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Ceramide synthases

Victoria E Palau, Kanishka Chakraborty, Daniel Wann, Janet Lightner, Keely Hilton, Marianne Brannon, William Stone, Koyamangalath Krishnan
BACKGROUND: Ceramide synthesis and metabolism is a promising target in cancer drug development. γ-tocotrienol (GT3), a member of the vitamin E family, orchestrates multiple effects that ensure the induction of apoptosis in both, wild-type and RAS-mutated pancreatic cancer cells. Here, we investigated whether these effects involve changes in ceramide synthesis and transport. METHODS: The effects of GT3 on the synthesis of ceramide via the de novo pathway, and the hydrolysis of sphingomyelin were analyzed by the expression levels of the enzymes serine palmitoyl transferase, ceramide synthase-6, and dihydroceramide desaturase, and acid sphingomyelinase in wild-type RAS BxPC3, and RAS-mutated MIA PaCa-2 and Panc 1 pancreatic cancer cells...
May 16, 2018: BMC Cancer
Songhwa Choi, Justin M Snider, Nicole Olakkengil, Johana M Lambert, Andrea K Anderson, Jessica S Ross-Evans, L Ashley Cowart, Ashley J Snider
Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, induced ER stress signaling, including activation of inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP1) signaling...
May 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
T August Li, Ronald L Schnaar
Gangliosides are expressed on all vertebrate cells and tissues, but are particularly abundant in the mammalian brain, where they constitute major cell-surface determinants on all nerve cells. The same four ganglioside structures, GM1, GD1a, GD1b, and GT1b, constitute the great majority of brain gangliosides in all mammals. Biosynthesis of these major brain gangliosides starts with addition of glucose to the ceramide lipid carrier followed by stepwise addition of up to six additional monosaccharides. This primarily involves the sequential action of seven glycosyltransferases, many of which appear to act specifically on glycolipid (rather than glycoprotein) acceptors...
2018: Progress in Molecular Biology and Translational Science
Frode Norheim, Thomas Bjellaas, Simon T Hui, Karthickeyan Chella Krishnan, Jakleen Lee, Sonul Gupta, Calvin Pan, Yehudit Hasin-Brumshtein, Brian W Parks, Daniel Li, Hai Bui, Marian Mosier, Yuping Wu, Adriana Huertas-Vazquez, Stanley W Hazen, Thomas E Gundersen, Margarete Mehrabian, Wilson Tang, Andrea L Hevener, Christian A Drevon, Aldons Jake Lusis
Elevated hepatic ceramides levels have been implicated in both insulin resistance (IR) and hepatic steatosis. To understand the factors contributing to hepatic ceramide levels in mice of both sexes, we have quantitated ceramides in a reference population of mice, the Hybrid Mouse Diversity Panel (HMDP) that has been previously characterized for a variety of metabolic syndrome traits. We observed significant positive correlations between Cer(d18:1/16:0) and IR/hepatic steatosis, consistent with previous findings, although the relationship broke down between sexes, as females were less insulin resistant but had higher Cer(d18:1/16:0) levels than males...
May 8, 2018: Journal of Lipid Research
Marcia C de Oliveira Otto, Rozenn N Lemaitre, Qi Sun, Irena B King, Jason H Y Wu, Ani Manichaikul, Stephen S Rich, Michael Y Tsai, Y D Chen, Myriam Fornage, Guan Weihua, Stella Aslibekyan, Marguerite R Irvin, Edmond K Kabagambe, Donna K Arnett, Majken K Jensen, Barbara McKnight, Bruce M Psaty, Lyn M Steffen, Caren E Smith, Ulf Risérus, Lars Lind, Frank B Hu, Eric B Rimm, David S Siscovick, Dariush Mozaffarian
BACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established. OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA...
2018: PloS One
Katrina Weston-Green, Ilijana Babic, Michael de Santis, Bo Pan, Magdalene K Montgomery, Todd Mitchell, Xu-Feng Huang, Jessica Nealon
BACKGROUND: Second generation antipsychotics (SGAs) induce glucometabolic side-effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness. Sphingolipids play a role in glycaemic balance and insulin resistance. Endoplasmic reticulum (ER) stress contributes to impaired insulin signalling and whole-body glucose intolerance. Diabetogenic SGA effects on ER stress and sphingolipids, such as ceramide and sphingomyelin, in peripheral metabolic tissues are unknown...
May 2, 2018: Journal of Biomedical Science
Renata Tiemi Okuro, Mariana Nascimento Machado, Natália Vasconcelos Casquilho, Alcendino Jardim-Neto, Alysson Roncally-Carvalho, Georgia Correa Atella, Walter Araujo Zin
AIM: This study assessed pulmonary outcomes generated by inhibiting key enzymes of sphingolipid metabolism pathways related to ceramide synthesis in a murine model of lung injury induced by lipopolysaccharide (LPS). METHODS: C57BL/6 male adult mice received LPS intratracheally and the expressions of acid sphingomyelinase (ASM), neutral sphingomyelinase (NSM), serine palmitoyl transferase (SPT) and dihydroceramide synthase (DS) were assessed at 2, 4, 6, 12 and 24 h after LPS instillation in lung homogenate (n = 30)...
April 24, 2018: Pulmonary Pharmacology & Therapeutics
Jackeline Franco, Christina Ferreira, Tiago J Paschoal Sobreira, John P Sundberg, Harm HogenEsch
Lipids are important structural and functional components of the skin. Alterations in the lipid composition of the epidermis are associated with inflammation and can affect the barrier function of the skin. SHARPIN-deficient cpdm mice develop a chronic dermatitis with similarities to atopic dermatitis in humans. Here, we used a recently-developed approach named multiple reaction monitoring (MRM)-profiling and single ion monitoring to rapidly identify discriminative lipid ions. Shorter fatty acyl residues and increased relative amounts of sphingosine ceramides were observed in cpdm epidermis compared to wild type mice...
2018: PloS One
Andreas Bickert, Paul Kern, Martina van Uelft, Stefanie Herresthal, Thomas Ulas, Katharina Gutbrod, Bernadette Breiden, Joachim Degen, Konrad Sandhoff, Joachim L Schultze, Peter Dörmann, Dieter Hartmann, Reinhard Bauer, Klaus Willecke
The replacement of two consecutive histidine residues by alanine residues in the catalytic center of ceramide synthase 2 in a new transgenic mouse mutant (CerS2 H/A) leads to inactivation of catalytic activity and reduces protein level to 60% of the WT level. We show here by qRT-PCR and transcriptome analyses that several transcripts of genes involved in lipid metabolism and cell division are differentially regulated in livers of CerS2 H/A mice. Thus, very long chain ceramides produced by CerS2 are required for transcriptional regulation of target genes...
April 10, 2018: Biochimica et Biophysica Acta
Seong-Hoon Yun, Eun-Hye Sim, Sang-Heum Han, Jin-Yeong Han, Sung-Hyun Kim, Alexandra S Silchenko, Valentin A Stonik, Joo-In Park
Marine triterpene glycosides are attractive candidates for the development of anticancer agents. Holotoxin A₁ is a triterpene glycoside found in the edible sea cucumber, Apostichopus (Stichopus) japonicus. We previously showed that cladoloside C₂, the 25(26)-dihydro derivative of holotoxin A₁ induced apoptosis in human leukemia cells by activating ceramide synthase 6. Thus, we hypothesized that holotoxin A₁, which is structurally similar to cladoloside C₂, might induce apoptosis in human leukemia cells through the same molecular mechanism...
April 10, 2018: Marine Drugs
Shikha Sharma, Mushtaq Ahmed, Yusuf Akhter
Fumonisin B1 toxin (FB1) is a well-known competitive inhibitor of ceramide synthase (CS) in yeast. However, FB1 is unable to obstruct CS from Trichoderma spp., which are well-known biocontrol agents. To explore the contrasting binding modes, a comparative structural analysis of complexes of FB1 with these two CS proteins was carried out. Formation of activation loop on the binding of substrates with the CS from yeast was observed but when inhibitor interacted with the activation loop, it transformed into helix leading to the potentially inactivated state of the enzyme...
April 3, 2018: Biochimie
Liansheng Zhong, Ji Na Kong, Michael B Dinkins, Silvia Leanhart, Zhihui Zhu, Stefka D Spassieva, Haiyan Qin, Hsuan-Pei Lin, Ahmed Elsherbini, Rebecca R Wang, Xue Jiang, Mariana Nikolova-Karakashian, Guanghu Wang, Erhard Bieberich
Sphingolipids are key signaling lipids in cancer. Genome-wide studies have identified neutral sphingomyelinase-2 (nSMase2), an enzyme generating ceramide from sphingomyelin (SM), as a potential repressor for heptocellular carcinoma. However, little is known about the sphingolipids regulated by nSMase2 and their roles in liver tumor development. We discovered growth of spontaneous liver tumors in 27.3% (9 of 33) of aged male nSMase2-deficient (fro/fro) mice. Lipidomics analysis showed marked increase of SM in the tumor...
March 22, 2018: Journal of Lipid Research
Akshaya K Meher, Michael Spinosa, John P Davis, Nicolas Pope, Victor E Laubach, Gang Su, Vlad Serbulea, Norbert Leitinger, Gorav Ailawadi, Gilbert R Upchurch
OBJECTIVE: Neutrophils promote experimental abdominal aortic aneurysm (AAA) formation via a mechanism that is independent from MMPs (matrix metalloproteinases). Recently, we reported a dominant role of IL (interleukin)-1β in the formation of murine experimental AAAs. Here, the hypothesis that IL-1β-induced neutrophil extracellular trap formation (NETosis) promotes AAA was tested. APPROACH AND RESULTS: NETs were identified through colocalized staining of neutrophil, Cit-H3 (citrullinated histone H3), and DNA, using immunohistochemistry...
April 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Cheng-Yi Chang, Jian-Ri Li, Chih-Cheng Wu, Jiaan-Der Wang, Ching-Ping Yang, Wen-Ying Chen, Wen-Yi Wang, Chun-Jung Chen
Nonsteroidal anti-inflammatory drugs (NSAIDs) are increasingly implicated in the prevention and treatment of cancers apart from their known inhibitory effects on eicosanoid production. One of the NSAIDs, indomethacin, in particular shows promising antineoplastic outcome against glioma. To extend such finding, we here studied in human H4 and U87 glioma cells the possible involvement of the ceramide/protein phosphatase 2 A (PP2A)/Akt axis in the indomethacin-induced apoptosis. We found that the induced apoptosis was accompanied by a series of biochemical events, including intracellular ceramide generation, PP2A activation, Akt dephosphorylation, Mcl-1 and FLICE inhibiting protein (FLIP) transcriptional downregulation, Bax mitochondrial distribution, and caspase 3 activation...
April 1, 2018: Experimental Cell Research
Sun Ryoung Choi, Ji Hee Lim, Min Young Kim, Eun Nim Kim, Yaeni Kim, Beom Soon Choi, Yong-Soo Kim, Hye Won Kim, Kyung-Min Lim, Min Jeong Kim, Cheol Whee Park
BACKGROUND: Adiponectin is known to take part in the regulation of energy metabolism. AdipoRon, an orally-active synthetic adiponectin agonist, binds to both adiponectin receptors (AdipoR)1/R2 and ameliorates diabetic complications. Among the lipid metabolites, the ceramide subspecies of sphingolipids have been linked to features of lipotoxicity, including inflammation, cell death, and insulin resistance. We investigated the role of AdipoRon in the prevention and development of type 2 diabetic nephropathy...
February 17, 2018: Metabolism: Clinical and Experimental
Mansa A Munshi, Justin M Gardin, Ashutosh Singh, Chiara Luberto, Robert Rieger, Tejas Bouklas, Bettina C Fries, Maurizio Del Poeta
Cryptococcus neoformans (C. neoformans) is estimated to cause about 220,000 new cases every year in patients with AIDS, despite advances in antifungal treatments. C. neoformans possesses a remarkable ability to disseminate through an immunocompromised host, making treatment difficult. Here, we examine the mechanism of survival of C. neoformans under varying host conditions and find a role for ceramide synthase in C. neoformans virulence. This study also provides a detailed lipidomics resource for the fungal lipid research community in addition to discovering a potential target for antifungal therapy...
February 6, 2018: Cell Reports
Seong-Hoon Yun, Eun-Hye Sim, Sang-Heum Han, Tae-Rang Kim, Mi-Ha Ju, Jin-Yeong Han, Jin-Sook Jeong, Sung-Hyun Kim, Alexandra S Silchenko, Valentin A Stonik, Joo-In Park
We previously demonstrated that the quinovose-containing hexaoside stichoposide C (STC) is a more potent anti-leukemic agent than the glucose-containing stichoposide D (STD), and that these substances have different molecular mechanisms of action. In the present study, we investigated the novel marine triterpene glycoside cladoloside C2 from Cladolabes schmeltzii , which has the same carbohydrate moiety as STC. We assessed whether cladoloside C2 could induce apoptosis in K562 and HL-60 cells. We also evaluated whether it showed antitumor action in mouse leukemia xenograft models, and its molecular mechanisms of action...
January 2, 2018: Oncotarget
Patrick Münzer, Sophie Mittelstädt, Sascha Geue, Mailin-Christin Manke, Britta Walker-Allgaier, Florian Lang, Meinrad Gawaz, Oliver Borst
Platelet aggregation, dense granule secretion and thrombus formation are dependent on sphingolipids like ceramide and sphingosine as well as sphingosine-1 phosphate. Sphingosine/ceramide metabolism involves ceramide synthases and ceramidases. However, the role of ceramide synthase and ceramidase in the regulation of platelet function remained ill-defined. The present study determined transmission light aggregometry, employed luciferase based ATP release measurements and studied in vitro thrombus formation under high arterial shear rates in order to define the impact of pharmacological inhibition of serine palmitoyltransferase, ceramide synthase and ceramidase on platelet function...
February 12, 2018: Biochemical and Biophysical Research Communications
Mariangela Sociale, Anna-Lena Wulf, Bernadette Breiden, Kathrin Klee, Melanie Thielisch, Franka Eckardt, Julia Sellin, Margret H Bülow, Sinah Löbbert, Nadine Weinstock, André Voelzmann, Joachim Schultze, Konrad Sandhoff, Reinhard Bauer
Maintenance of metabolic homeostasis requires adaption of gene regulation to the cellular energy state via transcriptional regulators. Here, we identify a role of ceramide synthase (CerS) Schlank, a multiple transmembrane protein containing a catalytic lag1p motif and a homeodomain, which is poorly studied in CerSs, as a transcriptional regulator. ChIP experiments show that it binds promoter regions of lipases lipase3 and magro via its homeodomain. Mutation of nuclear localization site 2 (NLS2) within the homeodomain leads to loss of DNA binding and deregulated gene expression, and NLS2 mutants can no longer adjust the transcriptional response to changing lipid levels...
January 23, 2018: Cell Reports
Kristi Helke, Peggi Angel, Ping Lu, Elizabeth Garrett-Mayer, Besim Ogretmen, Richard Drake, Christina Voelkel-Johnson
Colitis, an inflammatory disease of the digestive tract, is increasing in incidence and prevalence. Intestinal inflammation can occur as a consequence of dysfunctions in sphingolipid metabolism. In this study we used ceramide synthase 6 (CerS6) deficient mice, which have a reduced ability to generate long chain C16 -ceramide, to investigate the role of this enzyme in dextran sodium salt (DSS)-induced colitis. While CerS6-deficient mice are protected from T cell mediated colitis, in the T cell independent DSS model lack of CerS6 resulted in a more rapid onset of disease symptoms...
January 26, 2018: Scientific Reports
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