen LL, Koentgen F, Ohlsson L, Nilsson A, Duan RD. Crucial role of alkaline sphingomyelinase in sphingomyelin digestion: a study on enzyme knockout mice. J Lipid Res 2010; 52:771-81. [PMID: 21177474 DOI: 10.1194/jlr.m012880] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Alkaline sphingomyelinase (alk-SMase) hydrolyses sphingomyelin (SM) to ceramide in the gut. To evaluate the physiological importance of the enzyme, we generated alk-SMase knockout (KO) mice by the Cre-recombinase-Locus of X-over P1(Cre-LoxP) system and studied SM digestion. Both wild-type (WT) and KO mice were fed ³H-palmitic acid labeled SM together with milk SM by gavage. The lipids in intestinal content, intestinal tissues, serum, and liver were analyzed by TLC. In KO mice, nondigested ³H-SM in the intestinal content increased by 6-fold and the formation of ³H-ceramide decreased markedly, resulting in 98% reduction of ³H-ceramide/³H-SM ratio 1 h after gavage. The absorbed ³H-palmitic acid portion was decreased by 95%. After 3 h, a small increase in ³H-ceramide was identified in distal intestine in KO mice. In feces, ³H-SM was increased by 243% and ceramide decreased by 74% in the KO mice. The KO mice also showed significantly decreased radioactivity in liver and serum. Furthermore, alkaline phosphatase activity in the mucosa was reduced by 50% and histological comparison of two female littermates preliminarily suggested mucosal hypertrophy in KO mice. This study provides definite proof for crucial roles of alk-SMase in SM digestion and points to possible roles in regulating mucosal growth and alkaline phosphatase function.
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Affiliation(s)
- Yao Zhang
- Gastroenterology and Nutrition Laboratory, Biomedical Center B11, Lund University, S-221 84 Lund, Sweden
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30
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Feng D, Ohlsson L, Ling W, Nilsson A, Duan RD. Generating ceramide from sphingomyelin by alkaline sphingomyelinase in the gut enhances sphingomyelin-induced inhibition of cholesterol uptake in Caco-2 cells. Dig Dis Sci 2010; 55:3377-83. [PMID: 20393874 DOI: 10.1007/s10620-010-1202-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Accepted: 03/15/2010] [Indexed: 12/17/2022]
Abstract
Background Sphingomyelin (SM) is present in dietary products and cell plasma membranes. We previously showed that dietary SM inhibited cholesterol absorption in rats. In the intestinal tract, SM is mainly hydrolyzed by alkaline sphingomyelinase (alk-SMase) to ceramide.Aims We investigated the influence of SM and its hydrolytic products ceramide and sphingosine on cholesterol uptake in intestinal Caco-2 cells.Methods Micelles containing bile salt, monoolein, and (14)C-cholesterol were prepared with or without SM, ceramide,or sphingosine. The micelles were incubated with Caco-2 cells, and uptake of radioactive cholesterol was quantified.Results We found that confluent monolayer Caco-2 cells expressed NPC1L1, and the uptake of cholesterol in the cells was inhibited by ezetimibe, a specific inhibitor of NPC1L1. Incorporation of SM in the cholesterol micelles inhibited cholesterol uptake dose-dependently; 38% inhibition occurred at an equal mole ratio of SM and cholesterol.The inhibition was further enhanced to 45% by pretreating the cholesterol/SM micelles with recombinant alk-SMase, which hydrolyzed SM in the micelles by 85%, indicating ceramide has stronger inhibitory effects on cholesterol uptake. To confirm this, we further replaced SM in the micelles with ceramide and sphingosine, and found that at equal mole ratio to cholesterol, ceramide exhibited stronger inhibitory effect (50% vs 38%) on cholesterol uptake than SM, whereas sphingosine only had a weak effect at high concentrations.Conclusion Both SM and ceramide inhibit cholesterol uptake, the effect of ceramide being stronger than that of SM. Alk-SMase enhances SM-induced inhibition of cholesterol uptake by generating ceramide in the intestinal lumen.
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Affiliation(s)
- Dan Feng
- Gastroenterology and Nutrition Laboratory, Biomedical CenterB11, Institution of Clinical Sciences, University of Lund,221 84 Lund, Sweden
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Hoeglund AB, Bostic HE, Howard AL, Wanjala IW, Best MD, Baker DL, Parrill AL. Optimization of a pipemidic acid autotaxin inhibitor. J Med Chem 2010; 53:1056-66. [PMID: 20041668 DOI: 10.1021/jm9012328] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Autotaxin (ATX, NPP2) has recently been shown to be the lysophospholipase D responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA). LPA has a well-established role in cancer, and the production of LPA is consistent with the cancer-promoting actions of ATX. Increased ATX and LPA receptor expression have been found in numerous cancer cell types. The current study has combined ligand-based computational approaches (binary quantitative structure-activity relationship), medicinal chemistry, and experimental enzymatic assays to optimize a previously identified small molecule ATX inhibitor, H2L 7905958 (1). Seventy prospective analogs were analyzed via computational screening, from which 30 promising compounds were synthesized and screened to assess efficacy, potency, and mechanism of inhibition. This approach has identified four analogs as potent as or more potent than the lead. The most potent analog displayed an IC(50) of 900 nM with respect to ATX-mediated FS-3 hydrolysis with a K(i) of 700 nM, making this compound approximately 3-fold more potent than the previously described lead.
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Affiliation(s)
- Adrienne B Hoeglund
- Department of Chemistry, The University of Memphis, Memphis, Tennessee 38152, USA
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32
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Hoeglund AB, Howard AL, Wanjala IW, Pham TCT, Parrill AL, Baker DL. Characterization of non-lipid autotaxin inhibitors. Bioorg Med Chem 2010; 18:769-76. [DOI: 10.1016/j.bmc.2009.11.056] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Revised: 11/23/2009] [Accepted: 11/24/2009] [Indexed: 11/16/2022]
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Gault CR, Obeid LM, Hannun YA. An overview of sphingolipid metabolism: from synthesis to breakdown. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 688:1-23. [PMID: 20919643 DOI: 10.1007/978-1-4419-6741-1_1] [Citation(s) in RCA: 772] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Sphingolipids constitute a class of lipids defined by their eighteen carbon amino-alcohol backbones which are synthesized in the ER from nonsphingolipid precursors. Modification of this basic structure is what gives rise to the vast family of sphingolipids that play significant roles in membrane biology and provide many bioactive metabolites that regulate cell function. Despite the diversity of structure and function of sphingolipids, their creation and destruction are governed by common synthetic and catabolic pathways. In this regard, sphingolipid metabolism can be imagined as an array of interconnected networks that diverge from a single common entry point and converge into a single common breakdown pathway. In their simplest forms, sphingosine, phytosphingosine and dihydrosphingosine serve as the backbones upon which further complexity is achieved. For example, phosphorylation of the C1 hydroxyl group yields the final breakdown products and/or the important signaling molecules sphingosine-1-phosphate, phytosphingosine-1-phosphate and dihydrosphingosine-1-phosphate, respectively. On the other hand, acylation of sphingosine, phytosphingosine, or dihydrosphingosine with one of several possible acyl CoA molecules through the action of distinct ceramide synthases produces the molecules defined as ceramide, phytoceramide, or dihydroceramide. Ceramide, due to the differing acyl CoAs that can be used to produce it, is technically a class of molecules rather than a single molecule and therefore may have different biological functions depending on the acyl chain it is composed of. At the apex of complexity is the group of lipids known as glycosphingolipids (GSL) which contain dozens of different sphingolipid species differing by both the order and type of sugar residues attached to their headgroups. Since these molecules are produced from ceramide precursors, they too may have differences in their acyl chain composition, revealing an additional layer of variation. The glycosphingolipids are divided broadly into two categories: glucosphingolipids and galactosphingolipids. The glucosphingolipids depend initially on the enzyme glucosylceramide synthase (GCS) which attaches glucose as the first residue to the C1 hydroxyl position. Galactosphingolipids, on the other hand, are generated from galactosylceramide synthase (GalCerS), an evolutionarily dissimilar enzyme from GCS. Glycosphingolipids are further divided based upon further modification by various glycosyltransferases which increases the potential variation in lipid species by several fold. Far more abundant are the sphingomyelin species which are produced in parallel with glycosphingolipids, however they are defined by a phosphocholine headgroup rather than the addition of sugar residues. Although sphingomyelin species all share a common headgroup, they too are produced from a variety of ceramide species and therefore can have differing acyl chains attached to their C-2 amino groups. Whether or not the differing acyl chain lengths in SMs dictate unique functions or important biophysical distinctions has not yet been established. Understanding the function of all the existing glycosphingolipids and sphingomyelin species will be a major undertaking in the future since the tools to study and measure these species are only beginning to be developed (see Fig 1 for an illustrated depiction of the various sphingolipid structures). The simple sphingolipids serve both as the precursors and the breakdown products of the more complex ones. Importantly, in recent decades, these simple sphingolipids have gained attention for having significant signaling and regulatory roles within cells. In addition, many tools have emerged to measure the levels of simple sphingolipids and therefore have become the focus of even more intense study in recent years. With this thought in mind, this chapter will pay tribute to the complex sphingolipids, but focus on the regulation of simple sphingolipid metabolism.
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Affiliation(s)
- Christopher R Gault
- Department of Biochemistry, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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Andersson D, Kotarsky K, Wu J, Agace W, Duan RD. Expression of alkaline sphingomyelinase in yeast cells and anti-inflammatory effects of the expressed enzyme in a rat colitis model. Dig Dis Sci 2009; 54:1440-8. [PMID: 18989780 DOI: 10.1007/s10620-008-0509-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2008] [Accepted: 08/22/2008] [Indexed: 01/02/2023]
Abstract
Alkaline sphingomyelinase (Alk-SMase) is a key enzyme in the intestinal tract for digestion of dietary sphingomyelin (SM), which generates lipid messengers with cell-cycle regulating effects. The enzyme is significantly decreased in ulcerative colitis and colon cancer. Based on this information, we wanted to investigate whether the enzyme had preventive effects against murine colitis. We report herein a method to express a biologically active Alk-SMase from Pichia pastoris yeast cells. By using the expressed enzyme to treat a rat colitis model induced by dextran sulfate sodium, we found that intrarectal instillation of Alk-SMase once daily for 1 week significantly reduced the inflammation score and protected the colonic epithelium from inflammatory destruction. We found a tendency for decreased tumor necrosis factor (TNF)-alpha expression in the Alk-SMase-treated group. This study, for the first time, provides a method to produce the enzyme and shows the potential applicability of the enzyme in the treatment of inflammatory bowel diseases.
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Affiliation(s)
- David Andersson
- Gastroenterology Laboratory, Institution of Clinical Science, Biomedical Center, B11, Lund University, 22184, Lund, Sweden
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Matrix metalloproteinase-1 expression induced by IL-1β requires acid sphingomyelinase. FEBS Lett 2009; 583:915-20. [DOI: 10.1016/j.febslet.2009.02.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2008] [Revised: 02/03/2009] [Accepted: 02/04/2009] [Indexed: 11/18/2022]
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Saslowsky DE, Tanaka N, Reddy KP, Lencer WI. Ceramide activates JNK to inhibit a cAMP-gated K+ conductance and Cl- secretion in intestinal epithelia. FASEB J 2009; 23:259-70. [PMID: 18820034 PMCID: PMC2626619 DOI: 10.1096/fj.08-116467] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2008] [Accepted: 08/28/2008] [Indexed: 11/11/2022]
Abstract
Sphingomyelinases (SMases) hydrolyze membrane sphingomyelin to ceramide and are expressed by diverse host and microbial cell types populating mucosal surfaces. Exogenous bacterial SMase acts on the basolateral membrane of polarized human intestinal epithelial cells to repress the cAMP-induced Cl(-) secretory response, but how this occurs is unknown. We show here that SMase acts by down-regulating a cAMP-gated basolateral membrane K(+) conductance. Neither phosphocholine, ceramide-1-phosphate, nor sphingosine-1-phosphate recapitulates this effect, indicating that ceramide production is the decisive factor. Basolaterally applied SMase induced the phosphorylation of c-Jun NH(2)-terminal kinase (JNK), and inhibition of JNK rescued the effect of SMase on cAMP-dependant secretion. SMase secreted by normal human fibroblasts specifically recapitulated the effect on cAMP-induced Cl(-) secretion, indicating that cell types inhabiting the subepithelial space can provide such an activity to the basolateral membrane of intestinal enterocytes in trans. Thus, conversion of sphingomyelin to ceramide in basolateral membranes of intestinal cells rapidly activates JNK to inhibit a cAMP-gated K(+) conductance and thereby attenuates Cl(-) secretion. These results define a novel lipid-mediated pathway for regulation of salt and water homeostasis at mucosal surfaces.
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Affiliation(s)
- David E Saslowsky
- GI Cell Biology, Children's Hospital, and the Harvard Digestive Diseases Center, Boston, MA 02115, USA.
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Liu KX, Chen SQ, Huang WQ, Li YS, Irwin MG, Xia Z. Propofol pretreatment reduces ceramide production and attenuates intestinal mucosal apoptosis induced by intestinal ischemia/reperfusion in rats. Anesth Analg 2008; 107:1884-91. [PMID: 19020134 DOI: 10.1213/ane.0b013e3181884bbf] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Apoptosis has been shown to be a major mode of intestinal epithelial cell death caused by intestinal ischemia/reperfusion (II/R), a condition that is associated with increased oxidative stress. Ceramide has been proposed as a messenger of apoptosis. We investigated if pretreatment with propofol, an anesthetic with antioxidant properties, could reduce ceramide production, and consequently, mucosal epithelial apoptosis induced by II/R in rats. METHODS Rat II/R injury was produced by clamping the superior mesenteric artery for 1 h followed by 3 h of reperfusion. Thirty rats were randomly allocated into control, injury (II/R) and propofol (pretreatment) groups (n = 10 per group). In the propofol group, propofol 50 mg/kg, a dose that has been shown to cause the loss of reflex responses to a painful stimulus while remaining sensitive to skin incision in rats, was administered intraperitoneally 30 min before inducing intestinal ischemia, while animals in control and untreated injury groups received an equal volume of intralipid. Intestinal mucosal epithelial apoptosis was detected via electron microscopy and TUNEL analysis. Lipid oxidation product malondialdehyde and the activities of superoxide dismutase were assessed by colorimetric analyses. Ceramide generation and sphingomyelinase mRNA expression in intestinal mucosa were determined by high performance thin layer chromatography and reverse transcriptase polymerase chain reaction, respectively. RESULTS II/R caused intestinal mucosal epithelial apoptosis and over-production of ceramide accompanied by up-regulation of sphingomyelinase mRNA expression and increases in lipid oxidation (all P < 0.01 versus control). Propofol pretreatment significantly attenuated these changes (all P < 0.01, propofol versus injury). CONCLUSION The findings indicate that propofol pretreatment attenuates II/R-induced intestinal epithelial apoptosis, which might be attributable to its antioxidant property modulating the ceramide pathway.
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Affiliation(s)
- Ke-Xuan Liu
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, No.58, Zhongshan 2th Rd., Guangzhou, China, 510080.
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Hu Y, Le Leu RK, Belobrajdic D, Young GP. The potential of sphingomyelin as a chemopreventive agent in AOM-induced colon cancer model: wild-type and p53+/- mice. Mol Nutr Food Res 2008; 52:558-66. [PMID: 18324704 DOI: 10.1002/mnfr.200700258] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
A protective effect of sphingolipids on colorectal cancer (CRC) has been reported in certain mouse strains. It is unknown if sphingolipids are protective in a p53 deficiency mouse model of CRC. This study investigated the effect of sphingomyelin (SM) on intestinal sphingomyelinase (SMase) activity, colonic epithelial biology and azoxymethane (AOM)-induced CRC. Groups of wild-type (C57BL/6J) and p53+/- mice were fed 0.1% SM diet for 4 wk, administered a single AOM injection and then killed 6 h later to measure apoptosis and proliferation. Separately, both mouse types were fed 0.05% SM diet, administered three AOM injections and killed 33-38 wk later to measure tumour formation. SM significantly increased SMase activity and reduced proliferation (p < 0.05) in wild-type and p53+/- mice. SM did not regulate baseline apoptosis, apoptotic response to AOM or apoptosis in tumours, nor did it restore defective apoptosis in p53+/- mice. There was a nonsignificant trend to reduced tumour incidence with SM in wild-type (p = 0.15) and p53+/- (p = 0.12) mice. In conclusion, while increasing intestinal SMase activity and suppressing proliferation, SM did not promote any form of apoptosis and failed to achieve significant protection in these mice. Further investigation to understand the variable effect of SM in preventing CRC is warranted.
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Affiliation(s)
- Ying Hu
- Department of Medicine, Flinders University of South Australia, Bedford Park, Australia.
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Yabu T, Imamura S, Yamashita M, Okazaki T. Identification of Mg2+ -dependent neutral sphingomyelinase 1 as a mediator of heat stress-induced ceramide generation and apoptosis. J Biol Chem 2008; 283:29971-82. [PMID: 18678863 DOI: 10.1074/jbc.m805402200] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Neutral sphingomyelinases (SMases) are involved in the induction of ceramide-mediated proapoptotic signaling under heat stress conditions. Although ceramide is an important mediator of apoptosis, the neutral SMase that is activated under heat stress has not been identified. In this study, we cloned an Mg(2+)-dependent neutral SMase from a zebrafish embryonic cell cDNA library using an Escherichia coli expression-cloning vector. Screening of the clones using an SMase activity assay with C(6)-7-nitro-2-1,3-benzoxadiazol-4-yl-sphingomyelin as the substrate resulted in the isolation of one neutral SMase cDNA clone. This cDNA encoded a polypeptide of 420 amino acids (putative molecular weight: 46,900) containing two predicted transmembrane domains in its C-terminal region. The cloned neutral SMase 1 acted as a mediator of stress-induced apoptosis. Bacterially expressed recombinant neutral SMase 1 hydrolyzed [choline-methyl-(14)C]sphingomyelin optimally at pH 7.5 in the presence of an Mg(2+) ion. In zebrafish embryonic cells, the endogenous SMase enzyme was localized in the microsomal fraction. In FLAG-tagged SMase-overexpressing cells, neutral SMase 1 colocalized with a Golgi marker in a cytochemical analysis. Inactivation of the enzyme by an antisense phosphorothioate oligonucleotide repressed the induction of ceramide generation, caspase-3 activation, and apoptotic cell death by heat stress. Thus, neutral SMase 1 participates in an inducible ceramide-mediating, proapoptotic signaling pathway that operates in heat-induced apoptosis in zebrafish embryonic cells.
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Affiliation(s)
- Takeshi Yabu
- National Research Institute of Fisheries Science, 2-12-4 Fukuura, Kanazawa, Yokohama, Kanagawa 236-8648, Japan.
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VSL#3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2008; 22:237-42. [PMID: 18354751 DOI: 10.1155/2008/520383] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Alkaline sphingomyelinase, an enzyme found exclusively in bile and the intestinal brush border, hydrolyzes sphingomyelin into ceramide, sphingosine and sphingosine-1-phosphate, thereby inducing epithelial apoptosis. Reduced levels of alkaline sphingomyelinase have been found in premalignant and malignant intestinal epithelia and in ulcerative colitis tissue. Probiotic bacteria can be a source of sphingomyelinase. OBJECTIVE To determine the effect of VSL#3 probiotic therapy on mucosal levels of alkaline sphingomyelinase, both in a mouse model of colitis and in patients with ulcerative colitis. METHODS Interleukin-10 gene-deficient (IL10KO) and wild type control mice were treated with VSL#3 (10(9) colony-forming units per day) for three weeks, after which alkaline sphingomyelinase activity was measured in ileal and colonic tissue. As well, 15 patients with ulcerative colitis were treated with VSL#3 (900 billion bacteria two times per day for five weeks). Alkaline sphingomyelinase activity was measured through biopsies and comparison of ulcerative colitis disease activity index scores obtained before and after treatment. RESULTS Lowered alkaline sphingomyelinase levels were seen in the colon (P=0.02) and ileum (P=0.04) of IL10KO mice, as compared with controls. Treatment of these mice with VSL#3 resulted in upregulation of mucosal alkaline sphingomyelinase activity in both the colon (P=0.04) and the ileum (P=0.01). VSL#3 treatment of human patients who had ulcerative colitis decreased mean (+/- SEM) ulcerative colitis disease activity index scores from 5.3+/-1.8946 to 0.70+/-0.34 (P=0.02) and increased mucosal alkaline sphingomyelinase activity. CONCLUSION Mucosal alkaline sphingomyelinase activity is reduced in the intestine of IL10KO mice with colitis and in humans with ulcerative colitis. VSL#3 probiotic therapy upregulates mucosal alkaline sphingomyelinase activity.
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Dewettinck K, Rombaut R, Thienpont N, Le TT, Messens K, Van Camp J. Nutritional and technological aspects of milk fat globule membrane material. Int Dairy J 2008. [DOI: 10.1016/j.idairyj.2007.10.014] [Citation(s) in RCA: 380] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Saslowsky DE, Lencer WI. Conversion of apical plasma membrane sphingomyelin to ceramide attenuates the intoxication of host cells by cholera toxin. Cell Microbiol 2008; 10:67-80. [PMID: 18052945 DOI: 10.1111/j.1462-5822.2007.01015.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Cholera toxin (CT) enters host cells by binding to ganglioside GM1 in the apical plasma membrane (PM). GM1 carries CT retrograde from the PM to the endoplasmic reticulum (ER), where a portion of the toxin, the A1-chain, retro-translocates to the cytosol, causing disease. Trafficking in this pathway appears to depend on the association of CT-GM1 complexes with sphingomyelin (SM)- and cholesterol-rich membrane microdomains termed lipid rafts. Here, we find that in polarized intestinal epithelia, the conversion of apical membrane SM to ceramide by bacterial sphingomyelinase attenuates CT toxicity, consistent with the lipid raft hypothesis. The effect is reversible, specific to toxin entry via the apical membrane, and recapitulated by the addition of exogenous long-chain ceramides. Conversion of apical membrane SM to ceramide inhibits the efficiency of toxin endocytosis, but retrograde trafficking from the apical PM to the Golgi and ER is not affected. This result suggests that the cause for toxin resistance occurs at steps required for retro-translocation of the CT A1-chain to the cytosol.
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Affiliation(s)
- David E Saslowsky
- Children's Hospital, Harvard Digestive Diseases Center, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
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Duan RD, Cheng Y, Jönsson BAG, Ohlsson L, Herbst A, Hellström-Westas L, Nilsson A. Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites. Pediatr Res 2007; 61:61-6. [PMID: 17211142 DOI: 10.1203/01.pdr.0000250534.92934.c2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Intestinal alkaline sphingomyelinase (Alk-SMase) and neutral ceramidase may catalyze the hydrolysis of endogenous sphingomyelin (SM) and milk SM in human-milk fed infants. The enzymes generate sphingolipid metabolites that may influence gut maturation. Alk-SMase also inactivates platelet-activating factor (PAF) that is involved in the pathogenesis of necrotizing enterocolitis (NEC). We examined whether the two enzymes are expressed in both preterm and term infants and analyzed Alk-SMase, neutral ceramidase, SM, and sphingolipid metabolites in meconium. Meconium was collected from 46 preterm (gestational ages 23-36 wk) and 38 term infants (gestational ages 37-42 wk) and analyzed for Alk-SMase using C-choline-labeled SM and for neutral ceramidase using C-octanoyl-sphingosine as substrates. Molecular species of SM, ceramide, and sphingosine were analyzed by high-performance liquid chromatography mass spectroscopy. Meconium contained significant levels of Alk-SMase and ceramidase at all gestational ages. It also contained 16-24 carbon molecular species of SM, palmitoyl- and stearoyl-sphingosine, and sphingosine. There were positive correlations between levels of SM and ceramide and between ceramide and sphingosine levels. In conclusion, Alk-SMase and ceramidase are expressed in the gut of both preterm and term newborn infants and may generate bioactive sphingolipid messengers.
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Affiliation(s)
- Rui-Dong Duan
- Department of Clinical Sciences, Medicine (Gastroenterology and Nutrition), Lund University Hospital, Lund, Sweden
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Duan RD, Verkade HJ, Cheng Y, Havinga R, Nilsson A. Effects of bile diversion in rats on intestinal sphingomyelinases and ceramidase. Biochim Biophys Acta Mol Cell Biol Lipids 2006; 1771:196-201. [PMID: 17204455 DOI: 10.1016/j.bbalip.2006.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2006] [Revised: 11/14/2006] [Accepted: 12/04/2006] [Indexed: 11/22/2022]
Abstract
Alkaline sphingomyelinase (Alk-SMase) and neutral ceramidase (N-CDase) in the intestinal microvillar membrane are responsible for dietary sphingomyelin digestion. The activities of the enzymes require the presence of bile salt, and the enzymes can be released into the gut lumen in active forms by bile salts and trypsin. It is unclear to what extent that the intestinal presence of bile salts is critical for the intraluminal activity of these enzymes. We compared the activities of Alk-SMase, N-CDase, and other types of SMases in control and permanently bile diverted rats. In the intestinal tract of control rats, the activity of Alk-SMase was profoundly higher than those of acid and neutral SMases. Bile diversion reduced Alk-SMase activity by 85% in the small intestinal content, and by 68% in the faeces, but did not significantly change the activity in the intestinal mucosa. Western blot showed a marked reduction of the enzyme in the intestinal lumen but not mucosa. N-CDase activities both in the intestinal mucosa and content were reduced by bile diversion. Bile diversion also decreased aminopeptidase N activity in the content and increased that in the mucosa, but had no effects on that of alkaline phosphatase. In conclusion, the presence of bile salts is important for maintaining high intraluminal levels of Alk-SMase and N-CDase, two key enzymes for hydrolysis of sphingomyelin in the gut. We speculate that the sphingomyelin hydrolysis in cholestatic conditions is impaired not only by reduced hydrolytic activity but also by deficient dissociation of the enzymes from the membrane.
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Affiliation(s)
- R D Duan
- Gastroenterology Lab., Biomedical Center, B11, Lund University, S-221 84 Lund, Sweden.
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German JB, Dillard CJ. Composition, structure and absorption of milk lipids: a source of energy, fat-soluble nutrients and bioactive molecules. Crit Rev Food Sci Nutr 2006; 46:57-92. [PMID: 16403683 DOI: 10.1080/10408690590957098] [Citation(s) in RCA: 176] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Milkfat is a remarkable source of energy, fat-soluble nutrients and bioactive lipids for mammals. The composition and content of lipids in milkfat vary widely among mammalian species. Milkfat is not only a source of bioactive lipid components, it also serves as an important delivery medium for nutrients, including the fat-soluble vitamins. Bioactive lipids in milk include triacylglycerides, diacylglycerides, saturated and polyunsaturated fatty acids, and phospholipids. Beneficial activities of milk lipids include anticancer, antimicrobial, anti-inflammatory, and immunosuppression properties. The major mammalian milk that is consumed by humans as a food commodity is that from bovine whose milkfat composition is distinct due to their diet and the presence of a rumen. As a result of these factors bovine milkfat is lower in polyunsaturated fatty acids and higher in saturated fatty acids than human milk, and the consequences of these differences are still being researched. The physical properties of bovine milkfat that result from its composition including its plasticity, make it a highly desirable commodity (butter) and food ingredient. Among the 12 major milk fatty acids, only three (lauric, myristic, and palmitic) have been associated with raising total cholesterol levels in plasma, but their individual effects are variable-both towards raising low-density lipoproteins and raising the level of beneficial high-density lipoproteins. The cholesterol-modifying response of individuals to consuming saturated fats is also variable, and therefore the composition, functions and biological properties of milkfat will need to be re-evaluated as the food marketplace moves increasingly towards more personalized diets.
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Affiliation(s)
- J Bruce German
- Department of Food Science and Technology, University of California, Davis, CA, 95616, USA.
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Wu J, Nilsson Å, Jönsson B, Stenstad H, Agace W, Cheng Y, Duan RD. Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity. Biochem J 2006; 394:299-308. [PMID: 16255717 PMCID: PMC1386028 DOI: 10.1042/bj20051121] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Alkaline sphingomyelinase (alk-SMase) is a new member of the NPP (nucleotide pyrophosphatase/phosphodiesterase) family that hydrolyses SM (sphingomyelin) to generate ceramide in the intestinal tract. The enzyme may protect the intestinal mucosa from inflammation and tumorigenesis. PAF (platelet-activating factor) is a pro-inflammatory phospholipid involved in pathogenesis of inflammatory bowel diseases. We examined whether alk-SMase can hydrolyse and inactivate PAF. [3H]Octadecyl-labelled PAF was incubated with purified rat intestinal alk-SMase or recombinant human alk-SMase expressed in COS-7 cells. The hydrolytic products were assayed with TLC and MS. We found that alkSMase cleaved the phosphocholine head group from PAF and generated 1-O-alkyl-2-acetyl-sn-glycerol. Differing from the activity against SM, the activity against PAF was optimal at pH 7.5, inhibited by EDTA and stimulated by 0.1-0.25 mM Zn2+. The activity was abolished by site mutation of the predicted metal-binding sites that are conserved in all NPP members. Similar to the activity against SM, the activity against PAF was dependent on bile salt, particularly taurocholate and taurochenodeoxycholate. The V(max) for PAF hydrolysis was 374 mumol x h(-1) x (mg of protein)(-1). The hydrolysis of PAF and SM could be inhibited by the presence of SM and PAF respectively, the inhibition of PAF hydrolysis by SM being stronger. The PAF-induced MAPK (mitogen-activated protein kinase) activation and IL-8 (interleukin 8) release in HT-29 cells, and chemotaxis in leucocytes were abolished by alk-SMase treatment. In conclusion, alk-SMase hydrolyses and inactivates PAF by a phospholipase C activity. The finding reveals a novel function, by which alk-SMase may counteract the development of intestinal inflammation and colon cancer.
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Affiliation(s)
- Jun Wu
- *Gastroenterology Laboratory, Biomedical Centre, B11, Lund University, S-221 84 Lund, Sweden
| | - Åke Nilsson
- *Gastroenterology Laboratory, Biomedical Centre, B11, Lund University, S-221 84 Lund, Sweden
| | - Bo A. G. Jönsson
- †Department of Occupational and Environment Medicine, Institute of Laboratory Medicine, University Hospital, S-221 85 Lund, Sweden
| | - Hanna Stenstad
- ‡Immunology Unit, Lund University, S-221 84 Lund, Sweden
| | - William Agace
- ‡Immunology Unit, Lund University, S-221 84 Lund, Sweden
| | - Yajun Cheng
- *Gastroenterology Laboratory, Biomedical Centre, B11, Lund University, S-221 84 Lund, Sweden
| | - Rui-Dong Duan
- *Gastroenterology Laboratory, Biomedical Centre, B11, Lund University, S-221 84 Lund, Sweden
- To whom correspondence should be addressed (email )
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Ursolic acid and other pentacyclic triterpenoids stimulate intestinal alkaline sphingomyelinasein vitro. EUR J LIPID SCI TECH 2006. [DOI: 10.1002/ejlt.200500268] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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