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BBA - Biomembranes (v.1758, #12)
Ceramides and other bioactive sphingolipid backbones in health and disease: Lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy
by Wenjing Zheng; Jessica Kollmeyer; Holly Symolon; Amin Momin; Elizabeth Munter; Elaine Wang; Samuel Kelly; Jeremy C. Allegood; Ying Liu; Qiong Peng; Harsha Ramaraju; M. Cameron Sullards; Myles Cabot; Alfred H. Merrill Jr. (pp. 1864-1884).
Sphingolipids are comprised of a backbone sphingoid base that may be phosphorylated, acylated, glycosylated, bridged to various headgroups through phosphodiester linkages, or otherwise modified. Organisms usually contain large numbers of sphingolipid subspecies and knowledge about the types and amounts is imperative because they influence membrane structure, interactions with the extracellular matrix and neighboring cells, vesicular traffic and the formation of specialized structures such as phagosomes and autophagosomes, as well as participate in intracellular and extracellular signaling. Fortunately, “sphingolipidomic� analysis is becoming feasible (at least for important subsets such as all of the backbone “signaling� subspecies: ceramides, ceramide 1-phosphates, sphingoid bases, sphingoid base 1-phosphates, inter alia) using mass spectrometry, and these profiles are revealing many surprises, such as that under certain conditions cells contain significant amounts of “unusual� species: N-mono-, di-, and tri-methyl-sphingoid bases (including N, N-dimethylsphingosine); 3-ketodihydroceramides; N-acetyl-sphingoid bases (C2-ceramides); and dihydroceramides, in the latter case, in very high proportions when cells are treated with the anticancer drug fenretinide (4-hydroxyphenylretinamide). The elevation of DHceramides by fenretinide is befuddling because the 4,5- trans-double bond of ceramide has been thought to be required for biological activity; however, DHceramides induce autophagy and may be important in the regulation of this important cellular process. The complexity of the sphingolipidome is hard to imagine, but one hopes that, when partnered with other systems biology approaches, the causes and consequences of the complexity will explain how these intriguing compounds are involved in almost every aspect of cell behavior and the malfunctions of many diseases.
Keywords: Sphingolipidomics; Lipidomics; Signaling; Autophagy; Disease; CancerAbbreviations; 3KSa; 3-Ketosphinganine; 3KSR; 3-Ketosphinganine reductase; 4HPR; N-(4-hydroxyphenyl) retinamide; aSMase; acid sphingomyelinase; bSMase; alkaline sphingomyelinase; C2-Cer; N-Acetylsphingosine; Cer; ceramide; Cer1P; ceramide 1-phosphate; CERK; ceramide kinase; CERT; ceramide transporter; CGalT; UDP-galactose:ceramide galactosyltransferase; CGlcT; UDP-glucose:ceramide glucosyltransferase; DES; dihydroceramide desaturase(s); DHCer; dihydroceramide; ESI; electrospray; GalCer; galactosylceramide; GFP; green fluorescent protein; GlcCer; glucosylceramide; LC; liquid chromatography; LC3; microtubule-associated protein light chain 3; MS; mass spectrometry; MS/MS and MS; n; tandem mass spectrometry; NBD-Cer; N-[6-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoylceramide, NBD-Cer; nSMase; neutral sphingomyelinase; PAF; platelet-activating factor; PDK1; 3-phosphoinositide-dependent kinase 1; Phyto-; phytosphingosine containing; PI3K; phosphoinositide-3-kinase; PKA; protein kinase A; PKC; protein kinase C; PP1; phosphoprotein phosphatases 1; PP2A; phosphoprotein phosphatases 2A; Q; quadrupole, Q; S1P; sphingosine-1-phosphate; S1PP; sphingosine-1-phosphate phosphatase; Sa; sphinganine; Sa1P; sphinganine 1-phosphate; SDK1; sphingosine-dependent kinase 1; SM; sphingomyelin; SMase; sphingomyelinase; SMS; sphingomyelin synthase; SphK; sphingosine kinase(s); SPL; sphingosine 1-phosphate lyase; SPT; serine palmitoyltransferase; TNF; tumor necrosis factor
Intracellular trafficking of sphingolipids: Relationship to biosynthesis
by Anthony H. Futerman (pp. 1885-1892).
The intracellular routes of sphingolipid trafficking are related to the compartmentalized nature of sphingolipid metabolism, with synthesis beginning in the endoplasmic reticulum, continuing in the Golgi apparatus, and degradation occurring mainly in lysosomes. Whereas bulk sphingolipid transport between subcellular organelles occurs primarily via vesicle-mediated pathways, evidence is accumulating that sphingolipids are found in subcellular organelles that are not connected to each other by vesicular flow, implying additional trafficking routes. After discussing how sphingolipids are transported through the secretory pathway, I will review evidence for sphingolipid metabolism in organelles such as the mitochondria, and then discuss how this impacts upon our current understanding of the regulation of intracellular sphingolipid transport.
Keywords: Ceramide; Glycosphingolipid; Endoplasmic reticulum; Golgi apparatus; Plasma membrane; Mitochondria; Vesicular transport; CERT
Neutral sphingomyelinases and nSMase2: Bridging the gaps
by Christopher J. Clarke; Yusuf A. Hannun (pp. 1893-1901).
There is strong evidence indicating a role for ceramide as a second messenger in processes such as apoptosis, cell growth and differentiation, and cellular responses to stress. Ceramide formation from the hydrolysis of sphingomyelin is considered to be a major pathway of stress-induced ceramide production with magnesium-dependent neutral sphingomyelinase (N-SMase) identified as a prime candidate in this pathway. The recent cloning of a mammalian N-SMase–nSMase2- and generation of nSMase2 knockout/mutant mice have now provided vital tools with which to further study the regulation and roles of this enzyme in both a physiological and pathological context. In the present review, we summarize current knowledge on N-SMase relating this to what is known about nSMase2. We also discuss the future areas of nSMase2 research important for molecular understanding of this enzyme and its physiological roles.
Keywords: Neutral sphingomyelinase; nSMase2; Ceramide; Apoptosis
Biophysics of sphingolipids I. Membrane properties of sphingosine, ceramides and other simple sphingolipids
by Félix M. Goñi; Alicia Alonso (pp. 1902-1921).
Some of the simplest sphingolipids, namely sphingosine, ceramide, some closely related molecules (eicosasphingosine, phytosphingosine), and their phosphorylated compounds (sphingosine-1-phosphate, ceramide-1-phosphate), are potent metabolic regulators. Each of these lipids modifies in marked and specific ways the physical properties of the cell membranes, in what can be the basis for some of their physiological actions. This paper reviews the mechanisms by which these sphingolipid signals, sphingosine and ceramide in particular, are able to modify the properties of cell membranes.
Keywords: Abbreviations; DEPE; dielaidoyl phosphatidylethanolamine; DMPC; dimyristoyl phosphatidylcholine; DPH; 1,6-diphenylhexatriene; DPPC; dipalmitoyl phosphatidylcholine; DPPC; dipalmitoyl phosphatidylserine; DSC; differential scanning calorimetry; POPC; 1-palmitoyl-2-oleoyl phosphatidylcholine; SM; sphingomyelinSphingolipid; Ceramide; Sphingosine; Sphingosine-1-phosphate; Ceramide-1-phosphate; Membrane domain; Membrane order; Membrane permeability; Membrane fusion; Flip-flop
Biophysics of sphingolipids II. Glycosphingolipids: An assortment of multiple structural information transducers at the membrane surface
by Bruno Maggio; M.L. Fanani; C.M. Rosetti; N. Wilke (pp. 1922-1944).
Glycosphingolipids are ubiquitous components of animal cell membranes. They are constituted by the basic structure of ceramide with its hydroxyl group linked to single carbohydrates or oligosaccharide chains of different complexity. The combination of the properties of their hydrocarbon moiety with those derived from the variety and complexity of their hydrophilic polar head groups confers to these lipids an extraordinary capacity for molecular-to-supramolecular transduction across the lateral/transverse planes in biomembranes and beyond. In our opinion, most of the advances made over the last decade on the biophysical behavior of glycosphingolipids can be organized into three related aspects of increasing structural complexity: (1) intrinsic codes: local molecular interactions of glycosphingolipids translated into structural self-organization. (2) Surface topography: projection of molecular shape and miscibility of glycosphingolipids into formation of coexisting membrane domains. (3) Beyond the membrane interface: glycosphingolipid as modulators of structural topology, bilayer recombination and surface biocatalysis.
Keywords: Abbreviations; GSLs; glycosphingolipids; Cer; N-acysphingosine (ceramide); Brain neutral GSLs and gangliosides (ganglio-series) have the same hydrocarbon moiety composition; sphingosine-linked fatty acids are over 85% stearic, arachidic and nervonica acid, sphingosine base is over 82% 18:1 and 20:1 (4-sphinegenine); GalCer; Galβ1–1′Cer; GlcCer; Glcβ1–1′Cer; LacCer; Galβ1–4Glcβ1–1′Cer; Gg3Cer; GalNAcβ1–4Galβ1–4Glcβ1–1′Cer; Gg4Cer (asialo-GM1); Galβ1–3GalNAcβ1–4Galβ1–4Glcβ1–1′Cer; GM3 (II; 3; NeuGc-LacCer); NeuGcα2–3Galβ1–4Glcβ1–1′Cer; GD3 (II; 3; (NeuAc); 2; -LacCer); NeuAcα2–8NeuAcα2–3Galβ1–4Glcβ1–1′Cer; GM2 (II; 3; NeuAc-GgOse; 3; Cer); GalNAcβ1–4Gal(3–2αNeuAc)β1–4Glcβ1–1′Cer; GM1 (II; 3; NeuAc-CgOse; 4; Cer); Galβ1–3GalNAcβ1–4Gal(3–2αNeuAc)β1–4Glcβ1–1′Cer; GD1a (IV; 3; NeuAc, II; 3; NeuAc-CgOse; 4; Cer); NeuAcα2–3Galβ1–3GalNAcβ1–4Gal(3–2αNeuAc)β1–4Glcβ1–1′Cer; GT1b (IV; 3; NeuAc, II; 3; (NeuAc); 2; -CgOse; 4; Cer); NeuAcα2–3Galβ1–3GalNAcβ1–4Gal(3–2αNeuAc8–2αNeuAc)β1–4Glcβ1–1′Cer; Sulf; HSO; 4; -3Galβ1–1′Cer; PC; phosphatidylcholine; DPPC; dipalmitoylphosphatidylcholine; DOPC; dioleoylphosphatidylcholine; POPC; palmitoyloleoylphosphatidylcholine; DOPG; dioleoylphosphatidylglycerol; CHOL; cholesterol; SM; sphingomyelin; HI; Hexagonal I phase; HII; Hexagonal II phase; PLA; 2; Phospholipase A; 2; PLC; Phospholipase C; SMase; Sphingomyelinase; MBP; Myelin Basic Protein; T; m; melting temperature; IR; Infrared Spectroscopy; EPR; Electron Paramagnetic Resonance; AFM; Atomic Force Microscopy; BAM; Brewster Angle MicroscopyGanglioside; Glycosphingolipid-enriched domain; Glycosphingolipid in membrane topology; Membrane fusion; Glycosphingolipid–phospholipid interaction; Epifluorescence microscopy; Brewster angle microscopy; Phospholipase; Sphingomyelinase
Sphingolipids and the formation of sterol-enriched ordered membrane domains
by Bodil Ramstedt; J. Peter Slotte (pp. 1945-1956).
This review is focused on the formation of lateral domains in model bilayer membranes, with an emphasis on sphingolipids and their interaction with cholesterol. Sphingolipids in general show a preference for partitioning into ordered domains. One of the roles of cholesterol is apparently to modulate the fluidity of the sphingolipid domains and also to help segregate the domains for functional purposes. Cholesterol shows a preference for sphingomyelin over phosphatidylcholine with corresponding acyl chains. The interaction of cholesterol with different sphingolipids is largely dependent on the molecular properties of the particular sphingolipid in question. Small head group size clearly has a destabilizing effect on sphingolipid/cholesterol interaction, as exemplified by studies with ceramide and ceramide phosphoethanolamine. Ceramides actually displace sterol from ordered domains formed with saturated phosphatidylcholine or sphingomyelin. The N-linked acyl chain is known to be an important stabilizer of the sphingolipid/cholesterol interaction. However, N-acyl phosphatidylethanolamines failed to interact favorably with cholesterol and to form cholesterol-enriched lateral domains in bilayer membranes. Glycosphingolipids also form ordered domains in membranes but do not show a strong preference for interacting with cholesterol. It is clear from the studies reviewed here that small changes in the structure of sphingolipids alter their partitioning between lateral domains substantially.
Keywords: Cholesterol; Sphingomyelin; Glycosphingolipid; Hydrogen bonding; Miscibility
Inhibitors of sphingolipid metabolism enzymes
by Antonio Delgado; Josefina Casas; Amadeu Llebaria; José LuÃs Abad; Gemma Fabrias (pp. 1957-1977).
Sphingolipids are a family of lipids that play essential roles both as structural cell membrane components and in cell signalling. The cellular contents of the various sphingolipid species are controlled by enzymes involved in their metabolic pathways. In this context, the discovery of small chemical entities able to modify these enzyme activities in a potent and selective way should offer new pharmacological tools and therapeutic agents.
Keywords: Abbreviations; CBA; Conduritol B aziridine; CBE; Conduritol B epoxide; CDases; Ceramidases; Cer; Ceramide(s); CerK; Ceramide kinase; CerP; Ceramide-1-phosphate; CerS; Ceramide synthase; DAG; Diacylglycerol; DES; Dihydroceramide desaturase; DHS; d,l; -; threo; -Dihydrosphingosine; DMS; N,N; -Dimethylsphingosine; DNJ; Deoxynojirimycin; ER; Endoplasmic reticulum; ERT; Enzyme replacement therapy; FB1; Fumonisin B1; GlcCer; Glucosylceramide; GlcCerase; Glucocerebrosidase; GlcCerS; Glucosylceramide synthase; GSH; Glutathione; GSLs; Glycosphingolipids; LacCer; Lactosylceramide; LacCerS; Lactosylceramide synthase; NBDGJ; N; -Butyldeoxygalactonojirimycin; NBDNJ; N; -Butyldeoxynojirimycin; NNDNJ; N; -Nonyldeoxynojirimycin; NOE; N; -Oleoylethanolamine; NOV; N; -Octylvalienamine; PKC; Phosphokinase C; SAP; Sphingolipid-activator protein; SLs; Sphingolipids; SM; Sphingomyelin; SMase; Sphingomyelinase; SMS; Sphingomyelin synthase; Sph; Sphingosine; SphK; Sphingosine kinase; SphP; Sphingosine-1-phosphate; SphPL; Sphingosine-1-phosphate lyase; SPT; Serine palmitoyltransferase; SRT; Substrate reduction therapyBiosynthesis; Sphingolipids; Metabolism; Inhibitor; Enzyme
Sphingolipid metabolism in neural cells
by Gerhild van Echten-Deckert; Thomas Herget (pp. 1978-1994).
Sphingolipids were discovered more than a century ago in the brain. Cerebrosides and sphingomyelins were named so because they were first isolated from neural tissue. Although glycosphingolipids and especially those containing sialic acid in their oligosaccharide moiety are particularly abundant in the brain, sphingolipids are ubiquitous cellular membrane components. They form cell- and species-specific profiles at the cell surfaces that characteristically change in development, differentiation, and oncogenic transformation, indicating the significance of these lipid molecules for cell–cell and cell–matrix interactions as well as for cell adhesion, modulation of membrane receptors and signal transduction. This review summarizes sphingolipid metabolism with emphasis on aspects particularly relevant in neural cell types, including neurons, oligodendrocytes and neuroblastoma cells. In addition, the reader is briefly introduced into the methodology of lipid evaluation techniques and also into the putative physiological functions of glycosphingolipids and their metabolites in neural tissue.
Keywords: Sphingolipid; Ceramide; Gangliosides; Neuron; Neuroblastoma; Metabolomic
Sphingolipids in apoptosis, survival and regeneration in the nervous system
by Elena I. Posse de Chaves (pp. 1995-2015).
Simple sphingolipids such as ceramide, sphingosine and sphingosine 1-phosphate are key regulators of diverse cellular functions. Their roles in the nervous system are supported by extensive evidence derived primarily from studies in cultured cells. More recently animal studies and studies with human samples have revealed the importance of ceramide and its metabolites in the development and progression of neurodegenerative disorders. The roles of sphingolipids in neurons and glial cells are complex, cell dependent, and many times contradictory. In this review I will summarize the effects elicited by ceramide and ceramide metabolites in cells of the nervous system, in particular those effects related to cell survival and death, emphasizing the molecular mechanisms involved. I also discuss recent evidence for the implication of sphingolipids in the development and progression of certain dementias.
Keywords: Abbreviations; Aβ; amyloid β peptide; A-SMase; acid sphingomyelinase; BDNF; brain-derived neurotrophic factor; CNS; central nervous system; DAPK; death associated protein kinase; DIV; days; in vitro; ER; endoplasmic reticulum; ERK; extracellular signal-regulated kinase; GlcCer; glucosylceramide; GSH; glutathione; GSK3; glycogen synthase kinase-3; JNK; c-Jun amino terminal kinase; MAPK; mitogen-activated protein kinase; NGF; nerve growth factor; NOE; N-oleoyl ethanolamine; N-SMase; neutral sphingomyelinase; PNS; peripheral nervous system; PI3K; phosphatidylinositide-3-kinase; PKC; protein kinase C; RA; retinoic acid; ROS; reactive oxygen species; SM; sphingomyelin; SMase; sphingomyelinase; SPh; sphingosine; SPhK; sphingosine kinase; S1P; sphingosine-1-phosphate; S1P; 1–5; sphingosine-1-P receptor 1–5; STP; serine palmitoyltransferaseSphingolipid; Ceramide; Apoptosis; Neuron; Sphingosine 1-phosphate; Alzheimer's disease
Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases
by Nitai C. Hait; Carole A. Oskeritzian; Steven W. Paugh; Sheldon Milstien; Sarah Spiegel (pp. 2016-2026).
Sphingolipids are ubiquitous components of cell membranes and their metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) have important physiological functions, including regulation of cell growth and survival. Cer and Sph are associated with growth arrest and apoptosis. Many stress stimuli increase levels of Cer and Sph, whereas suppression of apoptosis is associated with increased intracellular levels of S1P. In addition, extracellular/secreted S1P regulates cellular processes by binding to five specific G protein coupled-receptors (GPCRs). S1P is generated by phosphorylation of Sph catalyzed by two isoforms of sphingosine kinases (SphK), type 1 and type 2, which are critical regulators of the “sphingolipid rheostat�, producing pro-survival S1P and decreasing levels of pro-apoptotic Sph. Since sphingolipid metabolism is often dysregulated in many diseases, targeting SphKs is potentially clinically relevant. Here we review the growing recent literature on the regulation and the roles of SphKs and S1P in apoptosis and diseases.
Keywords: Sphingosine kinase; Sphingosine-1-phosphate; Apoptosis; Cancer; Allergy; Asthma; Development
A house divided: Ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death
by Tarek A. Taha; Thomas D. Mullen; Lina M. Obeid (pp. 2027-2036).
Programmed cell death is an important physiological response to many forms of cellular stress. The signaling cascades that result in programmed cell death are as elaborate as those that promote cell survival, and it is clear that coordination of both protein- and lipid-mediated signals is crucial for proper cell execution. Sphingolipids are a large class of lipids whose diverse members share the common feature of a long-chain sphingoid base, e.g., sphingosine. Many sphingolipids have been shown to play essential roles in both death signaling and survival. Ceramide, an N-acylsphingosine, has been implicated in cell death following a myriad of cellular stresses. Sphingosine itself can induce cell death but via pathways both similar and dissimilar to those of ceramide. Sphingosine-1-phosphate, on the other hand, is an anti-apoptotic molecule that mediates a host of cellular effects antagonistic to those of its pro-apoptotic sphingolipid siblings. Extraordinarily, these lipid mediators are metabolically juxtaposed, suggesting that the regulation of their metabolism is of the utmost importance in determining cell fate. In this review, we briefly examine the role of ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death and highlight the potential roles that these lipids play in the pathway to apoptosis.
Keywords: Programmed cell death; Ceramide; Sphingosine; Sphingosine-1-phosphate (S1P); Sphingolipid; Apoptosis
Sphingosine 1-phosphate regulates cytoskeleton dynamics: Implications in its biological response
by Chiara Donati; Paola Bruni (pp. 2037-2048).
The bioactive sphingolipid sphingosine 1-phosphate (S1P) elicits robust cytoskeletal rearrangement in a large variety of cell systems, mainly acting through a panel of specific cell surface receptors, named S1P receptors. Recent studies have begun to delineate the molecular mechanisms involved in the complex process responsible for cytoskeletal rearrangement following S1P ligation to its receptors. Notably, changes of cell shape and/or motility induced by S1P via cytoskeletal remodelling are functional to the biological action exerted by S1P which appears to be highly cell-specific. This review focuses on the current knowledge of the regulatory mechanisms of cytoskeleton dynamics elicited by S1P, with special emphasis on the relationship between cytoskeletal remodelling and the biological effects evoked by the sphingolipid in various cell types.
Keywords: Sphingosine 1-phosphate; Sphingosine 1-phosphate receptors; Cytoskeleton rearrangement; Rho GTPases; Cell motility
Ceramide 1-phosphate/ceramide, a switch between life and death
by Antonio Gómez-Muñoz (pp. 2049-2056).
Ceramide is a well-characterized sphingolipid metabolite and second messenger that participates in numerous biological processes. In addition to serving as a precursor to complex sphingolipids, ceramide is a potent signaling molecule capable of regulating vital cellular functions. Perhaps its major role in signal transduction is to induce cell cycle arrest, and promote apoptosis. In contrast, little is known about the metabolic or signaling pathways that are regulated by the phosphorylated form of ceramide. It was first demonstrated that ceramide-1-phosphate (C1P) had mitogenic properties, and more recently it has been described as potent inhibitor of apoptosis and inducer of cell survival. C1P and ceramide are antagonistic molecules that can be interconverted in cells by kinase and phosphatase activities. An appropriate balance between the levels of these two metabolites seems to be crucial for cell and tissue homeostasis. Switching this balance towards accumulation of one or the other may result in metabolic dysfunction, or disease. Therefore, the activity of the enzymes that are involved in C1P and ceramide metabolism must be efficiently coordinated to ensure normal cell functioning.
Keywords: Abbreviations; C; 2; -ceramide; N-acetylsphingosine; C; 8; -ceramide; N-octanoylsphingosine; CERK; ceramide kinase; C1P; ceramide-1-phosphate; DAG; diacylglycerol; ERK; extracellular regulated kinase; MAPK; mitogen-activated protein kinase; M-CSF; monocyte-colony stimulating factor; PA; phosphatidate; PI3-K; phosphatidylinositol 3-kinase; PKA; cAMP-dependent protein kinase; PKB; protein kinase B; PLA; 2; phospholipase A; 2; PKC; protein kinase C; PLD; phospholipase D; SM; sphingomyelin; SMase; sphingomyelinase; S1P; sphingosine-1-phosphateApoptosis; Cell proliferation; Ceramide-1-phosphate; Phosphatidylinositol 3-kinase; Sphingosine 1-phosphate; Sphingomyelinases
Sphingolipid metabolism diseases
by Thomas Kolter; Konrad Sandhoff (pp. 2057-2079).
Human diseases caused by alterations in the metabolism of sphingolipids or glycosphingolipids are mainly disorders of the degradation of these compounds. The sphingolipidoses are a group of monogenic inherited diseases caused by defects in the system of lysosomal sphingolipid degradation, with subsequent accumulation of non-degradable storage material in one or more organs. Most sphingolipidoses are associated with high mortality. Both, the ratio of substrate influx into the lysosomes and the reduced degradative capacity can be addressed by therapeutic approaches. In addition to symptomatic treatments, the current strategies for restoration of the reduced substrate degradation within the lysosome are enzyme replacement therapy (ERT), cell-mediated therapy (CMT) including bone marrow transplantation (BMT) and cell-mediated “cross correction�, gene therapy, and enzyme-enhancement therapy with chemical chaperones. The reduction of substrate influx into the lysosomes can be achieved by substrate reduction therapy. Patients suffering from the attenuated form (type 1) of Gaucher disease and from Fabry disease have been successfully treated with ERT.
Keywords: Ceramide; Lysosomal storage disease; Saposin; Sphingolipidose
The skin barrier in healthy and diseased state
by Joke A. Bouwstra; Maria Ponec (pp. 2080-2095).
The primary function of the skin is to protect the body for unwanted influences from the environment. The main barrier of the skin is located in the outermost layer of the skin, the stratum corneum. The stratum corneum consists of corneocytes surrounded by lipid regions. As most drugs applied onto the skin permeate along the lipid domains, the lipid organization is considered to be very important for the skin barrier function. It is for this reason that the lipid organization has been investigated quite extensively. Due to the exceptional stratum corneum lipid composition, with long chain ceramides, free fatty acids and cholesterol as main lipid classes, the lipid organization is different from that of other biological membranes. In stratum corneum, two lamellar phases are present with repeat distances of approximately 6 and 13Â nm. Moreover the lipids in the lamellar phases form predominantly crystalline lateral phases, but most probably a subpopulation of lipids forms a liquid phase. Diseased skin is often characterized by a reduced barrier function and an altered lipid composition and organization. In order to understand the aberrant lipid organization in diseased skin, information on the relation between lipid composition and organization is crucial. However, due to its complexity and inter-individual variability, the use of native stratum corneum does not allow detailed systematic studies. To circumvent this problem, mixtures prepared with stratum corneum lipids can be used. In this paper first the lipid organization in stratum corneum of normal and diseased skin is described. Then the role the various lipid classes play in stratum corneum lipid organization and barrier function has been discussed. Finally, the information on the role various lipid classes play in lipid phase behavior has been used to interpret the changes in lipid organization and barrier properties of diseased skin.
Keywords: Abbreviations; CERs; ceramides; SAXD; small angle X-ray diffraction; WAXD; Wide angle X-ray diffraction; ED; electron diffraction; λ; wavelength of X-rays; d; periodicity; FFAs; free fatty acids; CHOL; cholesterol; SPP; short periodicity phase; LPP; long periodicity phase; CER1-ol; ceramide 1 oleate; CER1-lin; ceramide 1 linoleate; CER1-ste; ceramide 1 stearate; FFEM; freeze fracture electron microscopy; EFAD; essential fatty acid deficient; LI; lamellar ichthyosis
Glycosphingolipids and drug resistance
by Valerie Gouaze-Andersson; Myles C. Cabot (pp. 2096-2103).
Drug resistance, an all too frequent characteristic of cancer, represents a serious barrier to successful treatment. Although many resistance mechanisms have been described, those that involve membrane-resident proteins belonging to the ABC (ATP binding cassette) transporter superfamily are of particular interest. In addition to cancer, the ABC transporter proteins are active in diseases such as malaria and leishmaniasis. A recent renaissance in lipid metabolism, specifically ceramide and sphingolipids, has fueled research and provided insight into the role of glycosphingolipids in multidrug resistance. This article reviews current knowledge on ceramide, glucosylceramide synthase and cerebrosides, and the relationship of these lipids to cellular response to anticancer agents.
Keywords: Multidrug resistance; Glycosphingolipids; Glucosylceramide synthase; P-glycoprotein
Sphingolipids as modulators of cancer cell death: Potential therapeutic targets
by Bruno Ségui; Nathalie Andrieu-Abadie; Jean-Pierre Jaffrézou; Hervé Benoist; Thierry Levade (pp. 2104-2120).
Through modifications in the fine membrane structure, cell–cell or cell–matrix interactions, and/or modulation of intracellular signaling pathways, sphingolipids can affect the tumorigenic potential of numerous cell types. Whereas ceramide and its metabolites have been described as regulators of cell growth and apoptosis, these lipids as well as other sphingolipid molecules can modulate the ability of malignant cells to grow and resist anticancer treatments, and their susceptibility to non-apoptotic cell deaths. This review summarizes our current knowledge on the properties of sphingolipids in the regulation of cancer cell death and tumor development. It also provides an update on the potential perspectives of manipulating sphingolipid metabolism and using sphingolipid analogues in anticancer therapy.
Keywords: Abbreviations; GalCer; galactosylceramide; GlcCer; glucosylceramide; GCS; glucosylceramide synthase; MDR; multidrug resistance; ROS; reactive oxygen species; SL; sphingolipid; SM; sphingomyelin; SMase; sphingomyelinase; SMS; sphingomyelin synthase; S1P; sphingosine 1-phosphate; TNF; tumor necrosis factorCeramide; Apoptosis; Sphingolipid; Autophagy; Caspase; Lysosome
Sphingolipid players in the leukemia arena
by Clara Ricci; Francesco Onida; Riccardo Ghidoni (pp. 2121-2132).
Sphingolipids function as bioactive mediators of different cellular processes, mostly proliferation, survival, differentiation and apoptosis, besides being structural components of cellular membranes. Involvement of sphingolipid metabolism in cancerogenesis was demonstrated in solid tumors as well as in hematological malignancies. Herein, we describe the main biological and clinical aspects of leukemias and summarize data regarding sphingolipids as mediators of apoptosis triggered in response to anti-leukemic agents and synthetic analogs as inducers of cell death as well. We also report the contribution of molecules that modulate sphingolipid metabolism to development of encouraging strategies for leukemia treatment. Finally we address how deregulation of sphingolipid metabolism is associated to occurrence of therapy resistance both in vitro and in vivo. Sphingolipids can be considered promising therapeutic tools alone or in combination with other compounds, as well as valid targets in the attempt to eradicate leukemia and overcome drug resistance.
Keywords: Abbreviations; 4-HPR; fenretinide; ALL; acute lymphoblastic leukemia; AML; acute myeloid leukemia; AMMoL; acute myelomonocytic leukemia; APL; acute promyelocytic leukemia; Ara-c; cytosine arabinoside; aSMase; acid sphingomyelinase; ATRA; all–trans retinoic acid; B-CLL; chronic B-cell lymphoid leukemia; Cer; Ceramide; CML; chronic myelogenous leukemia; D609; tricyclodecan-9-yl-xanthogenate; d-e-MAPP; (1S,2R)-d-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol; DMS; N,N; -Dimethylsphingosine; DNR; daunorubicin; doxo; doxorubicin; DT; diphtheria toxin; EBV; Epstein–Barr Virus; Epo; erythropoietin; GCS; GlucosylCeramideSynthase; GlcCer; GlucosylCeramide; GM-CSF; granulocyte-macrophage colony-stimulating factor; GSH; glutathione; HDACIs; histone deacetylases inhibitors; HSC; hematopoietic stem cells; IM; Imatinib Mesylate; IR; ionizing radiation; LSC; leukemic stem cells; nSMase; neutral sphingomyelinase; Pgp; P-glycoprotein; Ph; Philadelphia Chromosome; PKC; protein kinases C; PPPP; dl-threo-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol; ROS; reactive oxygen species; S1P; sphingosine-1-phosphate; SAHA; suberoylanilide hydroximic acid; SK1; sphingosine kinase 1; SM; sphingomyelin; SMS; sphingomyelin synthase; SPLs; sphingolipids; SPT; serine-palmitoyl transferase; T-ALL; acute T-lymphoblastic leukemia; VCR; vincristineLeukemia; Sphingolipids; Ceramide; Apoptosis; Chemotherapeutics; Resistance
Acid ceramidase and human disease
by Jae-Ho Park; Edward H. Schuchman (pp. 2133-2138).
Acid ceramidase ( N-acylsphingosine deacylase, EC 3.5.1.23; AC) is the lipid hydrolase responsible for the degradation of ceramide into sphingosine and free fatty acids within lysosomes. The enzymatic activity was first identified over four decades ago, and is deficient in the inherited lipid storage disorder, Farber Lipogranulomatosis (Farber disease). Importantly, AC not only hydrolyzes ceramide into sphingosine, but also can synthesize ceramide from sphingosine and free fatty acids in vitro and in situ. This “reverse� enzymatic activity occurs at a distinct pH from the hydrolysis (“forward�) reaction (6.0vs. 4.5, respectively), suggesting that the enzyme may have diverse functions within cells dependent on its subcellular location and the local pH. Most information concerning the role of AC in human disease stems from work on Farber disease. This lipid storage disease is caused by mutations in the gene encoding AC, leading to a profound reduction in enzymatic activity. Recent studies have also shown that AC activity is aberrantly expressed in several human cancers, and that the enzyme may be a useful cancer drug target. For example, AC inhibitors have been used to slow the growth of cancer cells, alone or in combination with other established, anti-oncogenic treatments. Aberrant AC activity also has been described in Alzheimer's disease, and overexpression of AC may prevent insulin resistant (Type II) diabetes induced by free fatty acids. Current information concerning the biology of this enzyme and its role in human disease is reviewed within.
Keywords: Acid ceramidase; Farber disease; Ceramide; Apoptosis; Cancer
Membrane rafts in host–pathogen interactions
by Joachim Riethmüller; Andrea Riehle; Heike Grassmé; Erich Gulbins (pp. 2139-2147).
Central elements in the infection of mammalian cells with viral, bacterial and parasitic pathogens include the adhesion of the pathogen to surface receptors of the cell, recruitment of additional receptor proteins to the infection-site, a re-organization of the membrane and, in particular, the intracellular signalosome. Internalization of the pathogen results in the formation of a phagosome that is supposed to fuse with lysosomes to form phagolysosomes, which serve the degradation of the pathogen, an event actively prevented by some pathogens. In summary, these changes in the infected cell permit pathogens to trigger apoptosis (for instance of macrophages paralysing the initial immune response), to invade the cell and/or to survive in the cell, but they also serve the mammalian cell to defeat the infection, for instance by activation of transcription factors and the release of cytokines. Distinct membrane domains in the plasma membrane and intracellular vesicles that are mainly composed of sphingolipids and cholesterol or enriched with the sphingolipid ceramide, are critically involved in all of these events occurring during the infection. These membrane structures are therefore very attractive targets for novel drugs to interfere with bacterial, viral and parasitic infections.
Keywords: Bacteria; Viruses; Infections; Membrane; Rafts; Ceramide
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