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PubMed1996

Sphingomyelin consumption suppresses aberrant colonic crypt foci and increases the proportion of adenomas versus adenocarcinomas in CF1 mice treated with 1,2-dimethylhydrazine: implications for dietary sphingolipids and colon carcinogenesis.

Sphingolipids are hydrolyzed in the gastrointestinal tract to ceramide, sphingosine, and other metabolites that can modulate cell growth, differentiation, and apoptosis. To characterize the effects of dietary sphingolipids on colon carcinogenesis, female CF1 mice were administered 1,2-dimethylhydrazine and then fed an essentially sphingolipid-free diet supplemented with 0 to 0.1% (w/w) sphingomyelin (SM) purified from milk. As was found in a previous pilot study (D. L. Dillehay et al., J. Nutr., 124: 615-620, 1994), SM (@ 0.1%) reduced the number of aberrant colonic crypt foci (by 70%, P < 0.001) and aberrant crypts per focus (by 30%, P < 0.003), which are early indicators of colon carcinogenesis. In longer term studies, SM had no effect on colon tumor incidence or multiplicity; however, up to 31% of the tumors of mice fed SM were adenomas, whereas all of the tumors of mice fed the diet without SM were adenocarcinomas. These findings demonstrate that milk SM suppresses the appearance of more advanced, malignant tumors as well as early markers of colon carcinogenesis. Although the sphingolipid content of foods has not been widely studied, several foods (e.g., milk and soybeans) contain the sphingolipid levels used in these investigations; therefore, this class of compounds could be significant contributors to the cancer preventive effects of some foods.

1,2-Dimethylhydrazine↗
PubMed1992

Activator proteins and topology of lysosomal sphingolipid catabolism.

The lysosomal degradation of several sphingolipids by acid hydrolases is dependent on small non-enzymic cofactors, called sphingolipid activator proteins some of which have been identified as sphingolipid binding proteins. This review summarizes the information available on the structure, function, biosynthesis, gene organization and pathobiochemistry of the known sphingolipid activator proteins. It also offers models for their mode of action and for the topology of lysosomal digestion of glycolipids.

Animals↗
PubMed2003

Changes of sphingolipid species in the phenotype conversion from myofibroblasts to lipocytes in hepatic stellate cells.

Sphingolipids play a relevant role in cell-cell interaction, communication, and migration. We studied the sphingolipid content in the murine hepatic stellate cell line GRX, which expresses the myofibroblast phenotype, and can be induced in vitro to display the fat-storing phenotype. Lipid modifications along this induction were investigated by labeling sphingolipids with [(14)C]galactose, [(14)C]serine, or [(14)C]choline, and determination of fatty acid composition of sphingomyelin. The total ganglioside content and the GM2 synthase activity were lower in myofibroblasts. Both phenotypes presented similar gangliosides of the a-pathway: GM2, GM1, and GD1a as well as their precursor GM3. Sphingomyelin and all the gangliosides were expressed as doublets; the upper/lower band ratio increased in lipocytes, containing more long-chain fatty acids in retinol-induced lipocytes as compared to the insulin/indomethacin induced ones. Time-course experiments indicated a transfer of metabolic precursors from phosphatidylcholine to sphingomyelin in the two phenotypes. Taken together, these results indicate that myofibroblast and lipocytes can use distinct ceramide pools for sphingolipid synthesis. Differential ganglioside expression and presence of the long-chain saturated fatty acids suggested that they may participate in formation of distinct membrane microdomains or rafts with specific functions on the two phenotypes of GRX-cells.

Adipocytes↗
PubMed1984

Biosynthesis of phospholipids and sphingolipids from acetoacetate and glucose in different regions of developing brain in vivo.

The incorporation of 14C-label from subcutaneously injected [3-14C]acetoacetate and [U-14C]glucose into phospholipids and sphingolipids in different regions of developing rat brain was determined. In all regions, phosphatidylcholine was the lipid synthesized most readily from either substrate. The percentages of radioactivity in other phospholipids and most sphingolipids remained relatively constant throughout postnatal development. An exceptional increase in the percentage of radioactivity incorporated into cerebroside, coinciding with a decrease of incorporation into phosphatidylcholine, was first noted on day 12 and continued until a maximal level was reached between days 18 and 20 of postnatal age. These developmental changes in preferential synthesis of lipids were associated with increased demands for phospholipids and cerebroside during the early and late postnatal stages, respectively. There was no difference in accumulation of radioactivity from acetoacetate, expressed as dpm of [14C]acetoacetate recovered in phospholipids plus sphingolipids per g of tissue, among all brain regions during the first 5 days of life. During active myelination (12 to 20 days of age); however, the amount of 14C-label was highest in brain stem, ranging from 1.9- to 2.3-fold greater than values for cerebrum and thalamus. The region with the next highest accumulation was cerebellum, followed by midbrain. During the same period, brain stem was likewise the most active site of accumulation of radioactivity from 14C-labeled glucose. Higher amounts of [14C]acetoacetate label accumulated in lipids of brain stem and cerebellum, relative to midbrain, thalamus, and cerebrum, coincide with evidence that active myelination begins in the hindbrain and proceeds rostrally toward the forebrain. Ketone bodies could therefore serve as a potential source of phospholipids and sphingolipids for brain growth and maturation.

Acetoacetates↗
PubMed2006

Mass spectrometry-based profiling of phospholipids and sphingolipids in extracts from Saccharomyces cerevisiae.

Lipids are rapidly moving to centre stage in many fields of biological sciences. Lipidomics, the systems-level scale analysis of lipids and their interacting factors, is thus an emerging field which holds great promise for drug and biomarker discovery. Here we present a mass spectrometry-based approach for profiling of polar lipids, in particular phospholipids and sphingolipids, in Saccharomyces cerevisiae. The first step includes semi-quantitative surveys of lipids in an untargeted fashion, which is particularly powerful for detection of changes that cannot easily be anticipated. This leads to the identification of ions with increased or decreased signal intensities. Comprehensive theoretical calculation of the masses of yeast phospholipid and sphingolipid molecular species, based on fatty acyl and headgroup heterogeneity, is next used to tentatively assign ions of interest. Subsequent targeted analysis using tandem mass spectrometry allows for characterization and quantification of phospholipids and sphingolipids. Given the high degree of conservation in pathways of lipid metabolism between different organisms, it can be expected that this method will lead to the discovery of novel enzymatic activities and modulators of known ones, particularly when used in combination with genetic and chemogenetic libraries and screens. We validated the method using the EUROSCARF library of non-essential deletion mutants. Mutants of SCS7, a lipid hydroxylase, and SLC1, a putative acyl transferase with unknown substrate specificity, were profiled for their phospholipid and sphingolipid content. The observed changes in lipid profiles are consistent with previous observations and extend our knowledge on in vivo substrate use under permissive growth conditions.

Carbohydrate Sequence↗
PubMed1992

Farber bodies found in murine phagocytes after injection of ceramides and related sphingolipids.

Mice were injected subcutaneously with a single dose of sphingolipids. The sphingolipids tested were: ceramide with alpha-hydroxy fatty acids, ceramide with non-hydroxy fatty acids, glucocerebroside, sphingomyelin, and galactocerebroside. Lipids without sphingolipids served as a control. The mice were sacrificed 1, 2, 3, 4, 5 and 7 days after injection. Three mice were used for each experiment. The subcutaneous tissue at the injected area, the liver and the spleen were studied histologically. At 1-3 days after injection, numerous cytoplasmic inclusion bodies were observed in the macrophages and fibroblasts in the subcutaneous tissue, but not in the liver or the spleen. Ultrastructural studies of the inclusion bodies indicated that the sphingolipids taken up by the phagocytes retained their respective original shape during the 1-3 day stage. At days 4 and 5, the number of the inclusion bodies decreased, but they contained Farber bodies, i.e. curvilinear bodies 12 to 25 nm wide and up to 120 nm long. The mice with galactocerebroside were an exception, with parallel leaflets structures, but without the Farber bodies.

Animals↗
PubMed2003

How sphingolipids bind and shape proteins: molecular basis of lipid-protein interactions in lipid shells, rafts and related biomembrane domains.

Understanding the molecular mechanisms controlling the association of proteins with lipid rafts is a central issue in cell biology and medicine. A structurally conserved motif (the 'sphingolipid binding domain') has been characterized in unrelated cellular and microbial proteins targeted to lipid rafts. I propose that the structuration of a sphingolipid shell around the sphingolipid binding domain not only extracts the protein from the liquid-disordered phase of the plasma membrane, and ensures its delivery to lipid rafts, but also influences its conformation. The chaperone activity of sphingolipids in shells and rafts may play an important role in infectious and conformational diseases(human immunodeficiency virus-1, prions, Alzheimer).

Alzheimer Disease↗
PubMed2005

Enzymes of sphingolipid metabolism in Drosophila melanogaster.

Sphingolipids are important structural components of membranes that delimit the boundaries of cellular compartments, cells and organisms. They play an equally important role as second messengers, and transduce signals across or within the compartments they define to initiate physiological changes during development, differentiation and a host of other cellular events. For well over a century Drosophila melanogaster has served as a useful model organism to understand some of the fundamental tenets of development, differentiation and signaling in eukaryotic organisms. Directed approaches to study sphingolipid biology in Drosophila have been initiated only recently. Nevertheless, earlier phenotypic studies conducted on genes of unknown biochemical function have recently been recognized as mutants of enzymes of sphingolipid metabolism. Genome sequencing and annotation have aided the identification of homologs of recently discovered genes. Here we present an overview of studies on enzymes of the de novo sphingolipid biosynthetic pathway, known mutants and their phenotypic characterization in Drosophila.

Acyltransferases↗
PubMed2000

Sphingolipid receptor signaling and function in human bladder carcinoma cells: inhibition of LPA- but enhancement of thrombin-stimulated cell motility.

Sphingosine-1-phosphate (SPP) induces a variety of cellular responses, including Ca2+ signaling, proliferation, and inhibition of motility, apparently by acting at specific G protein coupled receptors. Here, the expression, signaling, and motile responses of sphingolipid receptors were examined in human bladder carcinoma (J82) cells, for which lysophosphatidic acid (LPA) and thrombin act as potent agonists. SPP potently and rapidly mobilized Ca2+, stimulated phospholipases C and D, and inhibited cAMP accumulation, without affecting growth of J82 cells, which express the recently identified SPP receptors, Edg-1 and Edg-3. The effects of SPP were mimicked by sphingosylphosphorylcholine (SPPC) and strongly attenuated by pertussis toxin (PTX). SPP and SPPC by themselves induced a small, PTX-sensitive motile response. However, stimulation of cell motility by LPA, which by itself was also PTX-sensitive, was blocked by SPP and SPPC. In contrast, motility stimulation by thrombin, which by itself was PTX-insensitive, was strongly augmented by the sphingolipids in a PTX-sensitive manner. The bidirectional regulation of LPA- and thrombin-stimulated motility was not due to selective alterations in the activation of Rho GTPases which control cell motility. In fact, RhoA activation and Rho-dependent actin stress fiber formation induced by LPA and thrombin were mimicked, but not altered by SPP and SPPC. We conclude that J82 cells express sphingolipid receptors, coupled via G proteins to several signaling pathways. Most importantly, these sphingolipid receptors potently regulate thrombin- and LPA-stimulated motility, but in opposite directions, suggesting that migration of these human bladder carcinoma cells is controlled by a complex network of interacting extracellular ligands.

Actins↗
PubMed2001

The involvement of sphingolipids in multidrug resistance.

Administration of most chemotherapeutic agents eventually results in the onset of apoptosis, despite the agents' variety in structure and molecular targets. Ceramide, the central molecule in cellular glycosphingolipid metabolism, has recently been identified as an important mediator of this process. Indeed, one of the events elicited by application of many cytotoxic drugs is an accumulation of this lipid. Treatment failure in cancer chemotherapy is largely attributable to multidrug resistance, in which tumor cells are typically cross-resistant to multiple chemotherapeutic agents. Different cellular mechanisms underlying this phenomenon have been described. Of these the drug efflux pump activity of P-glycoprotein and the multidrug resistance-associated proteins are the most extensively studied examples. Recently, an increased cellular capacity for ceramide glycosylation has been recognized as a novel multidrug resistance mechanism. Indeed, virtually all multidrug-resistant cells exhibit a deviating sphingolipid composition, most typically, increased levels of glucosylceramide. On the other hand, several direct molecular interactions between sphingolipids and drug efflux proteins have been described. Therefore, in addition to a role in the multidrug resistance phenotype by which ceramide accumulation and, thus, the onset of apoptosis are prevented, an indirect role for sphingolipids might be envisaged, by which the activity of these efflux proteins is modulated. In this review, we present an overview of the current understanding of the interesting relations that exist between sphingolipid metabolism and multidrug resistance.

ATP-Binding Cassette Transporters↗
PubMed2005

A computational approach to the inference of sphingolipid pathways from the genome of Aspergillus fumigatus.

A growing body of evidence suggests that sphingolipids are important bioactive molecules, in addition to being critical structural components of cellular membranes. These molecules have been implicated in regulating cell growth, differentiation, angiogenesis, apoptosis, and senescence. Many of the enzymes involved in sphingolipid biosynthesis are the targets of fungal toxins, thus underscoring the importance of this pathway. An international consortium has made considerable progress in sequencing the genome of Aspergillus fumigatus, one of the most common mold pathogens of humans; however, most genes have not yet been annotated. Here, we have identified genes involved in the sphingolipid pathway of A. fumigatus by comparative analysis with four other fungal species and the gene prediction program GlimmerM. Our results shows that A. fumigatus has most of the sphingolipid pathway genes found in other fungi, except for the CSG2 and IPT1 genes; the former is involved in the mannosylation of inositol phosphorylceramide (IPC) to mannose-inositol-phosphorylceramide and the latter involved in the synthesis of mannose-(inositol-P)(2)-ceramide from mannose-inositol-phosphorylceramide.

Aspergillus fumigatus↗
PubMed2006

A sphingolipid rich lipid fraction isolated from attenuated Leishmania donovani promastigote induces apoptosis in mouse and human melanoma cells in vitro.

Lipids, especially sphingolipids, are emerging as inducer of apoptosis in a wide range of immortal cells, potentiating their therapeutic application in cancer. In the present study, a sphingolipid rich lipid fraction (denoted here as ALL), isolated from an attenuated strain of Leishmania donovani promastigote, was tested for its tumoricidal activity taking melanoma, the dreaded form of skin cancer cells, as model. ALL was found to induce chromatin condensation, internucleosomal DNA fragmentation and phosphatidylserine externalization with enhanced cell population in sub-G1 region in both mouse and human melanoma systems, namely B16F10 and A375 respectively. These are the hallmarks of cells undergoing apoptosis. Further analysis demonstrated that ALL treated melanoma cells showed significant increase in ROS generation, mitochondrial membrane potential depolarization, release of cytochrome c, and caspase-3 activation, which are the events closely involved in apoptosis. These findings indicate that one or more bioactive sphingolipid(s)/ceramide(s) present in ALL could be the causative agent(s) for the induction of apoptosis in melanoma cells. Further studies are thus necessary to identify these specific bioactive sphingolipid(s)/ceramide(s) and to establish their mechanism of action, in order to explore their use as anticancer agents.

Animals↗
PubMed1981

Sphingolipid-induced enhancement of receptor-mediated uptake of low density lipoproteins in normal and receptor-deficient human skin fibroblasts.

(1) The receptor mediated endocytosis of homologous LDL by human skin fibroblasts can be significantly enhanced by prior incubation of the cells with sphingolipids. Gangliosides GM1 or GD1a, their desialylated derivatives and sphingosine stimulate binding and uptake to LDL by up to 40% of normal values. The effect is observed in normal fibroblasts, LDL receptor deficient fibroblasts or in tunicamycin-treated cells with a reduced number of functional receptors but is dependent on the time of preincubation of the cells and the concentration of the sphingolipid in the medium. (2) Detailed studies on the ganglioside effect revealed, that cell bound gangliosides intensify the LDL-induced suppression of [14C] acetate incorporation into cholesterol. (3) The receptor dependence and relative receptor specificity of the sphingolipid effect is evident from the fact that (a) after complete suppression of receptor synthesis gangliosides fail to stimulate uptake of LDL, that (b) fatty acids or lipids not containing sphingosine are without effect and that (c) the receptor specific internalisation of alpha 2-macroglobulin or epidermal growth factor is not influenced by exogenous sphingolipids.

Cholesterol↗
PubMed1977

Sphingolipid composition and catabolism in human fetal tissues.

Human fetal tissues derived from prostaglandin-induced abortuses (9--18 wk fertilization age) have been utilized to evaluate sphingolipid composition and catabolism. Sphingolipid composition (lipid-hexose, sulfatide, and lipid-bound NANA) was assessed in fetal brain. Sphingolipid catabolism was evaluated in fetal lung and brain through the measurement of relevant acid hydrolases (arylsulfatase A, beta-galactosidase, and hexosaminidase). During the fetal period studied, the parameters of sphingolipid composition revealed variability but no consistent pattern of change. Each acid hydrolase was readily detected. Enzyme specific activities revealed no variation during the 9 fetal wk studied. Cellulose acetate electrophoresis yielded the anticipated isoenzyme patterns for each acid hydrolase with little variation during the period of study. The compositional values support current concepts of cerebral development during this period of fetal life. Together with the catabolic analyses, these studies provide normative data relative to the assessment of metabolic abnormalities during this period of fetal development.

Brain↗
PubMed2005

Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice.

Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, and all these functions may have an impact on atherosclerotic development. Serine palmitoyl-CoA transferase (SPT) is the key enzyme in sphingolipid biosynthesis. To evaluate in vivo SPT activity and its role in sphingolipid metabolism, we applied homologous recombination to embryonic stem cells, producing mice with long chain base 1 (Sptlc1) and long chain base 2 (Sptlc2), two subunits of SPT, gene deficiency. Homozygous Sptlc11 and Sptlc2 mice are embryonic lethal, whereas heterozygous versions of both animals (Sptlc1(+/-), Sptlc2(+/-)) are healthy. Analysis showed that, compared with WT mice, Sptlc1(+/-) and Sptlc2(+/-) mice had: (1) decreased liver Sptlc1 and Sptlc2 mRNA by 44% and 57% (P<0.01 and P<0.0001, respectively); (2) decreased liver Sptlc1 mass by 50% and Sptlc2 mass by 70% (P<0.01 and P<0.01, respectively), moreover, Sptlc1 mass decreased by 70% in Sptlc2(+/-) mouse liver, while Sptlc2 mass decreased by 53% in Sptlc1(+/-) mouse liver (P<0.001 and P<0.01, respectively); (3) decreased liver SPT activity by 45% and 60% (P<0.01, respectively); (4) decreased liver ceramide (22% and 39%, P<0.05 and P<0.01, respectively) and sphingosine levels (22% and 31%, P<0.05 and P<0.01, respectively); (5) decreased plasma ceramide (45% and 39%, P<0.01, respectively), sphingosine-1-phosphate (31% and 32%, P<0.01, respectively) and sphingosine levels (22.5% and 25%, P<0.01, respectively); (6) dramatically decreased plasma lysosphingomyelin (17-fold and 16-fold, P<0.0001, respectively); and (7) no change of plasma sphingomyelin, triglyceride, total cholesterol, phospholipids, and liver sphingomyelin levels. These results indicated that both Sptlc1 and Sptlc2 interactions are necessary for SPT activity in vivo, and that SPT activity directly influences plasma sphingolipid levels. Furthermore, manipulation of SPT activity might well influence the course of such diseases as atherosclerosis.

Animals↗
PubMed2004

Sphingolipid metabolites in neural signalling and function.

Sphingolipid metabolites, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P) and complex sphingolipids (gangliosides), are recognized as molecules capable of regulating a variety of cellular processes. The role of sphingolipid metabolites has been studied mainly in non-neuronal tissues. These studies have underscored their importance as signals transducers, involved in control of proliferation, survival, differentiation and apoptosis. In this review, we will focus on studies performed over the last years in the nervous system, discussing the recent developments and the current perspectives in sphingolipid metabolism and functions.

Animals↗
PubMed2005

Inhibition of sphingolipid biosynthesis decreases phosphorylated ERK2 in LLC-PK1 cells.

Fumonisin B(1) (FB(1)) is a fungal toxin produced by Fusarium verticillioides that inhibits ceramide synthase (CS), a key enzyme in the de novo sphingolipid biosynthesis pathway. In LLC-PK(1) cells, FB(1) inhibits cell proliferation and induces apoptosis, which can be prevented by inhibitors of serine palmitoyltransferase (SPT). Inhibition of SPT prevents the FB(1)-induced accumulation of free sphinganine, a precursor of ceramide biosynthesis. However, not all of the effects of FB(1) in LLC-PK(1) cells can be explained solely by the increase in free sphingoid bases. The downstream signaling pathways that are affected by FB(1)-induced disruption of sphingolipid biosynthesis are not well understood. This study determined, in LLC-PK(1) cells, changes in p42 MAP kinase (phosphorylated ERK2 [pERK2]) phosphorylation in response to various inhibitors of key enzymes of the de novo sphingolipid biosynthesis pathway (CS, SPT, and glucosylceramide synthase [GlcCer synthase]). The results show that inhibition of any of the three enzymes caused a similar decrease in the extent of phosphorylation of ERK2 with no reduction in total ERK2. The co-treatment of FB(1) (CS inhibitor) with SPT inhibitors or the GlcCer synthase inhibitor had no effect on the FB(1)-induced reduction in pERK2 phosphorylation, indicating that FB(1)-mediated changes in phosphorylation of pERK2 was independent of increases in free sphinganine or its metabolites or a reduction in ceramide. Nonetheless, the decrease in pERK2 phosphorylation was dependent on inhibition of de novo sphingolipid biosynthesis. Decreased pERK2 activity could contribute to the physiological effects of FB(1) in LLC-PK(1) cells that are not due to alteration in pathways modulated by free sphingoid bases and their metabolites but are sensitive to inhibition of glycosphingolipid biosynthesis.

Acyltransferases↗
PubMed2006

Sphingolipid signaling and redox regulation.

Sphingolipids including ceramide and its derivatives such as ceramide-1-phosphate, glycosyl-ceramide, and sphinogosine (-1-phosphate) are now recognized as novel intracellular signal mediators for regulation of inflammation, apoptosis, proliferation, and differentiation. One of the important and regulated steps in these events is the generation of these sphingolipids via hydrolysis of sphingomyelin through the action of sphingomyelinases (SMase). Several lines of evidence suggest that reactive oxygen species (ROS; O2-, H2O2, and OH-,) and reactive nitrogen species (RNS; NO, and ONOO-) and cellular redox potential, which is mainly regulated by cellular glutathione (GSH), are tightly linked to the regulation of SMase activation. On the other hand, sphingolipids are also known to play an important role in maintaining cellular redox homeostasis through regulation of NADPH oxidase, mitochondrial integrity, and antioxidant enzymes. Therefore, this paper reviews the relationship between cellular redox and sphingolipid metabolism and its biological significance.

Animals↗