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PubMed2003

Differential branching of the sphingolipid metabolic pathways with the stage of development. Involvement of sphingosine kinase.

We have studied sphingomyelin metabolism in the papillae of neonatal (10-day-old) and adult (70-day-old) kidneys of male Wistar rats because sphingolipid second messengers generated by sphingomyelin metabolism are involved in cellular processes such as proliferation, differentiation and apoptosis. We showed that sphingomyelin and ceramide concentrations in homogenized rat papilla tissue increase with the time whereas sphingosine-1-phosphate content decreases. This is consistent with the finding of a higher biosynthesis of the latter sphingolipid in neonatal than in adult rat papillae. De novo synthetized ceramide was, however, higher in adult than in neonatal papilla homogenates probably accounting for the high ceramide content of the adult rat papilla. These results suggest an active de novo pathway not ending in sphingomyelin but instead arresting at ceramide in adult rat papilla tissue, partially metabolized into sphingosine-1-phosphate in neonatal rat papillae. The activity and the expression of sphingosine kinase, one of the enzymes involved in ceramide metabolism, was found to be higher in neonatal than adult rat kidney tissue. The intracellular distribution of sphingosine kinase was also different; in neonatal rat tissue the enzyme was predominantly associated with plasma membranes but it was cytosolic in adult rat papilla tissue. These findings seem to indicate that, in rat renal papillae, the developmental regulation of sphingosine kinase expression and activity addresses the sphingolipid metabolism to the formation of the proliferative metabolite sphingosine-1-phosphate in the neonatal period, and ceramide, which is associated with cell arrest and differentiation in the adult tissue. These data are consistent with the proliferative state necessary for tubular elongation during the neonatal period and the maintenance of the differentiated state in the adult tissue.

Aging↗
PubMed2007

Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites.

Intestinal alkaline sphingomyelinase (Alk-SMase) and neutral ceramidase may catalyze the hydrolysis of endogenous sphingomyelin (SM) and milk SM in human-milk fed infants. The enzymes generate sphingolipid metabolites that may influence gut maturation. Alk-SMase also inactivates platelet-activating factor (PAF) that is involved in the pathogenesis of necrotizing enterocolitis (NEC). We examined whether the two enzymes are expressed in both preterm and term infants and analyzed Alk-SMase, neutral ceramidase, SM, and sphingolipid metabolites in meconium. Meconium was collected from 46 preterm (gestational ages 23-36 wk) and 38 term infants (gestational ages 37-42 wk) and analyzed for Alk-SMase using C-choline-labeled SM and for neutral ceramidase using C-octanoyl-sphingosine as substrates. Molecular species of SM, ceramide, and sphingosine were analyzed by high-performance liquid chromatography mass spectroscopy. Meconium contained significant levels of Alk-SMase and ceramidase at all gestational ages. It also contained 16-24 carbon molecular species of SM, palmitoyl- and stearoyl-sphingosine, and sphingosine. There were positive correlations between levels of SM and ceramide and between ceramide and sphingosine levels. In conclusion, Alk-SMase and ceramidase are expressed in the gut of both preterm and term newborn infants and may generate bioactive sphingolipid messengers.

Amidohydrolases↗
PubMed2001

Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis.

There is a great deal of evidence that altered sphingolipid metabolism is associated with fumonisin-induced animal diseases including increased apoptotic and oncotic necrosis, and carcinogenesis in rodent liver and kidney. The biochemical consequences of fumonisin disruption of sphingolipid metabolism most likely to alter cell regulation are increased free sphingoid bases and their 1-phosphates, alterations in complex sphingolipids, and decreased ceramide (CER) biosynthesis. Because free sphingoid bases and CER can induce cell death, the fumonisin inhibition of CER synthase can inhibit cell death induced by CER but promote free sphingoid base-induced cell death. Theoretically, at any time the balance between the intracellular concentration of effectors that protect cells from apoptosis (decreased CER, increased sphingosine 1-phosphate) and those that induce apoptosis (increased CER, free sphingoid bases, altered fatty acids) will determine the cellular response. Because the balance between the rates of apoptosis and proliferation is important in tumorigenesis, cells sensitive to the proliferative effect of decreased CER and increased sphingosine 1-phosphate may be selected to survive and proliferate when free sphingoid base concentration is not growth inhibitory. Conversely, when the increase in free sphingoid bases exceeds a cell's ability to convert sphinganine/sphingosine to dihydroceramide/CER or their sphingoid base 1-phosphate, then free sphingoid bases will accumulate. In this case cells that are sensitive to sphingoid base-induced growth arrest will die and insensitive cells will survive. If the cells selected to die are normal phenotypes and the cells selected to survive are abnormal, then cancer risk will increase.

Animals↗
PubMed1975

Sphingolipid metabolism in Bacteroideaceae.

The lipid composition of the anaerobic Bacteroides thetaiotaomikron has been analyzed. Sphingomyelin, ceramide phosphinicoethanolamine, free even-numbered and branched chain sphingosine bases and ceramide represented about 50% of the total lipid extract. The main ester phospholipid was phosphatidylethanolamine. The alkali-stable sphingophospholipids were predominantly N-acylated with 3-hydroxypalmitic acid, whereas the ester phospholipids are preferentially substituted with normal even and odd-numbered and branched-chain fatty acids. When Bacteroides was grown in a medium supplemented with labelled palmitic acid, this fatty acid was utilized for acylation reactions and to a large extent for the de novo synthesis of sphinganine. This long-chain base was incorporated into the sphingolipids and was also present in free form. The 3-hydroxypalmitic acid present in sphingolipids is not derived from palmitic acid, since labelled palmitate did not serve as a precursor. Free sphinganine added to the culture medium was also utilized efficiently for the biosynthesis of the sphingolipids by growing Bacteroides cultures. The 3H/14C ratio in sphingomyelin and ceramide phosphinicoethanolamine is the same, when [1-14C]palmitic acid and [3-3H]sphinganine serve as precursors. Sphingomyelin, which is usually only present in higher animals, is synthesized de novo in this Bacteroides strain.

Bacteroides↗
PubMed1996

Sphingolipids: their role in intracellular signaling and renal growth.

Glycerophospholipids have long been recognized as substrates for the formation of important intracellular second messengers. Recently, another class of membrane-associated lipids, sphingolipids, has been identified as potentially important in cell-signaling events. Ceramides, long-chain bases, and sphingosine derivatives may be mediators of cellular growth, differentiation, and programmed death responses. These lipids have been proposed to act through the regulation of cell kinases, phosphatases, and gene transcription. Observations of sphingolipid abnormalities in two examples of aberrant renal growth, diabetes mellitus and autosomal recessive kidney disease, suggest that sphingolipids may play a role in the pathophysiology of common renal disorders.

Animals↗
PubMed2006

Fine tuning therapeutic targeting of the sphingolipid biosynthetic pathway to treat atherosclerosis.

The accumulation of sphingolipids, including sphingomyelin and glycosphingolipids, in atherosclerotic lesions is well known. Plasma sphingomyelin concentration is correlated with atherosclerosis development and is an independent predictor of coronary artery disease. Similarly, plasma glycosphingolipid levels are increased in conditions associated with atherosclerosis risk. Recent studies have focused on understanding the mechanisms by which specific intermediates and end-products of the sphingolipid biosynthetic pathway, such as sphingomyelin, glycosphingolipids, ceramide and sphingosine-1-phosphate may modulate vascular biology and atherosclerosis. Here we focus on recent work indicating that pharmacological modulation of the sphingolipid biosynthetic pathway could offer a novel treatment for atherosclerosis or, at the very least, provide mechanistic insights concerning the etiology of this disease which is the major cause of death in developed countries.

Animals↗
PubMed2006

Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy.

Dysregulated sphingolipid metabolism causes neuronal cell death and is associated with insulin resistance and diseases. Thus, we hypothesized that diabetes-induced changes in retinal sphingolipid metabolism may contribute to neuronal pathologies in diabetic retinopathy. ESI-MS/MS was used to measure ceramide content and ceramide metabolites in whole retinas after 2, 4, and 8 weeks of streptozotocin-induced diabetes. After 4 and 8 weeks of diabetes, a approximately 30% decrease in total ceramide content was observed, concomitant with a significant approximately 30% increase in glucosylceramide levels in fed diabetic rats compared with their age-matched controls. Acute insulin therapy as well as a short-term lowering of glucose via fasting did not affect the increase in glucosylceramide composition. To assess the putative biological consequences of the increase in glucosylceramide composition, R28 retinal neurons were treated with glucosylceramide synthase inhibitors. Inhibiting glycosphingolipid metabolism increased insulin sensitivity in retinal neurons. Glycosphingolipid inhibitors augmented insulin-stimulated p70 S6kinase activity in the presence of inhibitory concentrations of high glucose or glucosamine. Inhibition of glycosphingolipid synthesis also suppressed glucosamine- and interleukin-1beta-induced death. Consistent with these inhibitor studies, pharmacological accumulation of glycosphingolipids increased activation of the endoplasmic reticulum stress response, a putative modulator of insulin resistance and neuronal apoptosis. It is speculated that an increase in glucosylceramide, and possibly higher-order glycosphingolipids, could contribute to the pathogenesis of diabetic retinopathy by contributing to local insulin resistance, resulting in neuronal cell death. Thus, dysfunctional glycosphingolipid metabolism may contribute to metabolic stress in diabetes, and therapeutic strategies to restore normal sphingolipid metabolism may be a viable approach for treatment of diabetic retinopathy.

Animals↗
PubMed2001

Chromatographic resolution and quantitative assay of CNS tissue sphingoids and sphingolipids.

Quantitative separation of ceramide, sphingoids (dihydrosphingosine, sphingosine, psychosine), and glycosphingolipids as individual fractions was achieved with silicic acid, Dowex column chromatography, and specific solvent mixtures that have not been previously described. Purified ceramide, resolved as a single band, was assayed by thin-layer chromatography (TLC) followed by gas chromatography (GC) and high performance liquid chromatography (HPLC). Sphingoids, purified by Dowex, were assayed by GC and HPLC without mild alkaline hydrolysis, which reduces the yield by interfering with the free amino group of psychosine and dihydrosphingosine. Several less polar (than cerebroside) alkali-/acid-labile glycosphingolipids that elute with galactosylceramide were also identified. Neutral and acidic glycosphingolipids, quantitatively recovered and purified to homogeneity, were resolved by TLC. We used these techniques to determine sphingolipids and sphingoids of vertebrate central nervous system (CNS) tissue, using as little as 30-50 mg (wet weight) of tissue. In addition, phosphatidylcholine and sphingomyelin, relevant to ceramide metabolism, were quantitatively recovered in pure form and resolved by TLC. This method, used to study CNS sphingolipid content, may well be applicable to determine the sphingolipid composition of other tissues and cell culture, but further experiments are necessary to ascertain this.

Animals↗
PubMed1992

Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene.

Sphingolipid activator proteins (SAPs) are small, nonenzymic glycoproteins that stimulate lysosomal degradation of various sphingolipids. SAP-1, SAP-2, and two additional potential activator proteins are derived from a common precursor by proteolytic processing. A severe case of sphingolipid storage disease that led to death within 16 weeks was attributed to a possible total deficiency of the SAPs generated by this gene (Harzer, K., Paton, B. C., Poulos, A., Kustermann-Kuhn, B., Roggendorf, W., Grisar, T., and Popp, M. (1989) Eur. J. Pediatr. 149, 31-39). Analysis of the SAP precursor cDNA from the patient and his fetal sibling showed an A to T transversion in the initiation codon. Allele-specific oligonucleotide hybridization revealed that both parents are heterozygous carriers for this mutation. In pulse-chase experiments using antisera raised against SAP-1 or SAP-2, no cross-reacting material could be detected in the patients' fibroblasts.

Alleles↗
PubMed2005

Long- and short-term effects of thyroxine on sphingolipid metabolism in rat liver.

BACKGROUND: Thyroid hormones are well known as modulators of signal transduction. Early experiments showed that sustained elevation of diacylglycerol (DAG) and ceramide levels in liver cells of hypothyroid rats is an essential prerequisite for disturbances in agonist responsiveness of hepatocytes. In this paper the effects of thyroxine (L-T(4)) on sphingolipid mass, synthesis, and degradation are investigated. MATERIAL/METHODS: The experiments were performed on either [1(14)C]CH(3)COOH-labeled rat liver or hepatocytes and isolated liver cell plasma membranes. To determine sphingolipid synthesis and degradation in the liver, [(14)C]palmitic acid, [methyl-(14)C]-labeled sphingomyelin (SM), and phosphatidylcholine were used. RESULTS: The administration of L-T(4) to animals was accompanied by a time-dependent accumulation of newly synthesized ceramide, glucosyl ceramide, and SM in liver. In hyperthyroid liver, prominent ceramide accumulation and acidic SMase activation was found. The addition of hormone in a physiological dose to the incubation or perfusion medium led to a rapid stimulation of de novo ceramide synthesis, transient lipid accumulation in the liver, followed by SM synthase activation. CONCLUSIONS: Our results indicate that SMases, ceramide synthesis de novo, and SM synthase are under thyroid hormone control. The level of ceramide is markedly elevated in the hyperthyroid liver via the activation of acidic SMase and lipid synthesis de novo. In experiments in vitro, the hormone induces a short-lived accumulation of sphingolipid, probably due to its reduced efflux from the liver.

Animals↗
PubMed1980

Metabolic studies of N-bases of phospholipids and long chain bases of sphingolipids in two-weeks-old mouse brain tissue in comparison with one-month-old mouse visceral tissues.

After intraperitoneal administration of 15N-labeled serine, ethanolamine and choline to young mice showing active myelination, the incorporation of 15N-atom into N-bases of phospholipids and long chain bases of sphingolipids in brain tissue was particularly investigated in comparison with those in visceral tissues of adult mouse. After intraperitoneal injection of DL-[15N]-serine into mice, it was found that the 15N-atom was obviously incorporated into phosphatidylserine, phosphatidylethanolamine, ethanolamine-plasmalogen and long chain bases of cerebroside, sphingomyelin and gangliosides, but not significantly into phosphatidylcholine. The apparent maximum rates of the incorporation were also calculated. After administration of [15N]-ethanolamine, the 15N-atom was predominantly incorporated into phosphatidylethanolamine and next into ethanolamine-plasmalogen, but also not significantly into phosphatidylcholine. After administration of [15N]-choline chloride, the 15N-atom was incorporated into phosphatidylcholine and sphingomyelin, but not into other phospholipids and sphingolipids. These results suggested that serine, ethanolamine and choline are available for the biosynthesis of the N-bases of phospholipids in the brain tissue of young mouse and that serine is also utilized for the biosynthesis of long chain bases of sphingolipids. However, neither biosynthesis of choline from ethanolamine nor of phosphatidylcholine from phosphatidylethanolamine by methylation seemed to take place even in the brain tissue of young mouse, while the decarboxylation of phosphatidylserine into phosphatidylethanolamine was obviously observed. The decarboxylation rate of phosphatidylserine into phosphatidylethanolamine in the brain tissue of young mouse seemed to be approximately at the same level with the other tissues like liver, lung spleen and kidney of adult mouse.

Aging↗
PubMed1994

Suppressors of the Ca(2+)-sensitive yeast mutant (csg2) identify genes involved in sphingolipid biosynthesis. Cloning and characterization of SCS1, a gene required for serine palmitoyltransferase activity.

Suppressor mutations in Saccharomyces cerevisiae that block Ca(2+)-induced death of csg2 mutant cells were investigated. These mutants, called scs mutants (suppressor of Ca2+ sensitivity), fall into seven complementation groups (scs1-scs7). All mutant strains in two of the complementation groups (scs1 and scs2) simultaneously acquire a requirement for 10 mM Ca2+, whereas wild type grow with only trace amounts of Ca2+. SCS1 was cloned by complementation of its Ca(2+)-requiring phenotype and found to be homologous to a family of pyridoxal phosphate enzymes that catalyze acyltransfer reactions. Secondary phenotypes of the scs1 mutants indicate that SCS1 is required for serine palmitoyltransferase activity which catalyzes the first committed step in sphingolipid biosynthesis (palmitoyl-CoA + serine-->3-ketosphinganine+CoASH+CO2). Other scs mutants as well as the csg2 null mutant have altered sphingolipid metabolism. The data suggest that sphingolipid metabolism in yeast is either regulated by Ca2+ and/or is required for Ca2+ homeostasis.

Acyltransferases↗
PubMed1994

Modulation by sphingolipids of calcium signals evoked by epidermal growth factor.

Receptor-activated breakdown of complex sphingolipids has been proposed as a mechanism for generating sphingoid base-containing putative second messenger molecules whose actions may modulate responses to extracellular signals. In human epidermoid carcinoma A431 cells, sphingosine (1-10 microM) by itself had no effect on intracellular free calcium concentrations ([Ca2+]i), yet within seconds, markedly enhanced the epidermal growth factor (EGF)-evoked Ca2+ influx (by up to 2-fold), but failed to alter Ca2+ release from the intracellular stores. Ca2+ signals evoked by serum were not affected by sphingosine. The response to sphingosine was dose-dependent and saturable, exhibiting an EC50 of 2.3 microM. In contrast, a ceramide, N-acetylsphingosine (10 microM), sphingosine 1-phosphate (10 microM), and sphingosylphosphorylcholine (10 microM) inhibited EGF-evoked elevations in [Ca2+]i. The latter two compounds by themselves transiently increased [Ca2+]i. N-Octanoylsphingosine, N,N-dimethylsphingosine, sphingomyelin, and stearylamine were inactive. The potentiation of calcium signals by sphingosine occurred at all concentrations of EGF tested (0.15-15 nM) and did not alter the EGF receptor protein kinase activity as determined by antiphosphotyrosine immunoblotting. Antiphosphoserine immunoblotting revealed that sphingosine (10 microM for 3 min) increased the phosphoserine content of two proteins with approximate molecular masses of 40 and 70 kDa. Serine hyperphosphorylation of the 40-kDa protein was also observed in cells treated with EGF alone, whereas the intensity of the 70-kDa band was highest in cells treated with both sphingosine and EGF. The modulation of growth factor receptor-regulated signaling, including changes in [Ca2+]i, may constitute a mechanism by which elevations in cellular levels of specific sphingolipids, which occur transiently upon activation of certain receptors and chronically in sphingolipid storage diseases, exert their physiological and pathophysiological effects.

Calcium↗
PubMed1993

Inhibition of sphingolipid synthesis affects axonal outgrowth in cultured hippocampal neurons.

Neuronal growth is regulated by both extracellular and cellular determinants and is believed to proceed by the addition of new membrane material at the growth cone. To determine whether lipid synthesis is necessary to maintain neuronal growth, we have examined the effect of Fumonisin B1, an inhibitor of ceramide synthesis, on the development of cultured hippocampal neurons. Fumonisin B1 inhibits ceramide synthesis in hippocampal neurons both in vivo and in vitro. Ganglioside synthesis and content was reduced after Fumonisin B1 treatment, and ganglioside GD1b was not detectable at the cell surface by immunofluorescence. Inhibition of sphingolipid synthesis by Fumonisin B1 had a significant effect on axonal growth. Between days 2-3 in culture, mean axon length increased from 170 to 240 microns, but in Fumonisin-treated cells, no increase in axon length was observed. Addition of a fluorescent derivative of ceramide together with Fumonisin B1 reversed this effect, confirming that Fumonisin B1 acts via inhibition of ceramide synthase. Further, ceramide by itself caused a significant increase in axon length. We discuss three possible mechanisms by which inhibition of sphingolipid synthesis could disrupt axonal growth, among them the possibility that ongoing sphingolipid synthesis is necessary to provide new membrane material to the growing axon.

Animals↗
PubMed1998

Influence of sphingolipids on T lymphocyte activation.

Sphingolipid metabolism in immune cells results in formation of a second lipid messenger, e.g., ceramide, sphingosine, ceramide-1-phosphate, and sphingosine-1-phosphate. They are involved in a common signaling which controls the main stages of the lymphocyte development, differentiation, activation, and proliferation in response to a mitogenic and antigenic stimuli, and to initiate programmed cell death. Both, the sphingomyelin cycle products and inhibitor of ceramide synthase--fumonisin B1--have been shown to affect the CD3, CD4, CD8, CD45, and other T lymphocyte surface antigen expression, to disrupt lymphocyte subpopulation balance, to inhibit DNA synthesis in normal lymphocytes, and to suppress an immune response to T-dependent antigens in vivo. The common targets of the TCR/CD3-derived and sphingolipid-mediated signaling pathways may provide the sphingolipid effect on immune cells.

Animals↗
PubMed1998

On the character and functions of sphingolipids.

Sphingolipids form a large group of membrane lipids showing a diversity of molecular species. Specific functions associated with the saccharide part of glycosphingolipids including co-receptor functions, cell homing phenomena, and attachment by microbes and microbial toxins may not be unique for sphingolipids. However, there are saccharides which appear only in ceramide-bound form and not in other glycoconjugates, and such glycolipids have often been selected as attachment sites by microbes. During the last few years convincing evidence has been presented in favor of ceramide and sphingosine being signaling molecules for various cell functions. The influence of sphingolipids (ceramide) on the properties of the membrane bilayer is still largely unknown. However, based on the structure of ceramide and some experimental evidence one may formulate its role in membrane stability and barrier properties determined by hydrogen bonding in the amide region of ceramide. Furthermore, a natural variation in the number of hydroxyl groups (of fatty acid and long-chain base) may be important for regulation of the potential hydrogen bonds.

Animals↗
PubMed1998

[Sphingolipids and cancer].

The qualitative and quantitative changes in sphingolipids (ceramides, sphingomyelins, glycosphingolipids) occurring under tumor growth are considered. The influence of these changes on cell functions and immunity as well as the role of dietary sphingolipids in cancer and "sphingolipid" therapy of tumors are discussed.

Cell Transformation, Neoplastic↗
PubMed1995

Sphingolipid composition in Bacteroides species.

Sphingolipid profiles of strains from species of genus Bacteroides, and representative strains from Prevotella and Porphyromonas, were analyzed by thin-layer chromatography and infrared spectrophotometry. Two major types of phosphosphingolipid, ceramide phosphorylethanolamine and ceramide phosphorylglycerol, were detected in B. fragilis, B. ovatus, B. uniformis, B. caccae, B. eggerthii, B. thetaiotaomicron, and B. stercoris, but not in B. merdae, B. distasonis, and B. vulgatus. Strains from the genera Prevotella and Porphyromonas also contained these two sphingolipids. These sphingolipid profiles were conserved within the species tested, and may be useful for differentiation and recognition of relationships within the genera Bacteroides, Prevotella and Porphyromonas.

Journal Article↗