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Ceramide synthases

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https://www.readbyqxmd.com/read/28812237/pharmacological-effects-on-ceroid-lipofuscin-and-neuronal-structure-in-cln3-%C3%A2-ex7-8-mouse-brain-cultures
#1
Douglas E Brenneman, David A Pearce, Attila Kovacs, Shawn DeFrees
Juvenile Batten disease (JBD) is an inherited disorder that is characterized by the development of blindness, seizures, and progressive motor, psychiatric, and cognitive impairment. A model of JBD expressing the predominant human mutation (Cln3 (∆ex7/8) ) has been explored. Dissociated brain cultures from Cln3 (∆ex7/8) knock-in mice were compared to wild type (WT) for effects on granules of ceroid lipofuscin (CL) and neuronal structure. Utilizing high content image analysis of CL granules identified with antibodies to mitochondrial ATP synthase subunit c or tripeptidyl peptidase-1, significant increases in the areas for both immunoreactive granules were observed in Cln3 (∆ex7/8) cultures in comparison to WT...
August 15, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28742512/the-sphingomyelin-synthase-family-proteins-diseases-and-inhibitors
#2
Yang Chen, Yu Cao
Sphingomyelin (SM) is among the most important biomolecules in eukaryotes and acts as both constructive components and signal carrier in physiological process. SM is catalyzed by a membrane protein family, sphingomyelin synthases (SMSs), consisting of three members, SMS1, SMS2 and SMSr. SMSs modulate sphingomyelin and other sphingolipids levels, thereby regulating membrane mobility, ceramide-dependent apoptosis and DAG-dependent signaling pathway. SMSs was found associated with various diseases. Downregulation of SMS2 activity results in protective effects against obesity, atherosclerosis, and diabetes, makes SMS2 inhibitors potential medicines...
July 26, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28699686/ablation-of-ceramide-synthase-2-exacerbates-dextran-sodium-sulphate-induced-colitis-in-mice-due-to-increased-intestinal-permeability
#3
Ye-Ryung Kim, Giora Volpert, Kyong-Oh Shin, So-Yeon Kim, Sun-Hye Shin, Younghay Lee, Sun Hee Sung, Yong-Moon Lee, Jung-Hyuck Ahn, Yael Pewzner-Jung, Woo-Jae Park, Anthony H Futerman, Joo-Won Park
Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long-chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very-long acyl chain ceramides with concomitant increase of long chain bases and C16-ceramides, were more susceptible to dextran sodium sulphate-induced colitis, and their survival rate was markedly decreased compared with that of wild-type littermates...
July 12, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28695226/fenretinide-differentially-modulates-the-levels-of-long-and-very-long-chain-ceramides-by-downregulating-cers5-enzyme-evidence-from-bench-to-bedside
#4
Dušan Garić, Juan B De Sanctis, Gabriella Wojewodka, Daniel Houle, Shanon Cupri, Asmahan Abu-Arish, John W Hanrahan, Marian Hajduch, Elias Matouk, Danuta Radzioch
Cystic fibrosis is the most common genetic disease, in which symptoms may be alleviated but not fully eliminated. Ceramides have long been implicated in the inflammatory etiology of cystic fibrosis, with contradicting reports with regards to their role. Recently, significant biological and biophysical differences have been observed between long- and very long-chain ceramides. This work reveals that long-chain ceramides are upregulated whereas very long-chain ceramides are downregulated in cell lines, mouse animal model, and patients with cystic fibrosis, compared with their controls...
July 10, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28659495/ceramide-phosphoethanolamine-synthase-smsr-is-a-target-of-caspase-6-during-apoptotic-cell-death
#5
Birol Cabukusta, Niclas T Nettebrock, Matthijs Kol, Angelika Hilderink, Fikadu G Tafesse, Joost C M Holthuis
Ceramides are essential precursors of sphingolipids with a dual role as mediators of apoptotic cell death. Previous work revealed that the ER-resident ceramide phosphoethanolamine synthase SMSr/SAMD8 is a suppressor of ceramide-mediated apoptosis in cultured cells. Anti-apoptotic activity of SMSr requires a catalytically active enzyme but also relies on the enzyme's N -terminal sterile α-motif or SAM domain. Here we demonstrate that SMSr itself is a target of the apoptotic machinery. Treatment of cells with staurosporine or the death receptor ligand FasL triggers caspase-mediated cleavage of SMSr at a conserved aspartate located downstream of the enzyme's SAM domain and upstream of its first membrane span...
June 28, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28592871/incorporation-of-fluorescence-ceramide-based-hplc-assay-for-rapidly-and-efficiently-assessing-glucosylceramide-synthase-in-vivo
#6
Sachin K Khiste, Salman B Hosain, Yixuan Dong, Mohammad B Uddin, Kartik R Roy, Ronald A Hill, Zhijun Liu, Yong-Yu Liu
Glucosylceramide synthase (GCS) is a rate-limiting enzyme catalyzing ceramide glycosylation, thereby regulating cellular ceramide levels and the synthesis of glycosphingolipids (GSLs) in cellular membranes. Alterations of GCS not only affect membrane integrity, but also closely correlate with stem cell pluripotency, cancer drug resistance, GSL storage disorders and other diseases. Enzyme activities measured conventionally with currently available ex-vivo methods do not enable reliable assessment of the roles played by GCS in vivo...
June 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28572516/jaspine-b-induces-nonapoptotic-cell-death-in-gastric-cancer-cells-independently-of-its-inhibition-of-ceramide-synthase
#7
Francesca Cingolani, Fabio Simbari, Jose Luis Abad, Mireia Casasampere, Gemma Fabrias, Anthony H Futerman, Josefina Casas
Sphingolipids (SLs) have been extensively investigated in biomedical research due to their role as bioactive molecules in cells. Here, we describe the effect of a SL analog, jaspine B (JB), a cyclic anhydrophytosphingosine found in marine sponges, on the gastric cancer cell line, HGC-27. JB induced alterations in the sphingolipidome, mainly the accumulation of dihydrosphingosine, sphingosine, and their phosphorylated forms due to inhibition of ceramide synthases. Moreover, JB provoked atypical cell death in HGC-27 cells, characterized by the formation of cytoplasmic vacuoles in a time and dose-dependent manner...
August 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28571749/altered-expression-of-epidermal-lipid-bio-synthesis-enzymes-in-atopic-dermatitis-skin-is-accompanied-by-changes-in-stratum-corneum-lipid-composition
#8
M O Danso, W Boiten, V van Drongelen, K M Gmelig, G Gooris, A El Ghalbzouri, S Absalah, R Vreeken, S Kezic, J van Smeden, A P M Lavrijsen, J A Bouwstra
BACKGROUND: The barrier dysfunction in atopic dermatitis (AD) skin correlates with stratum corneum (SC) lipid abnormalities including reduction of global lipid content, shorter ceramide (CER) as well as free fatty acid (FFA) chain length and altered CER subclass levels. However, the underlying cause of these changes in lipid composition has not been fully investigated. AIM: We investigated whether the expression of CER and FFA biosynthesis enzymes are altered in AD skin compared with control skin and determine whether changes in enzyme expression can be related with changes in lipid composition...
May 18, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28522594/sphingomyelin-synthase-2-deficiency-inhibits-the-induction-of-murine-colitis-associated-colon-cancer
#9
Toshio Ohnishi, Chieko Hashizume, Makoto Taniguchi, Hidehiro Furumoto, Jia Han, Rongfen Gao, Shinichi Kinami, Takeo Kosaka, Toshiro Okazaki
Sphingomyelin synthase 2 (SMS2) is the synthetic enzyme of sphingomyelin (SM), which regulates membrane fluidity and microdomain structure. SMS2 plays a role in LPS-induced lung injury and inflammation; however, its role in inflammation-mediated tumorigenesis is unclear. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)-induced murine colitis and found inhibition of DSS-induced inflammation in SMS2-deficient (SMS2(-/-)) mice. DSS treatment induced a significant increase in ceramide levels, with a decrease of SM levels in SMS2(-/-) colon tissue, and demonstrated attenuation of the elevation of both inflammation-related gene expression and proinflammatory cytokines and chemokines, leukocyte infiltration, and MAPK and signal transducer and activator of transcription 3 activation...
May 18, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28515365/ceramide-synthesis-regulates-t-cell-activity-and-gvhd-development
#10
M Hanief Sofi, Jessica Heinrichs, Mohammed Dany, Hung Nguyen, Min Dai, David Bastian, Steven Schutt, Yongxia Wu, Anusara Daenthanasanmak, Salih Gencer, Aleksandra Zivkovic, Zdzislaw Szulc, Holger Stark, Chen Liu, Ying-Jun Chang, Besim Ogretmen, Xue-Zhong Yu
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for a variety of hematologic malignances, yet its efficacy is impeded by the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells. Hence, strategies to limit GVHD are highly desirable. Ceramides are known to contribute to inflammation and autoimmunity. However, their involvement in T-cell responses to alloantigens is undefined...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515139/changes-in-ceramide-metabolism-are-essential-in-madin-darby-canine-kidney-cell-differentiation
#11
Lucila Gisele Pescio, Bruno Jaime Santacreu, Vanina Gisela Lopez, Carlos Humberto Paván, Daniela Judith Romero, Nicolás Octavio Favale, Norma Beatriz Sterin-Speziale
Ceramides (Cers) and complex sphingolipids with defined acyl chain lengths play important roles in numerous cell processes. Six Cer synthase (CerS) isoenzymes (CerS1-6) are the key enzymes responsible for the production of the diversity of molecular species. In this study, we investigated the changes in sphingolipid metabolism during the differentiation of Madin-Darby canine kidney (MDCK) cells. By MALDI TOF TOF MS, we analyzed the molecular species of Cer, glucosylceramide (GlcCer), lactosylceramide (LacCer), and SM in nondifferentiated and differentiated cells (cultured under hypertonicity)...
July 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28490444/inhibiting-glucosylceramide-synthase-exacerbates-cisplatin-induced-acute-kidney-injury
#12
Tess V Dupre, Mark A Doll, Parag P Shah, Cierra N Sharp, Deanna Siow, Judit Megyesi, James Shayman, Alicja Bielawska, Jacek Bielawski, Levi J Beverly, Maria Hernandez-Corbacho, Christopher J Clarke, Ashley J Snider, Rick G Schnellmann, Lina M Obeid, Yusuf A Hannun, Leah J Siskind
Acute kidney injury (AKI), resulting from chemotherapeutic agents such as cisplatin, remains an obstacle in the treatment of cancer. Cisplatin-induced AKI involves apoptotic and necrotic cell death, pathways regulated by sphingolipids such as ceramide and glucosylceramide. Results from this study indicate that C57BL/6J mice treated with cisplatin had increased ceramide and hexosylceramide levels in the renal cortex 72 h following cisplatin treatment. Pretreatment of mice with inhibitors of acid sphingomyelinase and de novo ceramide synthesis (amitriptyline and myriocin, respectively) prevented accumulation of ceramides and hexosylceramide in the renal cortex and protected from cisplatin-induced AKI...
July 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28424433/-investigating-the-role-of-ceramide-metabolism-associated-cers5-lass5-gene-in-atherosclerosis-pathogenesis-in-endothelial-cells
#13
Neslihan Çoban, Filiz Güçlü Geyik, Özlem Yıldırım, Nihan Erginel Ünaltuna
OBJECTIVE: Ceramide, the backbone of sphingolipids, is the key component affecting atherosclerotic changes through its important second-messenger role. Previous studies have demonstrated protective role of AMP-activated protein kinase (AMPK) genes in regulating atherosclerosis and hypertension. Ceramide synthase 5 (LASS5 or CERS5) gene has function in de novo synthesis of ceramide, and has indirect effect on AMPK gene. Aim of the present study was to identify role of LASS5 gene in atherosclerosis...
March 2017: Türk Kardiyoloji Derneği Arşivi: Türk Kardiyoloji Derneğinin Yayın Organıdır
https://www.readbyqxmd.com/read/28405720/ceramide-synthase-2-deficiency-aggravates-aom-dss-induced-colitis-in-mice-role-of-colon-barrier-integrity
#14
Stephanie Oertel, Klaus Scholich, Andreas Weigert, Dominique Thomas, Julia Schmetzer, Sandra Trautmann, Marthe-Susanna Wegner, Heinfried H Radeke, Natalie Filmann, Bernhard Brüne, Gerd Geisslinger, Irmgard Tegeder, Sabine Grösch
Loss of intestinal barrier functions is a hallmark of inflammatory bowel disease like ulcerative colitis. The molecular mechanisms are not well understood, but likely involve dysregulation of membrane composition, fluidity, and permeability, which are all essentially regulated by sphingolipids, including ceramides of different chain length and saturation. Here, we used a loss-of-function model (CerS2(+/+) and CerS2(-/-) mice) to investigate the impact of ceramide synthase 2, a key enzyme in the generation of very long-chain ceramides, in the dextran sodium salt (DSS) evoked model of UC...
August 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28336574/switching-head-group-selectivity-in-mammalian-sphingolipid-biosynthesis-by-active-site-engineering-of-sphingomyelin-synthases
#15
Matthijs Kol, Radhakrishnan Panatala, Mirjana Nordmann, Leoni Swart, Leonie van Suijlekom, Birol Cabukusta, Angelika Hilderink, Tanja Grabietz, John G M Mina, Pentti Somerharju, Sergei Korneev, Fikadu G Tafesse, Joost C M Holthuis
SM is a fundamental component of mammalian cell membranes that contributes to mechanical stability, signaling, and sorting. Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, a reaction catalyzed by SM synthase (SMS)1 in the Golgi and SMS2 at the plasma membrane. Mammalian cells also synthesize trace amounts of the SM analog, ceramide phosphoethanolamine (CPE), but the physiological relevance of CPE production is unclear. Previous work revealed that SMS2 is a bifunctional enzyme producing both SM and CPE, whereas a closely related enzyme, SMS-related protein (SMSr)/SAMD8, acts as a monofunctional CPE synthase in the endoplasmic reticulum...
May 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28322796/modulation-of-the-sphingolipid-rheostat-is-involved-in-paclitaxel-resistance-of-the-human-prostate-cancer-cell-line-pc3-pr
#16
Yuka Aoyama, Sayaka Sobue, Naoki Mizutani, Chisato Inoue, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Mamoru Kyogashima, Motoshi Suzuki, Yoshinoti Nozawa, Takashi Murate
Taxoids are anti-cancer drugs frequently used to treat solid tumors, but they are sometimes ineffective and tumors may become resistant to their action. Here, we examined the involvement of sphingolipid metabolic enzymes in paclitaxel (PTX) resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. PTX (20 nM) suppressed cell proliferation and increased various ceramide species in PC3, but not PC3-PR, cells. PC3-PR contained higher S1P levels than did PC3, regardless of PTX treatment...
April 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28320857/regulation-of-very-long-acyl-chain-ceramide-synthesis-by-acyl-coa-binding-protein
#17
Natalia Santos Ferreira, Hanne Engelsby, Ditte Neess, Samuel L Kelly, Giora Volpert, Alfred H Merrill, Anthony H Futerman, Nils J Færgeman
Ceramide and more complex sphingolipids constitute a diverse group of lipids that serve important roles as structural entities of biological membranes and as regulators of cellular growth, differentiation, and development. Thus, ceramides are vital players in numerous diseases including metabolic and cardiovascular diseases, as well as neurological disorders. Here we show that acyl-coenzyme A-binding protein (ACBP) potently facilitates very-long acyl chain ceramide synthesis. ACBP increases the activity of ceramide synthase 2 (CerS2) by more than 2-fold and CerS3 activity by 7-fold...
May 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28273483/ceramide-is-metabolized-to-acylceramide-and-stored-in-lipid-droplets
#18
Can E Senkal, Mohamed F Salama, Ashley J Snider, Janet J Allopenna, Nadia A Rana, Antonius Koller, Yusuf A Hannun, Lina M Obeid
In an approach aimed at defining interacting partners of ceramide synthases (CerSs), we found that fatty acyl-CoA synthase ACSL5 interacts with all CerSs. We demonstrate that ACSL5-generated FA-CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Functionally, inhibition of ceramide channeling to acylceramide enhanced accumulation of de novo ceramide and resulted in augmentation of ceramide-mediated apoptosis. Mechanistically, we show that acylceramide generation is catalyzed by diacylglycerol acyltransferase 2 (DGAT2) on lipid droplets...
March 7, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28223344/an-intestinal-farnesoid-x-receptor-ceramide-signaling-axis-modulates-hepatic-gluconeogenesis-in-mice
#19
Cen Xie, Changtao Jiang, Jingmin Shi, Xiaoxia Gao, Dongxue Sun, Lulu Sun, Ting Wang, Shogo Takahashi, Mallappa Anitha, Kristopher W Krausz, Andrew D Patterson, Frank J Gonzalez
Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota-FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-β-muricholic acid, which selectively suppresses intestinal FXR signaling...
March 2017: Diabetes
https://www.readbyqxmd.com/read/28198542/ceramide-synthase-2-facilitates-s1p-dependent-egress-of-thymocytes-into-the-circulation-in-mice
#20
Michael Rieck, Christiane Kremser, Katarzyna Jobin, Elisabeth Mettke, Christian Kurts, Markus Gräler, Klaus Willecke, Waldemar Kolanus
Well-defined gradients of the lipid mediator sphingosine-1-phosphate (S1P) direct chemotactic egress of mature thymocytes from the thymus into the circulation. Although it is known that these gradients result from low S1P levels in the thymic parenchyma and high S1P concentrations at the exit sites and in the plasma, the biochemical mechanisms that regulate these differential S1P levels remain unclear. Several studies demonstrated that ceramide synthase 2 (Cers2) regulates the levels of the S1P precursor sphingosine...
April 2017: European Journal of Immunology
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