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Imam I, Rautureau GJP, Violot S, Mulard ED, Magne D, Ballut L. Structural and Functional Integration of Tissue-Nonspecific Alkaline Phosphatase Within the Alkaline Phosphatase Superfamily: Evolutionary Insights and Functional Implications. Metabolites 2024; 14:659. [PMID: 39728440 PMCID: PMC11677397 DOI: 10.3390/metabo14120659] [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: 09/26/2024] [Revised: 11/08/2024] [Accepted: 11/19/2024] [Indexed: 12/28/2024] Open
Abstract
Phosphatases are enzymes that catalyze the hydrolysis of phosphate esters. They play critical roles in diverse biological processes such as extracellular nucleotide homeostasis, transport of molecules across membranes, intracellular signaling pathways, or vertebrate mineralization. Among them, tissue-nonspecific alkaline phosphatase (TNAP) is today increasingly studied, due to its ubiquitous expression and its ability to dephosphorylate a very broad range of substrates and participate in several different biological functions. For instance, TNAP hydrolyzes inorganic pyrophosphate (PPi) to allow skeletal and dental mineralization. Additionally, TNAP hydrolyzes pyridoxal phosphate to allow cellular pyridoxal uptake, and stimulate vitamin B6-dependent reactions. Furthermore, TNAP has been identified as a key enzyme in non-shivering adaptive thermogenesis, by dephosphorylating phosphocreatine in the mitochondrial creatine futile cycle. This latter recent discovery and others suggest that the list of substrates and functions of TNAP may be much longer than previously thought. In the present review, we sought to examine TNAP within the alkaline phosphatase (AP) superfamily, comparing its sequence, structure, and evolutionary trajectory. The AP superfamily, characterized by a conserved central folding motif of a mixed beta-sheet flanked by alpha-helices, includes six subfamilies: AP, arylsulfatases (ARS), ectonucleotide pyrophosphatases/phosphodiesterases (ENPP), phosphoglycerate mutases (PGM), phosphonoacetate hydrolases, and phosphopentomutases. Interestingly, TNAP and several ENPP family members appear to participate in the same metabolic pathways and functions. For instance, extra-skeletal mineralization in vertebrates is inhibited by ENPP1-mediated ATP hydrolysis into the mineralization inhibitor PPi, which is hydrolyzed by TNAP expressed in the skeleton. Better understanding how TNAP and other AP family members differ structurally will be very useful to clarify their complementary functions. Structurally, TNAP shares the conserved catalytic core with other AP superfamily members but has unique features affecting substrate specificity and activity. The review also aims to highlight the importance of oligomerization in enzyme stability and function, and the role of conserved metal ion coordination, particularly magnesium, in APs. By exploring the structural and functional diversity within the AP superfamily, and discussing to which extent its members exert redundant, complementary, or specific functions, this review illuminates the evolutionary pressures shaping these enzymes and their broad physiological roles, offering insights into TNAP's multifunctionality and its implications for health and disease.
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Affiliation(s)
- Iliass Imam
- Molecular Microbiology and Structural Biochemistry, UMR 5086, CNRS, University Lyon, F-69367 Lyon, France; (I.I.); (S.V.)
| | - Gilles Jean Philippe Rautureau
- Institute of Chemistry and Biochemistry (ICBMS), UMR 5246, CNRS, University Lyon, F-69622 Villeurbanne, France; (G.J.P.R.); (E.D.M.)
| | - Sébastien Violot
- Molecular Microbiology and Structural Biochemistry, UMR 5086, CNRS, University Lyon, F-69367 Lyon, France; (I.I.); (S.V.)
| | - Eva Drevet Mulard
- Institute of Chemistry and Biochemistry (ICBMS), UMR 5246, CNRS, University Lyon, F-69622 Villeurbanne, France; (G.J.P.R.); (E.D.M.)
| | - David Magne
- Institute of Chemistry and Biochemistry (ICBMS), UMR 5246, CNRS, University Lyon, F-69622 Villeurbanne, France; (G.J.P.R.); (E.D.M.)
| | - Lionel Ballut
- Molecular Microbiology and Structural Biochemistry, UMR 5086, CNRS, University Lyon, F-69367 Lyon, France; (I.I.); (S.V.)
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He J, Wang D, Guo K, Ji R. Camel milk polar lipids ameliorate dextran sulfate sodium-induced colitis in mice by modulating the gut microbiota. J Dairy Sci 2024; 107:6413-6424. [PMID: 38369112 DOI: 10.3168/jds.2023-23930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 01/17/2024] [Indexed: 02/20/2024]
Abstract
Milk contains abundant polar lipids, which are vital constituents of biological membranes. These polar lipids are present in the human diet as phospholipids and sphingolipids. Nevertheless, the limited focus has been on the attributes and role of camel milk polar lipids (MPL). In this study, camel MPL were isolated, and the composition of their lipidome was determined using ultra-high-performance liquid chromatography-tandem MS. This study characterized a total of 333 polar lipids, which encompassed glycerophospholipids and sphingolipids. Camel milk is rich in polar lipids, mainly phosphatidylethanolamine, sphingomyelin, and phosphatidylcholine. The results indicated that MPL intervention relieved the clinical symptoms and colon tissue damage in mice with dextran sulfate sodium-induced colitis, along with suppressing the expression of proinflammatory cytokines. Moreover, the administration of MPL partially alleviated mouse gut microbiota dysbiosis by increasing the abundance of probiotics (such as Lachnospiraceae_NK4A136_group and Muribaculaceae) and decreasing the number of harmful bacteria (such as Bacteroides and Parabacteroides). This study was conducted to investigate the potent protective effects of MPL in camel milk treatments on a mouse model of colitis and provided new ideas for the application of camel milk.
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Affiliation(s)
- Jing He
- College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010010, China; China-Mongolia Joint Laboratory of Biopolymer Application "One Belt One Road," Hohhot 010018, China
| | - DanLin Wang
- College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010010, China
| | - Kunjie Guo
- College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010010, China
| | - Rimutu Ji
- College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010010, China; China-Mongolia Joint Laboratory of Biopolymer Application "One Belt One Road," Hohhot 010018, China.
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Briand-Mésange F, Gennero I, Salles J, Trudel S, Dahan L, Ausseil J, Payrastre B, Salles JP, Chap H. From Classical to Alternative Pathways of 2-Arachidonoylglycerol Synthesis: AlterAGs at the Crossroad of Endocannabinoid and Lysophospholipid Signaling. Molecules 2024; 29:3694. [PMID: 39125098 PMCID: PMC11314389 DOI: 10.3390/molecules29153694] [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: 06/21/2024] [Revised: 07/27/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cβ1 (PLCβ1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6-7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders.
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Affiliation(s)
- Fabienne Briand-Mésange
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
| | - Isabelle Gennero
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Service de Biochimie, Institut Fédératif de Biologie, 31059 Toulouse, France
| | - Juliette Salles
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Service de Psychiatrie D’urgences, de Crise et de Liaison, Institut des Handicaps Neurologiques, Psychiatriques et Sensoriels, 31059 Toulouse, France
| | - Stéphanie Trudel
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Service de Biochimie, Institut Fédératif de Biologie, 31059 Toulouse, France
| | - Lionel Dahan
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France;
| | - Jérôme Ausseil
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Service de Biochimie, Institut Fédératif de Biologie, 31059 Toulouse, France
| | - Bernard Payrastre
- I2MC-Institute of Metabolic and Cardiovascular Diseases, INSERM UMR1297 and University of Toulouse III, 31400 Toulouse, France;
- Centre Hospitalier Universitaire de Toulouse, Laboratoire d’Hématologie, 31400 Toulouse, France
| | - Jean-Pierre Salles
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Centre Hospitalier Universitaire de Toulouse, Unité d’Endocrinologie et Maladies Osseuses, Hôpital des Enfants, 31059 Toulouse, France
| | - Hugues Chap
- Infinity-Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, INSERM, CNRS, Paul Sabatier University, 31059 Toulouse, France; (F.B.-M.); (I.G.); (J.S.); (S.T.); (J.A.); (J.-P.S.)
- Académie des Sciences, Inscriptions et Belles Lettres de Toulouse, Hôtel d’Assézat, 31000 Toulouse, France
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Sprenger RR, Bilgin M, Ostenfeld MS, Bjørnshave A, Rasmussen JT, Ejsing CS. Dietary intake of a MFGM/EV-rich concentrate promotes accretion of very long odd-chain sphingolipids and increases lipid metabolic turnover at the whole-body level. Food Res Int 2024; 190:114601. [PMID: 38945615 DOI: 10.1016/j.foodres.2024.114601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/28/2024] [Accepted: 06/03/2024] [Indexed: 07/02/2024]
Abstract
Lipids from cow milk fat globule membranes (MFGMs) and extracellular vesicles (EVs) are considered beneficial for neurodevelopment, cognitive maintenance and human health in general. Nevertheless, it is largely unknown whether intake of infant formulas and medical nutrition products rich in these particles promote accretion of specific lipids and whether this affects metabolic homeostasis. To address this, we carried out a 16-week dietary intervention study where mice were supplemented with a MFGM/EV-rich concentrate, a control diet supplemented with a whey protein concentrate and devoid of milk lipids, or regular chow. Assessment of commonly used markers of metabolic health, including body weight, glucose intolerance and liver microanatomy, demonstrated no differences across the dietary regimes. In contrast, in-depth lipidomic analysis revealed accretion of milk-derived very long odd-chain sphingomyelins and ceramides in blood plasma and multiple tissues of mice fed the MFGM/EV diet. Furthermore, lipidomic flux analysis uncovered that mice fed the MFGM/EV diet have increased lipid metabolic turnover at the whole-body level. These findings help fill a long-lasting knowledge gap between the intake of MFGM/EV-containing foods and the health-promoting effects of their lipid constituents. In addition, the findings suggest that dietary sphingomyelins or ceramide-breakdown products with very long-chains can be used as structural components of cellular membranes, lipoprotein particles and signaling molecules that modulate metabolic homeostasis and health.
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Affiliation(s)
- Richard R Sprenger
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark
| | - Mesut Bilgin
- Lipidomics Core Facility, Danish Cancer Institute, Copenhagen, Denmark
| | | | | | - Jan T Rasmussen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Christer S Ejsing
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Tian Y, Li X, Wang X, Pei ST, Pan HX, Cheng YQ, Li YC, Cao WT, Petersen JDD, Zhang P. Alkaline sphingomyelinase deficiency impairs intestinal mucosal barrier integrity and reduces antioxidant capacity in dextran sulfate sodium-induced colitis. World J Gastroenterol 2024; 30:1405-1419. [PMID: 38596488 PMCID: PMC11000083 DOI: 10.3748/wjg.v30.i10.1405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/26/2023] [Accepted: 01/29/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Ulcerative colitis is a chronic inflammatory disease of the colon with an unknown etiology. Alkaline sphingomyelinase (alk-SMase) is specifically expressed by intestinal epithelial cells, and has been reported to play an anti-inflammatory role. However, the underlying mechanism is still unclear. AIM To explore the mechanism of alk-SMase anti-inflammatory effects on intestinal barrier function and oxidative stress in dextran sulfate sodium (DSS)-induced colitis. METHODS Mice were administered 3% DSS drinking water, and disease activity index was determined to evaluate the status of colitis. Intestinal permeability was evaluated by gavage administration of fluorescein isothiocyanate dextran, and bacterial translocation was evaluated by measuring serum lipopolysaccharide. Intestinal epithelial cell ultrastructure was observed by electron microscopy. Western blotting and quantitative real-time reverse transcription-polymerase chain reaction were used to detect the expression of intestinal barrier proteins and mRNA, respectively. Serum oxidant and antioxidant marker levels were analyzed using commercial kits to assess oxidative stress levels. RESULTS Compared to wild-type (WT) mice, inflammation and intestinal permeability in alk-SMase knockout (KO) mice were more severe beginning 4 d after DSS induction. The mRNA and protein levels of intestinal barrier proteins, including zonula occludens-1, occludin, claudin-3, claudin-5, claudin-8, mucin 2, and secretory immunoglobulin A, were significantly reduced on 4 d after DSS treatment. Ultrastructural observations revealed progressive damage to the tight junctions of intestinal epithelial cells. Furthermore, by day 4, mitochondria appeared swollen and degenerated. Additionally, compared to WT mice, serum malondialdehyde levels in KO mice were higher, and the antioxidant capacity was significantly lower. The expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in the colonic mucosal tissue of KO mice was significantly decreased after DSS treatment. mRNA levels of Nrf2-regulated downstream antioxidant enzymes were also decreased. Finally, colitis in KO mice could be effectively relieved by the injection of tertiary butylhydroquinone, which is an Nrf2 activator. CONCLUSION Alk-SMase regulates the stability of the intestinal mucosal barrier and enhances antioxidant activity through the Nrf2 signaling pathway.
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Affiliation(s)
- Ye Tian
- International School of Public Health and One Health, Hainan Medical University, Haikou 571199, Hainan Province, China
| | - Xin Li
- Medical Laboratory Science and Technology College, Harbin Medical University - Daqing Campus, Daqing 163000, Heilongjiang Province, China
| | - Xu Wang
- Department of Laboratory Diagnosis, Qiqihar Tuberculosis Control Center, Qiqihar 161000, Heilongjiang Province, China
| | - Si-Ting Pei
- International School of Public Health and One Health, Hainan Medical University, Haikou 571199, Hainan Province, China
| | - Hong-Xin Pan
- International School of Public Health and One Health, Hainan Medical University, Haikou 571199, Hainan Province, China
| | - Yu-Qi Cheng
- Medical Laboratory Science and Technology College, Harbin Medical University - Daqing Campus, Daqing 163000, Heilongjiang Province, China
| | - Yi-Chen Li
- Medical Laboratory Science and Technology College, Harbin Medical University - Daqing Campus, Daqing 163000, Heilongjiang Province, China
| | - Wen-Ting Cao
- International School of Public Health and One Health, Hainan Medical University, Haikou 571199, Hainan Province, China
| | - Jin-Dong Ding Petersen
- International School of Public Health and One Health, Hainan Medical University, Haikou 571199, Hainan Province, China
- Department of Public Health, University of Copenhagen, Copenhagen 1353, Denmark
- Department of Public Health, University of Southern Denmark, Odense 5000, Denmark
| | - Ping Zhang
- International School of Public Health and One Health, Hainan Medical University, Haikou 571199, Hainan Province, China
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Alyamani M, Kadivar M, Erjefält J, Johansson-Lindbom B, Duan RD, Nilsson Å, Marsal J. Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations. Front Immunol 2023; 13:1050625. [PMID: 36741374 PMCID: PMC9894718 DOI: 10.3389/fimmu.2022.1050625] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/21/2022] [Indexed: 01/21/2023] Open
Abstract
Background and aim Alkaline sphingomyelinase (NPP7) is expressed by intestinal epithelial cells and is crucial for the digestion of dietary sphingomyelin. NPP7 also inactivates proinflammatory mediators including platelet-activating factor and lysophosphatidylcholine. The aim of this study was to examine a potential role for NPP7 in the homeostasis of the intestinal immune system. Methods We quantified the numbers of B-lymphocytes, plasma cells, T-lymphocytes including regulatory T-lymphocytes (Tregs), natural killer cells, dendritic cells, macrophages, and neutrophils, in the small and large intestines, the mesenteric lymph nodes and the spleens of heterozygous and homozygous NPP7 knockout (KO) and wildtype (WT) mice. Tissues were examined by immunohistochemistry and stainings quantified using computerized image analysis. Results The numbers of both small and large intestinal CD3ε+, CD4+, and CD8α+ T-lymphocytes were significantly higher in NPP7 KO compared to WT mice (with a dose-response relationship in the large intestine), whereas Treg numbers were unchanged, and dendritic cell numbers reduced. In contrast, the numbers of CD3ε+ and CD4+ T-lymphocytes in mesenteric lymph nodes were significantly reduced in NPP7 KO mice, while no differences were observed in spleens. The numbers of B-lymphocytes, plasma cells, natural killer cells, macrophages, and neutrophils were similar between genotypes. Conclusion NPP7 contributes to the regulation of dendritic cell and T-lymphocyte numbers in mesenteric lymph nodes and both the small and large intestines, thus playing a role in the homeostasis of gut immunity. Although it is likely that the downstream effects of NPP7 activity involve the sphingomyelin metabolites ceramide and spingosine-1-phosphate, the exact mechanisms behind this regulatory function of NPP7 need to be addressed in future studies.
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Affiliation(s)
- Manar Alyamani
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden,Unit of Airway Inflammation, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Mohammad Kadivar
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden,Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
| | - Jonas Erjefält
- Unit of Airway Inflammation, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Bengt Johansson-Lindbom
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Rui-Dong Duan
- Section of Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Åke Nilsson
- Section of Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden,Department of Gastroenterology, Skane University Hospital, Lund/Malmö, Sweden
| | - Jan Marsal
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden,Section of Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden,Department of Gastroenterology, Skane University Hospital, Lund/Malmö, Sweden,*Correspondence: Jan Marsal,
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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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Raza Y, Atallah J, Luberto C. Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies. Int J Mol Sci 2022; 23:12745. [PMID: 36361536 PMCID: PMC9654982 DOI: 10.3390/ijms232112745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/07/2022] [Accepted: 10/17/2022] [Indexed: 09/19/2023] Open
Abstract
Dysregulation of sphingolipid metabolism plays a complex role in hematological malignancies, beginning with the first historical link between sphingolipids and apoptosis discovered in HL-60 leukemic cells. Numerous manuscripts have reviewed the field including the early discoveries that jumpstarted the studies. Many studies discussed here support a role for sphingolipids, such as ceramide, in combinatorial therapeutic regimens to enhance anti-leukemic effects and reduce resistance to standard therapies. Additionally, inhibitors of specific nodes of the sphingolipid pathway, such as sphingosine kinase inhibitors, significantly reduce leukemic cell survival in various types of leukemias. Acid ceramidase inhibitors have also shown promising results in acute myeloid leukemia. As the field moves rapidly, here we aim to expand the body of literature discussed in previously published reviews by focusing on advances reported in the latter part of the last decade.
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Affiliation(s)
- Yasharah Raza
- Department of Pharmacological Sciences, Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, NY 11794, USA
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
| | - Jane Atallah
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
| | - Chiara Luberto
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
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The unfolding role of ceramide in coordinating retinoid-based cancer therapy. Biochem J 2021; 478:3621-3642. [PMID: 34648006 DOI: 10.1042/bcj20210368] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/30/2022]
Abstract
Sphingolipid-mediated regulation in cancer development and treatment is largely ceramide-centered with the complex sphingolipid metabolic pathways unfolding as attractive targets for anticancer drug discovery. The dynamic interconversion of sphingolipids is tightly controlled at the level of enzymes and cellular compartments in response to endogenous or exogenous stimuli, such as anticancer drugs, including retinoids. Over the past two decades, evidence emerged that retinoids owe part of their potency in cancer therapy to modulation of sphingolipid metabolism and ceramide generation. Ceramide has been proposed as a 'tumor-suppressor lipid' that orchestrates cell growth, cell cycle arrest, cell death, senescence, autophagy, and metastasis. There is accumulating evidence that cancer development is promoted by the dysregulation of tumor-promoting sphingolipids whereas cancer treatments can kill tumor cells by inducing the accumulation of endogenous ceramide levels. Resistance to cancer therapy may develop due to a disrupted equilibrium between the opposing roles of tumor-suppressor and tumor-promoter sphingolipids. Despite the undulating effect and complexity of sphingolipid pathways, there are emerging opportunities for a plethora of enzyme-targeted therapeutic interventions that overcome resistance resulting from perturbed sphingolipid pathways. Here, we have revisited the interconnectivity of sphingolipid metabolism and the instrumental role of ceramide-biosynthetic and degradative enzymes, including bioactive sphingolipid products, how they closely relate to cancer treatment and pathogenesis, and the interplay with retinoid signaling in cancer. We focused on retinoid targeting, alone or in combination, of sphingolipid metabolism nodes in cancer to enhance ceramide-based therapeutics. Retinoid and ceramide-based cancer therapy using novel strategies such as combination treatments, synthetic retinoids, ceramide modulators, and delivery formulations hold promise in the battle against cancer.
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Goh YQ, Cheam G, Wang Y. Understanding Choline Bioavailability and Utilization: First Step Toward Personalizing Choline Nutrition. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:10774-10789. [PMID: 34392687 DOI: 10.1021/acs.jafc.1c03077] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Choline is an essential macronutrient involved in neurotransmitter synthesis, cell-membrane signaling, lipid transport, and methyl-group metabolism. Nevertheless, the vast majority are not meeting the recommended intake requirement. Choline deficiency is linked to nonalcoholic fatty liver disease, skeletal muscle atrophy, and neurodegenerative diseases. The conversion of dietary choline to trimethylamine by gut microbiota is known for its association with atherosclerosis and may contribute to choline deficiency. Choline-utilizing bacteria constitutes less than 1% of the gut community and is modulated by lifestyle interventions such as dietary patterns, antibiotics, and probiotics. In addition, choline utilization is also affected by genetic factors, further complicating the impact of choline on health. This review overviews the complex interplay between dietary intakes of choline, gut microbiota and genetic factors, and the subsequent impact on health. Understanding of gut microbiota metabolism of choline substrates and interindividual variability is warranted in the development of personalized choline nutrition.
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Affiliation(s)
- Ying Qi Goh
- Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921
| | - Guoxiang Cheam
- School of Biological Sciences, Nanyang Technological University, Singapore 639798
| | - Yulan Wang
- Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921
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11
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Nilsson Å, Duan RD, Ohlsson L. Digestion and Absorption of Milk Phospholipids in Newborns and Adults. Front Nutr 2021; 8:724006. [PMID: 34490332 PMCID: PMC8417471 DOI: 10.3389/fnut.2021.724006] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 07/19/2021] [Indexed: 12/25/2022] Open
Abstract
Milk polar lipids provide choline, ethanolamine, and polyunsaturated fatty acids, which are needed for the growth and plasticity of the tissues in a suckling child. They may also inhibit cholesterol absorption by interacting with cholesterol during micelle formation. They may also have beneficial luminal, mucosal, and metabolic effects in both the neonate and the adult. The milk fat globule membrane contains large proportions of sphingomyelin (SM), phosphatidylcholine (PC), and phosphatidylethanolamine (PE), and some phosphatidylserine (PS), phosphatidylinositol (PI), and glycosphingolipids. Large-scale technical procedures are available for the enrichment of milk fat globule membrane (MFGM) in milk replacement formulations and food additives. Pancreatic phospholipase A2 (PLA2) and mucosal phospholipase B digest glycero-phospholipids in the adult. In the neonate, where these enzymes may be poorly expressed, pancreatic lipase-related protein 2 probably has a more important role. Mucosal alkaline SM-ase and ceramidase catalyze the digestion of SM in both the neonate and the adult. In the mucosa, the sphingosine is converted into sphingosine-1-phosphate, which is both an intermediate in the conversion to palmitic acid and a signaling molecule. This reaction sequence also generates ethanolamine. Here, we summarize the pathways by which digestion and absorption may be linked to the biological effects of milk polar lipids. In addition to the inhibition of cholesterol absorption and the generation of lipid signals in the gut, the utilization of absorbed choline and ethanolamine for mucosal and hepatic phospholipid synthesis and the acylation of absorbed lyso-PC with polyunsaturated fatty acids to chylomicron and mucosal phospholipids are important.
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Affiliation(s)
- Åke Nilsson
- Division of Medicine, Gastroenterology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Rui-Dong Duan
- Gastroenterology and Nutrition Laboratory, Division of Medicine, Department of Clinical Science, Lund University, Lund, Sweden
| | - Lena Ohlsson
- Division of Medicine, Experimental Vascular Medicine, Department of Clinical Science, Lund University, Lund, Sweden
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12
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Rohrhofer J, Zwirzitz B, Selberherr E, Untersmayr E. The Impact of Dietary Sphingolipids on Intestinal Microbiota and Gastrointestinal Immune Homeostasis. Front Immunol 2021; 12:635704. [PMID: 34054805 PMCID: PMC8160510 DOI: 10.3389/fimmu.2021.635704] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 04/23/2021] [Indexed: 12/12/2022] Open
Abstract
The large surfaces of gastrointestinal (GI) organs are well adapted to their diverse tasks of selective nutritional uptake and defense against the external environment. To maintain a functional balance, a vast number of immune cells is located within the mucosa. A strictly regulated immune response is required to impede constant inflammation and to maintain barrier function. An increasing prevalence of GI diseases has been reported in Western societies over the past decades. This surge in GI disorders has been linked to dietary changes followed by an imbalance of the gut microbiome, leading to a chronic, low grade inflammation of the gut epithelium. To counteract the increasing health care costs associated with diseases, it is paramount to understand the mechanisms driving immuno-nutrition, the associations between nutritional compounds, the commensal gut microbiota, and the host immune response. Dietary compounds such as lipids, play a central role in GI barrier function. Bioactive sphingolipids (SLs), e.g. sphingomyelin (SM), sphingosine (Sph), ceramide (Cer), sphingosine-1- phosphate (S1P) and ceramide-1-phosphate (C1P) may derive from dietary SLs ingested through the diet. They are not only integral components of cell membranes, they additionally modulate cell trafficking and are precursors for mediators and second messenger molecules. By regulating intracellular calcium levels, cell motility, cell proliferation and apoptosis, SL metabolites have been described to influence GI immune homeostasis positively and detrimentally. Furthermore, dietary SLs are suggested to induce a shift in the gut microbiota. Modes of action range from competing with the commensal bacteria for intestinal cell attachment to prevention from pathogen invasion by regulating innate and immediate defense mechanisms. SL metabolites can also be produced by gut microorganisms, directly impacting host metabolic pathways. This review aims to summarize recent findings on SL signaling and functional variations of dietary SLs. We highlight novel insights in SL homeostasis and SL impact on GI barrier function, which is directly linked to changes of the intestinal microbiota. Knowledge gaps in current literature will be discussed to address questions relevant for understanding the pivotal role of dietary SLs on chronic, low grade inflammation and to define a balanced and healthy diet for disease prevention and treatment.
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Affiliation(s)
- Johanna Rohrhofer
- Gastrointestinal Immunology Group, Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Benjamin Zwirzitz
- Unit of Food Microbiology, Institute of Food Safety, Food Technology and Veterinary Public Health, University of Veterinary Medicine, Vienna, Austria
| | - Evelyne Selberherr
- Unit of Food Microbiology, Institute of Food Safety, Food Technology and Veterinary Public Health, University of Veterinary Medicine, Vienna, Austria
| | - Eva Untersmayr
- Gastrointestinal Immunology Group, Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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13
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Anto L, Warykas SW, Torres-Gonzalez M, Blesso CN. Milk Polar Lipids: Underappreciated Lipids with Emerging Health Benefits. Nutrients 2020; 12:E1001. [PMID: 32260440 PMCID: PMC7230917 DOI: 10.3390/nu12041001] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/01/2020] [Accepted: 04/02/2020] [Indexed: 12/24/2022] Open
Abstract
Milk fat is encased in a polar lipid-containing tri-layer milk fat globule membrane (MFGM), composed of phospholipids (PLs) and sphingolipids (SLs). Milk PLs and SLs comprise about 1% of total milk lipids. The surfactant properties of PLs are important for dairy products; however, dairy products vary considerably in their polar lipid to total lipid content due to the existence of dairy foods with different fat content. Recent basic science and clinical research examining food sources and health effects of milk polar lipids suggest they may beneficially influence dysfunctional lipid metabolism, gut dysbiosis, inflammation, cardiovascular disease, gut health, and neurodevelopment. However, more research is warranted in clinical studies to confirm these effects in humans. Overall, there are a number of potential effects of consuming milk polar lipids, and they should be considered as food matrix factors that may directly confer health benefits and/or impact effects of other dietary lipids, with implications for full-fat vs. reduced-fat dairy.
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Affiliation(s)
- Liya Anto
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; (L.A.); (S.W.W.)
| | - Sarah Wen Warykas
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; (L.A.); (S.W.W.)
| | | | - Christopher N. Blesso
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; (L.A.); (S.W.W.)
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14
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Hasi RY, Miyagi M, Kida T, Fukuta T, Kogure K, Hayashi J, Kawakami R, Kanemaru K, Tanaka T. Quantitative Analysis of Glycosylinositol Phosphoceramide and Phytoceramide 1-Phosphate in Vegetables. J Nutr Sci Vitaminol (Tokyo) 2020; 65:S175-S179. [PMID: 31619623 DOI: 10.3177/jnsv.65.s175] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Previously, we found an unidentified sphingolipid in cabbage, and determined it as phytoceramide 1-phosphate (PC1P). PC1P is found to be produced from glycosylinositol phosphoceramide (GIPC) by the action of phospholipase D (PLD) activity. Although GIPC is abundant sphingolipid, especially in cruciferous vegetables, amount of daily intake, digestibility and nutritional activity of GIPC are not well understood. Here, we investigated amounts of GIPC and PC1P in vegetables. GIPC was found in all vegetables examined (13 kinds) at levels 3-20 mg/100 g (wet weight). On the other hand, PC1P was present in limited vegetables which show higher GIPC-PLD activity, such as inner cabbage leaves (5.2 mg/100 g). Because PC1P is formed during homogenization by activated GIPC-PLD, level of PC1P in boiled cabbage leaves was very low. Although digestibility of GIPC is unknown at present, a portion of dietary GIPC is considered to be converted to PC1P during mastication by plant-derived GIPC-PLD activity in some vegetables.
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Affiliation(s)
| | - Makoto Miyagi
- Graduate School of Biomedical Sciences, Tokushima University
| | - Takashi Kida
- Graduate School of Biomedical Sciences, Tokushima University
| | - Tatsuya Fukuta
- Graduate School of Biomedical Sciences, Tokushima University
| | - Kentaro Kogure
- Graduate School of Biomedical Sciences, Tokushima University
| | - Junji Hayashi
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University
| | - Ryushi Kawakami
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University
| | - Kaori Kanemaru
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University
| | - Tamotsu Tanaka
- Graduate School of Biomedical Sciences, Tokushima University.,Graduate School of Technology, Industrial and Social Sciences, Tokushima University
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15
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García-Cano I, Rocha-Mendoza D, Kosmerl E, Jiménez-Flores R. Purification and characterization of a phospholipid-hydrolyzing phosphoesterase produced by Pediococcus acidilactici isolated from Gouda cheese. J Dairy Sci 2020; 103:3912-3923. [PMID: 32147264 DOI: 10.3168/jds.2019-17965] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/08/2020] [Indexed: 02/01/2023]
Abstract
Lipolysis occurs during ripening of dairy products as a result of esterase or lipase activity. Lactic acid bacteria (LAB) are considered to be weakly lipolytic bacteria compared with other species. In cheeses with extended ripening periods, lipolytic LAB may have several advantages. Pediococcus acidilactici is a LAB frequently found in fermented dairy products, but no previous reports exist on their production of esterases or lipases. Our interest in the relationship of LAB and enzymatic characterization is due to the multiple reports of the benefits of LAB in the gut microbiome, particularly at the intestinal membrane. Pediococci have been characterized as probiotic and especially active in membrane interactions. The aim of this project was to purify, characterize, and identify the phosphoesterase produced by P. acidilactici originally isolated from Gouda cheese and determine its phospholipid (PL) hydrolysis profile, with a focus on increased absorption of these compounds in the human gut. Native zymograms were performed to identify a protein with lipolytic activity in the intracellular fraction of P. acidilactici. The enzyme was purified via size-exclusion HPLC, concentrated via ultrafiltration, and identified using sequence analysis in liquid chromatography (LC)-MS/MS. The purified fraction was subjected to biochemical characterization as a function of pH, temperature, ion concentration, hydrolysis of different substrates, and PL. A single protein with a molecular weight of 86 kDa and esterase activity was detected by zymography. Analysis of the LC-MS/MS results identified a putative metallophosphoesterase with a calculated molecular weight of 45.5 kDa, suggesting that this protein is active as a homodimer. The pure protein showed an optimal activity between pH 8.0 to 9.0. The optimal temperature for activity was 37°C, and the enzyme lost 15% of activity after incubation at 90°C for 1 h. This enzyme showed activity on short-chain fatty acids and exhibited high hydrolysis of phosphatidylinositol. It also hydrolyzed phosphatidylserine, phosphatidylcholine, and sphingomyelin. Phosphatidylethanolamine was hydrolyzed but with less efficiency. The characteristics and lipolytic actions exerted by this protein obtained from LAB hold promise for a potential strain of esterase or lipase that may exert human health benefits through increased digestibility and absorption of nutrients found in dairy products.
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Affiliation(s)
- Israel García-Cano
- Department of Food Science and Technology, The Ohio State University, Columbus 43210
| | - Diana Rocha-Mendoza
- Department of Food Science and Technology, The Ohio State University, Columbus 43210
| | - Erica Kosmerl
- Department of Food Science and Technology, The Ohio State University, Columbus 43210
| | - Rafael Jiménez-Flores
- Department of Food Science and Technology, The Ohio State University, Columbus 43210.
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16
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Bocheńska K, Gabig-Cimińska M. Unbalanced Sphingolipid Metabolism and Its Implications for the Pathogenesis of Psoriasis. Molecules 2020; 25:E1130. [PMID: 32138315 PMCID: PMC7179243 DOI: 10.3390/molecules25051130] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 02/26/2020] [Accepted: 02/29/2020] [Indexed: 02/06/2023] Open
Abstract
Sphingolipids (SLs), which have structural and biological responsibilities in the human epidermis, are importantly involved in the maintenance of the skin barrier and regulate cellular processes, such as the proliferation, differentiation and apoptosis of keratinocytes (KCs). As many dermatologic diseases, including psoriasis (PsO), intricately characterized by perturbations in these cellular processes, are associated with altered composition and unbalanced metabolism of epidermal SLs, more education to precisely determine the role of SLs, especially in the pathogenesis of skin disorders, is needed. PsO is caused by a complex interplay between skin barrier disruption, immune dysregulation, host genetics and environmental triggers. The contribution of particular cellular compartments and organelles in SL metabolism, a process related to dysfunction of lysosomes in PsO, seems to have a significant impact on lysosomal signalling linked to a modulation of the immune-mediated inflammation accompanying this dermatosis and is not fully understood. It is also worth noting that a prominent skin disorder, such as PsO, has diminished levels of the main epidermal SL ceramide (Cer), reflecting altered SL metabolism, that may contribute not only to pathogenesis but also to disease severity and/or progression. This review provides a brief synopsis of the implications of SLs in PsO, aims to elucidate the roles of these molecules in complex cellular processes deregulated in diseased skin tissue and highlights the need for increased research in the field. The significance of SLs as structural and signalling molecules and their actions in inflammation, in which these components are factors responsible for vascular endothelium abnormalities in the development of PsO, are discussed.
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Affiliation(s)
- Katarzyna Bocheńska
- Department of Medical Biology and Genetics, University of Gdańsk, Wita Stwosza 59, 80–308 Gdańsk, Poland;
| | - Magdalena Gabig-Cimińska
- Department of Medical Biology and Genetics, University of Gdańsk, Wita Stwosza 59, 80–308 Gdańsk, Poland;
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Laboratory of Molecular Biology, Kładki 24, 80–822 Gdańsk, Poland
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17
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Ramiro-Cortijo D, Singh P, Liu Y, Medina-Morales E, Yakah W, Freedman SD, Martin CR. Breast Milk Lipids and Fatty Acids in Regulating Neonatal Intestinal Development and Protecting against Intestinal Injury. Nutrients 2020; 12:E534. [PMID: 32092925 PMCID: PMC7071444 DOI: 10.3390/nu12020534] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/14/2020] [Accepted: 02/16/2020] [Indexed: 12/13/2022] Open
Abstract
Human breast milk is the optimal source of nutrition for infant growth and development. Breast milk fats and their downstream derivatives of fatty acids and fatty acid-derived terminal mediators not only provide an energy source but also are important regulators of development, immune function, and metabolism. The composition of the lipids and fatty acids determines the nutritional and physicochemical properties of human milk fat. Essential fatty acids, including long-chain polyunsaturated fatty acids (LCPUFAs) and specialized pro-resolving mediators, are critical for growth, organogenesis, and regulation of inflammation. Combined data including in vitro, in vivo, and human cohort studies support the beneficial effects of human breast milk in intestinal development and in reducing the risk of intestinal injury. Human milk has been shown to reduce the occurrence of necrotizing enterocolitis (NEC), a common gastrointestinal disease in preterm infants. Preterm infants fed human breast milk are less likely to develop NEC compared to preterm infants receiving infant formula. Intestinal development and its physiological functions are highly adaptive to changes in nutritional status influencing the susceptibility towards intestinal injury in response to pathological challenges. In this review, we focus on lipids and fatty acids present in breast milk and their impact on neonatal gut development and the risk of disease.
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Affiliation(s)
- David Ramiro-Cortijo
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; (D.R.-C.); (P.S.); (Y.L.); (E.M.-M.); (S.D.F.)
| | - Pratibha Singh
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; (D.R.-C.); (P.S.); (Y.L.); (E.M.-M.); (S.D.F.)
| | - Yan Liu
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; (D.R.-C.); (P.S.); (Y.L.); (E.M.-M.); (S.D.F.)
| | - Esli Medina-Morales
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; (D.R.-C.); (P.S.); (Y.L.); (E.M.-M.); (S.D.F.)
| | - William Yakah
- Department of Neonatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA;
| | - Steven D. Freedman
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA; (D.R.-C.); (P.S.); (Y.L.); (E.M.-M.); (S.D.F.)
- Division of Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Camilia R. Martin
- Department of Neonatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA;
- Division of Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
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18
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Protective properties of milk sphingomyelin against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. J Nutr Biochem 2019; 73:108224. [DOI: 10.1016/j.jnutbio.2019.108224] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/25/2019] [Accepted: 07/31/2019] [Indexed: 12/20/2022]
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19
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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: 40] [Impact Index Per Article: 6.7] [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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20
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Zhang P, Chen Y, Zhang T, Zhu J, Zhao L, Li J, Wang G, Li Y, Xu S, Nilsson Å, Duan RD. Deficiency of alkaline SMase enhances dextran sulfate sodium-induced colitis in mice with upregulation of autotaxin. J Lipid Res 2018; 59:1841-1850. [PMID: 30087205 DOI: 10.1194/jlr.m084285] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 08/04/2018] [Indexed: 12/28/2022] Open
Abstract
Intestinal alkaline SMase (Alk-SMase) cleaves phosphocholine from SM, platelet-activating factor (PAF), and lysophosphatidylcholine. We recently found that colitis-associated colon cancer was 4- to 5-fold enhanced in Alk-SMase KO mice. Here, we further studied the pathogenesis of colitis induced by dextran sulfate sodium (DSS) in WT and KO mice. Compared with WT mice, KO mice demonstrated greater body weight loss, more severe bloody diarrhea, broader inflammatory cell infiltration, and more serious epithelial injury. Higher levels of PAF and lower levels of interleukin (IL)10 were identified in KO mice 2 days after DSS treatment. A greater and progressive increase of lysophosphatidic acid (LPA) was identified. The change was associated with increased autotaxin expression in both small intestine and colon, which was identified by immunohistochemistry study, Western blot, and sandwich ELISA. The upregulation of autotaxin coincided with an early increase of PAF. IL6 and TNFα were increased in both WT and KO mice. At the later stage (day 8), significant decreases in IL6, IL10, and PAF were identified, and the decreases were greater in KO mice. In conclusion, deficiency of Alk-SMase enhances DSS-induced colitis by mechanisms related to increased autotaxin expression and LPA formation. The early increase of PAF might be a trigger for such reactions.
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Affiliation(s)
- Ping Zhang
- Medical Laboratory Science and Technology College, Harbin Medical University, Daqing Campus, Daqing, China
| | - Ying Chen
- Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Tao Zhang
- Medical Laboratory Science and Technology College, Harbin Medical University, Daqing Campus, Daqing, China
| | - Jiang Zhu
- Medical Laboratory Science and Technology College, Harbin Medical University, Daqing Campus, Daqing, China
| | - Lei Zhao
- Medical Laboratory Science and Technology College, Harbin Medical University, Daqing Campus, Daqing, China
| | - Jianshuang Li
- Medical Laboratory Science and Technology College, Harbin Medical University, Daqing Campus, Daqing, China
| | - Guangzhi Wang
- Medical Laboratory Science and Technology College, Harbin Medical University, Daqing Campus, Daqing, China
| | - Yongchun Li
- Medical Laboratory Science and Technology College, Harbin Medical University, Daqing Campus, Daqing, China
| | - Shuchang Xu
- Department of Gastroenterology, Tongji Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Åke Nilsson
- Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Rui-Dong Duan
- Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences, Lund University, Lund, Sweden
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21
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Murthy AVR, Guyomarc'h F, Lopez C. Palmitoyl ceramide promotes milk sphingomyelin gel phase domains formation and affects the mechanical properties of the fluid phase in milk-SM/DOPC supported membranes. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2018; 1860:635-644. [DOI: 10.1016/j.bbamem.2017.12.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 12/06/2017] [Accepted: 12/07/2017] [Indexed: 01/08/2023]
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22
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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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Carlsson ER, Grundtvig JLG, Madsbad S, Fenger M. Changes in Serum Sphingomyelin After Roux-en-Y Gastric Bypass Surgery Are Related to Diabetes Status. Front Endocrinol (Lausanne) 2018; 9:172. [PMID: 29922223 PMCID: PMC5996901 DOI: 10.3389/fendo.2018.00172] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 04/03/2018] [Indexed: 12/19/2022] Open
Abstract
Metabolic surgery is superior to lifestyle intervention in reducing weight and lowering glycemia and recently suggested as treatment for type 2 diabetes mellitus. Especially Roux-en-Y gastric bypass (RYGB) has been focus for much research, but still the mechanisms of action are only partly elucidated. We suggest that several mechanisms might be mediated by sphingolipids like sphingomyelin. We measured serum sphingomyelin before and up to 2 years after RYGB surgery in 220 patients, divided before surgery in one non-diabetic subgroup and two diabetic subgroups, one of which contained patients obtaining remission of type 2 diabetes after RYGB, while patients in the other still had diabetes after RYGB. Pre- and postoperative sphingomyelin levels were compared within and between groups. Sphingomyelin levels were lower in diabetic patients than in non-diabetic patients before surgery. Following RYGB, mean sphingomyelin concentration fell significantly in the non-diabetic subgroup and the preoperative difference between patients with and without diabetes disappeared. Changes in diabetic subgroups were not significant. Relative to bodyweight, an increase in sphingomyelin was seen in all subgroups, irrespective of diabetes status. We conclude that RYGB has a strong influence on sphingomyelin metabolism, as seen reflected in changed serum levels. Most significantly, no differences between the two diabetic subgroups were detected after surgery, which might suggest that patients in both groups still are in a "diabetic state" using the non-diabetic subgroup as a reference.
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Affiliation(s)
- Elin Rebecka Carlsson
- Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | | | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Mogens Fenger
- Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
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Chung RWS, Wang Z, Bursill CA, Wu BJ, Barter PJ, Rye KA. Effect of long-term dietary sphingomyelin supplementation on atherosclerosis in mice. PLoS One 2017; 12:e0189523. [PMID: 29240800 PMCID: PMC5730175 DOI: 10.1371/journal.pone.0189523] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/27/2017] [Indexed: 12/19/2022] Open
Abstract
Sphingomyelin (SM) levels in the circulation correlate positively with atherosclerosis burden. SM is a ubiquitous component of human diets, but it is unclear if dietary SM increases circulating SM levels. Dietary choline increases atherosclerosis by raising circulating trimethylamine N-oxide (TMAO) levels in mice and humans. As SM has a choline head group, we ask in this study if dietary SM accelerates atherosclerotic lesion development by increasing circulating SM and TMAO levels. Three studies were performed: (Study 1) C57BL/6 mice were maintained on a high fat diet with or without SM supplementation for 4 weeks prior to quantification of serum TMAO and SM levels; (Study 2) atherosclerosis was studied in apoE-/- mice after 16 weeks of a high fat diet without or with SM supplementation and (Study 3) apoE-/- mice were maintained on a chow diet for 19 weeks without or with SM supplementation and antibiotic treatment prior to quantification of atherosclerotic lesions and serum TMAO and SM levels. SM consumption did not increase circulating SM levels or atherosclerosis in high fat-fed apoE-/- mice. Serum TMAO levels in C57BL/6 mice were low and had no effect atherosclerosis lesion development. Dietary SM supplementation significantly reduced atherosclerotic lesion area in the aortic arch of chow-fed apoE-/- mice. This study establishes that dietary SM does not affect circulating SM levels or increase atherosclerosis in high fat-fed apoE-/- mice, but it is anti-atherogenic in chow-fed apoE-/- mice.
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Affiliation(s)
| | - Zeneng Wang
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, United States of America
| | | | - Ben J. Wu
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Philip J. Barter
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Kerry-Anne Rye
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
- * E-mail:
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25
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Zhou Y, Lin XW, Begum MA, Zhang CH, Shi XX, Jiao WJ, Zhang YR, Yuan JQ, Li HY, Yang Q, Mao C, Zhu ZR. Identification and characterization of Laodelphax striatellus (Insecta: Hemiptera: Delphacidae) neutral sphingomyelinase. INSECT MOLECULAR BIOLOGY 2017; 26:392-402. [PMID: 28374513 DOI: 10.1111/imb.12302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The neutral sphingomyelinase (nSMase) 1 homologue gene LsSMase was cloned from Laodelphax striatellus, a direct sap-sucker and virus vector of gramineous plants, and expressed via a Bac to Bac baculovirus expression system. The LsSMase-enhanced green fluorescent protein fusion protein was located in the endoplasmic reticulum in a similar manner to mammalian nSMase 1. The biochemical properties of LsSMase were determined in detail. The optimal pH and temperature for recombinant LsSMase were 8 and 37 °C, respectively. LsSMase was an Mg2+ or Mn2+ dependent enzyme, but different concentration of each were needed. The activity of LsSMase was significantly stimulated by Ethylene glycol bis(2-aminoethyl ether)tetraacetic acid (EGTA), whereas it was inhibited by ethylenediaminetetraacetic acid. Millimolar concentrations of Zn2+ completely inhibited LsSMase. The reducing agents dithiothreitol and β-mercaptoethanol varied in their effects on activity. Phospholipids were not found to stimulate LsSMase.
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Affiliation(s)
- Y Zhou
- State Key Laboratory of Rice Biology; Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects; and Institute of Insect Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China
| | - X-W Lin
- State Key Laboratory of Rice Biology; Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects; and Institute of Insect Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - M-A Begum
- State Key Laboratory of Rice Biology; Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects; and Institute of Insect Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - C-H Zhang
- State Key Laboratory of Rice Biology; Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects; and Institute of Insect Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - X-X Shi
- State Key Laboratory of Rice Biology; Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects; and Institute of Insect Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - W-J Jiao
- State Key Laboratory of Rice Biology; Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects; and Institute of Insect Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Y-R Zhang
- State Key Laboratory of Rice Biology; Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects; and Institute of Insect Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - J-Q Yuan
- Center for Chemical Analysis and Detection, Zhejiang University, Hangzhou, Zhejiang, China
| | - H-Y Li
- Institute of Biotechnology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Q Yang
- Institute of Plant Protection, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, China
| | - C Mao
- Department of Medicine, State University of New York at Stony Brook. Stony Brook, NY, USA
| | - Z-R Zhu
- State Key Laboratory of Rice Biology; Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects; and Institute of Insect Sciences, Zhejiang University, Hangzhou, Zhejiang, China
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26
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Dietary Milk Sphingomyelin Reduces Systemic Inflammation in Diet-Induced Obese Mice and Inhibits LPS Activity in Macrophages. BEVERAGES 2017. [DOI: 10.3390/beverages3030037] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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27
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Tomonaga N, Manabe Y, Sugawara T. Digestion of Ceramide 2-Aminoethylphosphonate, a Sphingolipid from the Jumbo Flying Squid Dosidicus gigas, in Mice. Lipids 2017; 52:353-362. [PMID: 28243820 DOI: 10.1007/s11745-017-4239-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Accepted: 02/10/2017] [Indexed: 10/20/2022]
Abstract
Ceramide 2-aminoethylphosphonate (CAEP), a sphingophosphonolipid containing a carbon-phosphorus bond, is frequently found in marine organisms and has a unique triene type of sphingoid base in its structure. CAEP has not been evaluated as a food ingredient, although it is generally contained in Mollusca organisms such as squids and shellfish, which are consumed worldwide. In this study, we aimed to elucidate the effects of CAEP as a food component by evaluating the digestion of CAEP extracted from the skin of the jumbo flying squid Dosidicus gigas. Our results revealed that dietary CAEP was digested to free sphingoid bases via ceramides by the mouse small intestinal mucosa. At pH 7.2, CAEP was hydrolyzed more rapidly than the major mammalian sphingolipid sphingomyelin; however, the hydrolysis of CAEP was similar to that of sphingomyelin at pH 9.0. Thus, the digestion of CAEP may be catalyzed by alkaline spingomyelinase and other enzymes. Our findings provide important insights into the digestion of the dietary sphingophosphonolipid CAEP in marine foods.
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Affiliation(s)
- Nami Tomonaga
- Laboratory of Technology of Marine Bioproducts, Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawaoiwakecho, Sakyo-ku, Kyoto, 606-8502, Japan
| | - Yuki Manabe
- Laboratory of Technology of Marine Bioproducts, Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawaoiwakecho, Sakyo-ku, Kyoto, 606-8502, Japan
| | - Tatsuya Sugawara
- Laboratory of Technology of Marine Bioproducts, Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawaoiwakecho, Sakyo-ku, Kyoto, 606-8502, Japan.
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28
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Feng D, Zou J, Zhang S, Li X, Lu M. Hypocholesterolemic Activity of Curcumin Is Mediated by Down-regulating the Expression of Niemann-Pick C1-like 1 in Hamsters. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:276-280. [PMID: 28000447 DOI: 10.1021/acs.jafc.6b04102] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
We previously demonstrated that curcumin reduces cholesterol absorption in Caco-2 cells through down-regulating Niemann-Pick C1-like 1 (NPC1L1) expression, but the in vivo effect of curcumin on intestinal cholesterol absorption remains unknown. The present study aimed to investigate the effects and mechanisms of curcumin consumption on cholesterol absorption in hamsters. Male hamsters were fed a high-fat diet supplemented with or without curcumin (0.05% w/w) for 12 weeks. Curcumin supplementation significantly decreased serum total cholesterol (TC) (from 6.86 ± 0.27 to 3.50 ± 0.24 mmol/L), triglyceride (TG) (from 5.07 ± 0.34 to 3.72 ± 0.40 mmol/L), and low-density lipoprotein cholesterol (from 2.58 ± 0.19 to 1.71 ± 0.15 mmol/L) levels as well as liver TC (from 11.6 ± 0.05 to 7.2 ± 0.03 mg/g) and TG (from 30.3 ± 0.22 to 25.2 ± 0.18 mg/g) levels (P < 0.05 for all). In contrast, curcumin treatment markedly enhanced fecal cholesterol output (P < 0.01). Moreover, curcumin supplementation down-regulated the mRNA and protein expressions of sterol regulatory element binding protein-2 (SREBP-2) and NPC1L1 in the small intestine (P < 0.05). Our current results indicate that curcumin inhibits cholesterol absorption in hamsters by suppressing SREBP-2 and subsequently down-regulating NPC1L1 expression, which may be responsible for the hypocholesterolemic effects of curcumin.
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Affiliation(s)
- Dan Feng
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University , Guangzhou 510080, China
| | - Jun Zou
- Department of Cardiology, Affiliated NanHai Hospital of Southern Medical University , Foshan 528200, China
| | - Shanshan Zhang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University , Guangzhou 510080, China
| | - Xuechun Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University , Guangzhou 510080, China
| | - Minqi Lu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University , Guangzhou 510080, China
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29
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Hernández-Corbacho MJ, Salama MF, Canals D, Senkal CE, Obeid LM. Sphingolipids in mitochondria. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1862:56-68. [PMID: 27697478 DOI: 10.1016/j.bbalip.2016.09.019] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/01/2016] [Accepted: 09/24/2016] [Indexed: 01/16/2023]
Abstract
Sphingolipids are bioactive lipids found in cell membranes that exert a critical role in signal transduction. In recent years, it has become apparent that sphingolipids participate in growth, senescence, differentiation and apoptosis. The anabolism and catabolism of sphingolipids occur in discrete subcellular locations and consist of a strictly regulated and interconnected network, with ceramide as the central hub. Altered sphingolipid metabolism is linked to several human diseases. Hence, an advanced knowledge of how and where sphingolipids are metabolized is of paramount importance in order to understand the role of sphingolipids in cellular functions. In this review, we provide an overview of sphingolipid metabolism. We focus on the distinct pathways of ceramide synthesis, highlighting the mitochondrial ceramide generation, transport of ceramide to mitochondria and its role in the regulation of mitochondrial-mediated apoptosis, mitophagy and implications to disease. We will discuss unanswered questions and exciting future directions. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
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Affiliation(s)
- María José Hernández-Corbacho
- Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, NY 11794, USA
| | - Mohamed F Salama
- Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, NY 11794, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Daniel Canals
- Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, NY 11794, USA
| | - Can E Senkal
- Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, NY 11794, USA
| | - Lina M Obeid
- Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, NY 11794, USA; The Northport VA Medical Center, Northport, NY 11768, USA.
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30
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Abstract
Sphingomyelin (SM), glycosphingolipids, and gangliosides are important polar lipids in the milk fat globule membrane but are not found in standard milk replacement formulas. Because digestion and absorption of SM and glycosphingolipids generate the bioactive metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P), and because intact gangliosides may have beneficial effects in the gut, this may be important for gut integrity and immune maturation in the neonate. The brush border enzymes that hydrolyze milk SM, alkaline sphingomyelinase (nucleotide phosphodiesterase pyrophosphatase 7), and neutral ceramidase are expressed at birth in both term and preterm infants. Released sphingosine is absorbed, phosphorylated to S1P, and converted to palmitic acid via S1P-lyase in the gut mucosa. Hypothetically, S1P also may be released from absorptive cells and exert important paracrine actions favoring epithelial integrity and renewal, as well as immune function, including secretory IgA production and migration of T lymphocyte subpopulations. Gluco-, galacto-, and lactosylceramide are hydrolyzed to ceramide by lactase-phlorizin hydrolase, which also hydrolyzes lactose. Gangliosides may adhere to the brush border and is internalized, modified, and possibly transported into blood, and may exert protective functions by their interactions with bacteria, bacterial toxins, and the brush border.
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Affiliation(s)
- Åke Nilsson
- Department of Clinical Sciences, Medicine (Gastroenterology), Lund University, Skane University Hospital, Lund, Sweden.
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31
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Adada M, Luberto C, Canals D. Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases. Chem Phys Lipids 2016. [DOI: 10.1016/j.chemphyslip.2015.07.008] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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32
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Teixeira V, Costa V. Unraveling the role of the Target of Rapamycin signaling in sphingolipid metabolism. Prog Lipid Res 2015; 61:109-33. [PMID: 26703187 DOI: 10.1016/j.plipres.2015.11.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 11/04/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023]
Abstract
Sphingolipids are important bioactive molecules that regulate basic aspects of cellular metabolism and physiology, including cell growth, adhesion, migration, senescence, apoptosis, endocytosis, and autophagy in yeast and higher eukaryotes. Since they have the ability to modulate the activation of several proteins and signaling pathways, variations in the relative levels of different sphingolipid species result in important changes in overall cellular functions and fate. Sphingolipid metabolism and their route of synthesis are highly conserved from yeast to mammalian cells. Studies using the budding yeast Saccharomyces cerevisiae have served in many ways to foster our understanding of sphingolipid dynamics and their role in the regulation of cellular processes. In the past decade, studies in S. cerevisiae have unraveled a functional association between the Target of Rapamycin (TOR) pathway and sphingolipids, showing that both TOR Complex 1 (TORC1) and TOR Complex 2 (TORC2) branches control temporal and spatial aspects of sphingolipid metabolism in response to physiological and environmental cues. In this review, we report recent findings in this emerging and exciting link between the TOR pathway and sphingolipids and implications in human health and disease.
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Affiliation(s)
- Vitor Teixeira
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IBMC, Instituto de Biologia Molecular e Celular, Porto, Portugal; ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Departamento de Biologia Molecular, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Vítor Costa
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IBMC, Instituto de Biologia Molecular e Celular, Porto, Portugal; ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Departamento de Biologia Molecular, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
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Metabolic Conversion of Ceramides in HeLa Cells - A Cholesteryl Phosphocholine Delivery Approach. PLoS One 2015; 10:e0143385. [PMID: 26599810 PMCID: PMC4658033 DOI: 10.1371/journal.pone.0143385] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 11/04/2015] [Indexed: 11/19/2022] Open
Abstract
Ceramides can be delivered to cultured cells without solvents in the form of complexes with cholesteryl phosphocholine. We have analysed the delivery of three different radiolabeled D-erythro-ceramides (C6-Cer, C10-Cer and C16-Cer) to HeLa cells, and followed their metabolism as well as the cell viability. We found that all three ceramides were successfully taken up by HeLa cells when complexed to CholPC in an equimolar ratio, and show that the ceramides show different rates of cellular uptake and metabolic fate. The C6-Cer had the highest incorporation rate, followed by C10-Cer and C16-Cer, respectively. The subsequent effect on cell viability strongly correlated with the rate of incorporation, where C6-Cer had the strongest apoptotic effects. Low-dose (1 μM) treatment with C6-Cer favoured conversion of the precursor to sphingomyelin, whereas higher concentrations (25–100 μM) yielded increased conversion to C6-glucosylceramide. Similar results were obtained for C10-Cer. In the lower-dose C16-Cer experiments, most of the precursor was degraded, whereas at high-dose concentrations the precursor remained un-metabolized. Using this method, we demonstrate that ceramides with different chain lengths clearly exhibit varying rates of cellular uptake. The cellular fate of the externally delivered ceramides are clearly connected to their rate of incorporation and their subsequent effects on cell viability may be in part determined by their chain length.
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Mevalonate inhibits acid sphingomyelinase activity, increases sphingomyelin levels and inhibits cell proliferation of HepG2 and Caco-2 cells. Lipids Health Dis 2015; 14:130. [PMID: 26493087 PMCID: PMC4618740 DOI: 10.1186/s12944-015-0137-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 10/15/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Sphingomyelin (SM) and cholesterol are two types of lipid closely related biophysically. Treating the cells with exogenous sphingomyelinase (SMase) induces trafficking of cholesterol from membrane to intracellular pools and inhibition of cholesterol synthesis. In the present work, we address a question whether increased cholesterol synthesis affects hydrolysis of SM by endogenous SMases. METHODS Both HepG2 and Caco-2 cells were incubated with mevalonate. The SMase activity was determined and its mRNA examined by qPCR. The cellular levels of cholesterol, SM, and phosphatidylcholine (PC) were determined and cell proliferation rate assayed. RESULTS We found that mevalonate dose-dependently decreased acid but not neutral SMase activity in both HepG2 and Caco-2 cells with HepG2 cells being more sensitive to mevalonate. Kinetic examination in HepG2 cells revealed that acid SMase activity was increasing with cell proliferation, and such an increase was reversed by mevalonate treatment. Acid SMase mRNA was not significantly decreased and Western blot showed signs of proteolysis of acid SMase by mevalonate. After mevalonate treatment, the levels of cholesterol were significantly increased associated with increases in SM and PC. The cell growth was retarded by mevalonate and the effect was more obvious in HepG2 cells than in Caco-2 cells. CONCLUSION Mevalonate can trigger a mechanism to enhance SM levels by inhibition of acid SMase. The effect may ensure the coordinate changes of SM and cholesterol in the cells. Mevalonate also affects cell growth with mechanism required further characterization.
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35
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García-Barros M, Coant N, Snider AJ. Sphingolipids in Intestinal Inflammation and Tumorigenesis. INTESTINAL TUMORIGENESIS 2015:257-286. [DOI: 10.1007/978-3-319-19986-3_9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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36
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Carroll B, Donaldson JC, Obeid L. Sphingolipids in the DNA damage response. Adv Biol Regul 2014; 58:38-52. [PMID: 25434743 DOI: 10.1016/j.jbior.2014.11.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 11/06/2014] [Accepted: 11/07/2014] [Indexed: 12/16/2022]
Abstract
Recently, sphingolipid metabolizing enzymes have emerged as important targets of many chemotherapeutics and DNA damaging agents and therefore play significant roles in mediating the physiological response of the cell to DNA damage. In this review we will highlight points of connection between the DNA damage response (DDR) and sphingolipid metabolism; specifically how certain sphingolipid enzymes are regulated in response to DNA damage and how the bioactive lipids produced by these enzymes affect cell fate.
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Affiliation(s)
- Brittany Carroll
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jane Catalina Donaldson
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Lina Obeid
- Northport VA Medical Center, Northport, NY 11768, USA; Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
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37
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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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Duan RD, Hindorf U, Cheng Y, Bergenzaun P, Hall M, Hertervig E, Nilsson Å. Changes of activity and isoforms of alkaline sphingomyelinase (nucleotide pyrophosphatase phosphodiesterase 7) in bile from patients undergoing endoscopic retrograde cholangiopancreatography. BMC Gastroenterol 2014; 14:138. [PMID: 25100243 PMCID: PMC4141583 DOI: 10.1186/1471-230x-14-138] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 07/24/2014] [Indexed: 01/02/2023] Open
Abstract
Background Alkaline sphingomyelinase (NPP7) is an ecto-enzyme expressed in intestinal mucosa, which hydrolyses sphingomyelin (SM) to ceramide and inactivates platelet activating factor. It is also expressed in human liver and released in the bile. The enzyme may have anti-tumour and anti-inflammatory effects in colon and its levels are decreased in patients with colon cancer and ulcerative colitis. Active NPP7 is translated from a transcript of 1.4 kb, whereas an inactive form from a 1.2 kb mRNA was found in colon and liver cancer cell lines. While the roles of NPP7 in colon cancer have been intensively studied, less is known about the function and implications of NPP7 in the bile. The present study examines the changes of NPP7 in bile of patients with various hepatobiliary diseases. Methods Bile samples were obtained at endoscopic retrograde cholangiopancreatography (ERCP) in 59 patients with gallstone, other benign disease, tumour, and primary sclerosing cholangitis (PSC). The NPP7 activity was determined. The appearance of the 1.4 and 1.2 kb products in the bile was examined by Western blot. The results were correlated to the diseases and also plasma bilirubin and alkaline phosphatase. Results NPP7 activity in the tumour group was significantly lower than in the gallstone group (p < 0.05). The activity in the tumour plus PSC group was also lower than in gallstone plus other benign disease group (p < 0.05). Within the tumour group NPP7 activity was lowest in cholangiocarcinoma patients, being only 19% of that in gallstone patients. Bilirubin correlated inversely to NPP7 and was higher in the tumour than in the gallstone group. Western blot identified both the 1.4 kb and the 1.2 kb products in most bile samples. The density ratio for the 1.4/1.2 kb products correlated to NPP7 activity significantly. Two patients (one PSC and one cholangiocarcinoma) lacking NPP7 activity had only the 1.2 kb form in bile. Conclusion NPP7 activity and the ratio of 1.4/1.2 kb products in bile are significantly decreased in malignancy, particularly in cholangiocarcinoma. The implications of the finding in diagnosis of cholangiocarcinoma and 1.2 kb product in hepatobiliary diseases require further investigation.
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Affiliation(s)
- Rui-Dong Duan
- Gastroenterology & Nutrition Laboratory, BMC, B11, Department of Clinical Sciences in Lund, University of Lund, S-22184 Lund, Sweden.
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Zhang P, Chen Y, Cheng Y, Hertervig E, Ohlsson L, Nilsson A, Duan RD. Alkaline sphingomyelinase (NPP7) promotes cholesterol absorption by affecting sphingomyelin levels in the gut: A study with NPP7 knockout mice. Am J Physiol Gastrointest Liver Physiol 2014; 306:G903-8. [PMID: 24650549 DOI: 10.1152/ajpgi.00319.2013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We previously showed that dietary sphingomyelin (SM) inhibited cholesterol absorption in animals. The key enzyme hydrolyzing SM in the gut is alkaline sphingomyelinase (alk-SMase, nucleotide pyrophosphatase/phosphodiesterase 7). Here using the fecal dual-isotope ratio method we compared cholesterol absorption in the wild-type (WT) and alk-SMase knockout (KO) mice. The animals were fed an emulsion containing [(14)C]cholesterol and [(3)H]sitosterol. The radioactivities in the lipids of the fecal samples collected 4, 8, and 24 h thereafter were determined, and the ratio of (14)C/(3)H was calculated. We found that the fecal [(14)C]cholesterol recovery in the KO mice was significantly higher than in the WT mice. A maximal 92% increase occurred 8 h after feeding. Recovery of [(3)H]sitosterol did not differ between the two groups. Accordingly, the (14)C-to-(3)H ratio of fecal lipids was 133% higher at 8 h and 75% higher at 24 h in the KO than in the WT mice. Decreased [(14)C]cholesterol was also found in the serum of the KO mice 4 h after feeding. Supplement of SM in the emulsion reduced the differences in fecal [(14)C]cholesterol recovery between the WT and KO mice because of a greater increase of [(14)C]cholesterol recovery in the WT mice. Without treatment, the KO mice had significantly higher SM levels in the intestinal content and feces, but not in the intestinal mucosa or serum. The expression of Niemann-Pick C1 like 1 protein in the small intestine was not changed. In conclusion, alk-SMase is a physiological factor promoting cholesterol absorption by reducing SM levels in the intestinal lumen.
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Affiliation(s)
- Ping Zhang
- Gastroenterology and Nutrition Lab, Institution of Clinical Sciences, University of Lund, Lund, Sweden; Daqing Campus, Harbin Medical University, Daqing, China
| | - Ying Chen
- Gastroenterology and Nutrition Lab, Institution of Clinical Sciences, University of Lund, Lund, Sweden; Gastroenterology, Tongji Hospital, Tongji University, Shanghai, China; and
| | - Yajun Cheng
- Gastroenterology and Nutrition Lab, Institution of Clinical Sciences, University of Lund, Lund, Sweden
| | - Erik Hertervig
- Gastroenterology Clinic, Skåne University Hospital, Lund, Sweden
| | - Lena Ohlsson
- Gastroenterology and Nutrition Lab, Institution of Clinical Sciences, University of Lund, Lund, Sweden
| | - Ake Nilsson
- Gastroenterology and Nutrition Lab, Institution of Clinical Sciences, University of Lund, Lund, Sweden; Gastroenterology Clinic, Skåne University Hospital, Lund, Sweden
| | - Rui-Dong Duan
- Gastroenterology and Nutrition Lab, Institution of Clinical Sciences, University of Lund, Lund, Sweden;
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Wiersma-Koch H, Sunden F, Herschlag D. Site-directed mutagenesis maps interactions that enhance cognate and limit promiscuous catalysis by an alkaline phosphatase superfamily phosphodiesterase. Biochemistry 2013; 52:9167-76. [PMID: 24261692 DOI: 10.1021/bi4010045] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Catalytic promiscuity, an evolutionary concept, also provides a powerful tool for gaining mechanistic insights into enzymatic reactions. Members of the alkaline phosphatase (AP) superfamily are highly amenable to such investigation, with several members having been shown to exhibit promiscuous activity for the cognate reactions of other superfamily members. Previous work has shown that nucleotide pyrophosphatase/phosphodiesterase (NPP) exhibits a >10⁶-fold preference for the hydrolysis of phosphate diesters over phosphate monoesters, and that the reaction specificity is reduced 10³-fold when the size of the substituent on the transferred phosphoryl group of phosphate diester substrates is reduced to a methyl group. Here we show additional specificity contributions from the binding pocket for this substituent (herein termed the R' substituent) that account for an additional ~250-fold differential specificity with the minimal methyl substituent. Removal of four hydrophobic side chains suggested on the basis of structural inspection to interact favorably with R' substituents decreases phosphate diester reactivity 10⁴-fold with an optimal diester substrate (R' = 5'-deoxythymidine) and 50-fold with a minimal diester substrate (R' = CH₃). These mutations also enhance the enzyme's promiscuous phosphate monoesterase activity by nearly an order of magnitude, an effect that is traced by mutation to the reduction of unfavorable interactions with the two residues closest to the nonbridging phosphoryl oxygen atoms. The quadruple R' pocket mutant exhibits the same activity toward phosphate diester and phosphate monoester substrates that have identical leaving groups, with substantial rate enhancements of ~10¹¹-fold. This observation suggests that the Zn²⁺ bimetallo core of AP superfamily enzymes, which is equipotent in phosphate monoester and diester catalysis, has the potential to become specialized for the hydrolysis of each class of phosphate esters via addition of side chains that interact with the substrate atoms and substituents that project away from the Zn²⁺ bimetallo core.
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Affiliation(s)
- Helen Wiersma-Koch
- Department of Biochemistry, Stanford University , Stanford, California 94305, United States
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Sphingosine 1-phosphate is a key metabolite linking sphingolipids to glycerophospholipids. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1841:766-72. [PMID: 23994042 DOI: 10.1016/j.bbalip.2013.08.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 08/09/2013] [Accepted: 08/13/2013] [Indexed: 12/18/2022]
Abstract
The sphingolipid metabolite sphingosine 1-phosphate (S1P) is a well-known lipid mediator. As a lipid mediator, S1P must be present in extracellular space and bind to its cell surface receptors (S1P1-5). However, most S1P, synthesized intracellularly, is metabolized without being released into extracellular space, in other words, without functioning as a lipid mediator in the vast majority of cells except those supplying plasma and lymph S1P such as blood cells and endothelial cells. Instead, intracellular S1P plays an important role as an intermediate of the sole sphingolipid-to-glycerophospholipid metabolic pathway. The degradation of S1P by S1P lyase is the first irreversible reaction (committed step) of this pathway. This metabolic pathway is conserved in eukaryotes from yeast to human, indicating its much older origin than the function of S1P as a lipid mediator, which is found to be present only in vertebrates and chordates. The sphingolipid-to-glycerophospholipid metabolism takes place ubiquitously in mammalian tissues, and its defect causes an aberration of several tissue functions as well as abnormal lipid metabolism. Although this metabolic pathway has been known for over four decades, only recently the precise reactions and enzymes involved in this pathway have been revealed. This review will focus on the recent advances in our understanding of the sphingolipid metabolic pathway via S1P and its physiological and pathological roles. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.
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Zimmermann H, Zebisch M, Sträter N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 2012; 8:437-502. [PMID: 22555564 PMCID: PMC3360096 DOI: 10.1007/s11302-012-9309-4] [Citation(s) in RCA: 803] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 02/01/2012] [Indexed: 12/12/2022] Open
Abstract
Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ecto-nucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5'-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.
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Affiliation(s)
- Herbert Zimmermann
- Institute of Cell Biology and Neuroscience, Molecular and Cellular Neurobiology, Biologicum, Goethe-University Frankfurt, Max-von-Laue-Str. 13, 60438, Frankfurt am Main, Germany.
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Sphingolipid and ceramide homeostasis: potential therapeutic targets. Biochem Res Int 2012; 2012:248135. [PMID: 22400113 PMCID: PMC3286894 DOI: 10.1155/2012/248135] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2011] [Accepted: 10/20/2011] [Indexed: 12/26/2022] Open
Abstract
Sphingolipids are ubiquitous in eukaryotic cells where they have been attributed a plethora of functions from the formation of structural domains to polarized cellular trafficking and signal transduction. Recent research has identified and characterised many of the key enzymes involved in sphingolipid metabolism and this has led to a heightened interest in the possibility of targeting these processes for therapies against cancers, Alzheimer's disease, and numerous important human pathogens. In this paper we outline the major pathways in eukaryotic sphingolipid metabolism and discuss these in relation to disease and therapy for both chronic and infectious conditions.
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Parrill AL, Wanjala IW, Pham TCT, Baker DL. Computational identification and experimental characterization of substrate binding determinants of nucleotide pyrophosphatase/phosphodiesterase 7. BMC BIOCHEMISTRY 2011; 12:65. [PMID: 22177013 PMCID: PMC3282672 DOI: 10.1186/1471-2091-12-65] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 12/16/2011] [Indexed: 11/10/2022]
Abstract
BACKGROUND Nucleotide pyrophosphatase/phosphodiesterase 7 (NPP7) is the only member of the mammalian NPP enzyme family that has been confirmed to act as a sphingomyelinase, hydrolyzing sphingomyelin (SM) to form phosphocholine and ceramide. NPP7 additionally hydrolyzes lysophosphatidylcholine (LPC), a substrate preference shared with the NPP2/autotaxin(ATX) and NPP6 mammalian family members. This study utilizes a synergistic combination of molecular modeling validated by experimental site-directed mutagenesis to explore the molecular basis for the unique ability of NPP7 to hydrolyze SM. RESULTS The catalytic function of NPP7 against SM, LPC, platelet activating factor (PAF) and para-nitrophenylphosphorylcholine (pNPPC) is impaired in the F275A mutant relative to wild type NPP7, but different impacts are noted for mutations at other sites. These results are consistent with a previously described role of F275 to interact with the choline headgroup, where all substrates share a common functionality. The L107F mutation showed enhanced hydrolysis of LPC, PAF and pNPPC but reduced hydrolysis of SM. Modeling suggests this difference can be explained by the gain of cation-pi interactions with the choline headgroups of all four substrates, opposed by increased steric crowding against the sphingoid tail of SM. Modeling also revealed that the long and flexible hydrophobic tails of substrates exhibit considerable dynamic flexibility in the binding pocket, reducing the entropic penalty that might otherwise be incurred upon substrate binding. CONCLUSIONS Substrate recognition by NPP7 includes several important contributions, ranging from cation-pi interactions between F275 and the choline headgroup of all substrates, to tail-group binding pockets that accommodate the inherent flexibility of the lipid hydrophobic tails. Two contributions to the unique ability of NPP7 to hydrolyze SM were identified. First, the second hydrophobic tail of SM occupies a second hydrophobic binding pocket. Second, the leucine residue present at position 107 contrasts with a conserved phenylalanine in NPP enzymes that do not utilize SM as a substrate, consistent with the observed reduction in SM hydrolysis by the NPP7-L107F mutant.
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Affiliation(s)
- Abby L Parrill
- Department of Chemistry and the Computational Research on Materials Institute, The University of Memphis, Memphis, TN 38152, USA.
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Truman JP, Al Gadban MM, Smith KJ, Hammad SM. Acid sphingomyelinase in macrophage biology. Cell Mol Life Sci 2011; 68:3293-305. [PMID: 21533981 PMCID: PMC3178716 DOI: 10.1007/s00018-011-0686-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Revised: 03/28/2011] [Accepted: 04/05/2011] [Indexed: 12/21/2022]
Abstract
Macrophages play a central role in innate immune responses, in disposal of cholesterol, and in tissue homeostasis and remodeling. To perform these vital functions macrophages display high endosomal/lysosomal activities. Recent studies have highlighted that acid sphingomyelinase (ASMase), which generates ceramide from sphingomyelin, is involved in modulation of membrane structures and signal transduction in addition to its metabolic role in the lysosome. In this review, we bring together studies on ASMase, its different forms and locations that are necessary for the macrophage to accomplish its diverse functions. We also address the importance of ASMase to several disease processes that are mediated by activated macrophages.
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Affiliation(s)
- Jean-Philip Truman
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 114 Doughty Street 629A, MSC 815, Charleston, SC 29425 USA
| | - Mohammed M. Al Gadban
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 114 Doughty Street 629A, MSC 815, Charleston, SC 29425 USA
| | - Kent J. Smith
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 114 Doughty Street 629A, MSC 815, Charleston, SC 29425 USA
| | - Samar M. Hammad
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 114 Doughty Street 629A, MSC 815, Charleston, SC 29425 USA
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Abstract
Intensive research over the past 2 decades has implicated ceramide in the regulation of several cell responses. However, emerging evidence points to dramatic complexities in ceramide metabolism and structure that defy the prevailing unifying hypothesis on ceramide function that is based on the understanding of ceramide as a single entity. Here, we develop the concept that "ceramide" constitutes a family of closely related molecules, subject to metabolism by >28 enzymes and with >200 structurally distinct mammalian ceramides distinguished by specific structural modifications. These ceramides are synthesized in a combinatorial fashion with distinct enzymes responsible for the specific modifications. These multiple pathways of ceramide generation led to the hypothesis that individual ceramide molecular species are regulated by specific biochemical pathways in distinct subcellular compartments and execute distinct functions. In this minireview, we describe the "many ceramides" paradigm, along with the rationale, supporting evidence, and implications for our understanding of bioactive sphingolipids and approaches for unraveling these pathways.
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Affiliation(s)
- Yusuf A Hannun
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SouthCarolina 29425, USA.
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