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PubMed1992

Interbilayer interactions between sphingomyelin and sphingomyelin/cholesterol bilayers.

Pressure versus fluid spacing relations have been obtained for sphingomyelin bilayers in the gel phase and equimolar sphingomyelin/cholesterol in the liquid-crystalline phase by the use of X-ray diffraction analysis of osmotically stressed aqueous dispersions and oriented multilayers. For interbilayer separations in the range of 5-20 A, the repulsive hydration pressure decays exponentially with increasing fluid spacing. The decay length (lambda) of this repulsive pressure is about 2 A for both bovine brain and N-tetracosanoylsphingomyelin, similar to that previously found for phosphatidylcholine bilayers. However, both the magnitude of the hydration pressure and the magnitude of the dipole potential (V) measured for monolayers in equilibrium with liposomes are considerably smaller for sphingomyelin than for either gel or liquid-crystalline phosphatidylcholine bilayers. Addition of equimolar cholesterol increases both the magnitude of the hydration pressure and the dipole potential. These data suggest that the magnitude of the hydration pressure depends on the electric field at the interface as given by (V/lambda)2. For sphingomyelin bilayers, there is a sharp upward break in the pressure-fluid spacing relation at an interbilayer spacing of about 5 A, indicating the onset of steric hindrance between the head groups of apposing bilayers.

Animals↗

PubMed1980

Interaction of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in the transport of cholesteryl ester into sphingomyelin liposomes.

When isolated lecithin:cholesterol acyltransferase was incubated with cholesterol-lecithin liposomes in the presence of apolipoprotein A-1, cholesteryl ester accumulated until a maximal ester/lecithin weight ratio of 0.03 was reached. This was independent of the amount of enzyme present or the proportion of cholesterol relative to lecithin. The inhibition of transferase associated with accumulation of cholesteryl ester was relieved by additional lecithin-cholesterol liposomes but not by addition of sphingomyelin liposomes containing the same proportion of substrate unesterified cholesterol. These results indicate that it is the accumulation of cholesteryl ester product which directly inhibits transferase activity. When isolated cholesteryl ester transfer protein from human plasma was included in the reaction mixture, cholesteryl ester was transported to sphingomyelin-cholesterol liposomes, with associated release of transferase from product inhibition. Cholesteryl ester incorporated directly into the liposomes or synthesized from free cholesterol via the transferase reaction was equally transferred to sphingomyelin acceptor liposomes, indicating that the cholesteryl ester in these particles formed a single miscible pool for transfer.

Apolipoproteins↗

PubMed1979

Thermal behavior of synthetic sphingomyelin-cholesterol dispersions.

The thermotropic behavior of aqueous dispersions of palmitoylsphingomyelin-cholesterol and lignoceryl-sphingomyelin-cholesterol mixtures has been examined by high-sensitivity differential scanning calorimetry. When less than 25 mol % cholesterol is mixed with either sphingomyelin, the calorimetric endotherm is composed of a sharp and a broad component. The sharp-component enthalpy change decreases as the mole percent cholesterol increases with the extrapolated zero enthalpy point being 25 to 30 mol %. With palmitoylsphingomyelin, the temperature of maximum heat capacity of the sharp component decreases monotonically with increasing cholesterol content, while the lignocerylsphingomyelin sharp-component maximum remains constant until more than 20 mol % sterol is present. The broad-component enthalpy change maximizes at 3--4 kcal/mol between 10 and 20 mol % cholesterol and decreases as the ratio of cholesterol is increased or decreased from this range for both sphingomyelins. The results are compared with those from a previous study on dipalmitoylphosphatidylcholine-cholesterol mixtures and are interpreted as evidence for the coexistence of cholesterol-rich and cholesterol-poor phases.

Animals↗

PubMed1977

A nuclear magnetic resonance study of sphingomyelin in bilayer systems.

The physical properties of small single-walled vesicles composed of the zwitterionic phospholipid sphingomyelin have been studied using 1H and 31P nuclear magnetic resonance spectroscopy. The temperature variation of proton line widths and spin-lattice relaxation times and the chemical shift behavior for sphingomyelin vesicles are compared with results previously determined for phosphatidylcholine vesicles. Differences between the two systems are interpreted as indications of the presence of both inter- and intramolecular hydrogen bonding in sphingomyelin bilayers.

Animals↗

PubMed1976

Effect of Triton X-100 on the hydrolysis of sphingomyelin by sphingomyelinase of rat brain.

Mixed dispersions of the nonionic detergent Triton X-100 and sphingomyelin were used as substrate for sphingomyelinase of rat brain. The dependence of the rate of hydrolysis on the concentration of sphingomyelin was measured in two ways: at a fixed concentration of Triton X-100 or at varying concentrations of this detergent, while maintaining a fixed molar ratio of Triton X-100 to sphingomyelin. In either case, the upsilon vs. S curves deviated from the hyperbolic shape predicted by the Michaelis-Menten kinetic theory. These deviations are discussed and interpreted on the basis of the physicochemical properties of the mixed dispersions of detergent and lipid studied in previous papers.

Animals↗

PubMed1976

High-performance liquid chromatography of phosphatidylcholine and sphingomyelin with detection in the region of 200 nm.

A sensitive method for the separation of phosphatidylcholine and sphingomyelin by high-performance liquid chromatographic analysis is described. The elution of the phospholipids from a microparticulate (10 mum) silica-gel chromatographic column was monitored with an ultraviolet spectromonitor at 203 nm. Acetonitrile/methanol/water (65:21:14, by vol.) was used as the solvent. It was shown by using synthetic phosphatidylcholines of knowm fatty acid composition and of varying degree of unsaturation that the absorption at 203 nm was primarily due to the isolated double bonds and the response measured varied with the degree of unsaturation. Approx. 1 nmol of phosphatidylcholine, containing at least one double bond per molecule, can be detected. The amounts of phosphatidylcholine and sphingomyelin could be determined by high-performance liquid chromatography and ultraviolet absorption if the apparent extinction coefficient of the material analyzed was established. Alternatively, peaks were collected and the phospholipids were determined by the analysis of phosphorus. The analysis of phosphatidylcholine and sphingomyelin present in the lipid extracts from animal tissues, blood and amniotic fluids were made without interference from other phospholipids or ultraviolet-absorbing material. The method described here is complementary to the high-performance liquid chromatographic method described previously for the analysis of ethanolamine-containing phosphoglycerides and serine-containing phosphoglycerides [Jungalwala, Turel, Evans and McCluer (1975) Biochem. J. 145, 517-526].

Amniotic Fluid↗

PubMed1976

Properties of a toxin from the sea anemone Stoichacis helianthus, including specific binding to sphingomyelin.

Stoichactis helianthus toxin, a protein derived presumably from the nematocysts, was purified to homogeneity. It has a molecular weight of about 16,000, an isoelectric pH of 9.8, and it contains approximately 3.7% carbohydrate. It is powerfully hemolytic for erythrocytes derived from a variety of animal species, those of the cat being the most sensitive and those of the guinea pig the most resistant. The toxin is lytic also for rabbit blood platelets, and it destroys cultured fibroblasts but is inactive for several kinds of bacterial protoplasts and spheroplasts. The hemolytic activity is specifically inhibited by sphingomyelin, and it is proposed that this phospholipid is the constituent of the membrane which functions as receptor for the toxin. Supporting evidence includes the findings that enzymes known to destroy sphingomyelin (a) prevent erythrocyte membranes from inhibiting hemolysis, and (b) render erythrocytes resistant to lysis by the toxin. The mechanism underlying hemolysis may involve translocation of membrane sphingomyelin by virtue of a specific affinity of the coelenterate protein for this phospholipid.

Animals↗

PubMed1980

Compositional domain structure in phosphatidylcholine--cholesterol and sphingomyelin--cholesterol bilayers.

the lateral distribution of cholesterol in phospholipid bilayers has been investigated through a method of Monte Carlo calculations, using interaction energies deduced from calorimetric results for cholesterol-phospholipid mixtures. Analysis of computer-generated bilayer configurations allows calculation of the spatial localization and relative abundance of distinct regions of varying cholesterol content along the plane of the bilayer. An interfacial phospholipid region between cholesterol-bound and cholesterol-free domains is found to extend one lipid beyond the cholesterol-bound domain for mixtures of cholesterol with palmitoyl sphingomyelin, lignoceroyl sphingomyelin, and dipalmitoyl phosphatidylcholine. The results indicate that the degree of nonideality in the mixing of cholesterol is dependent on fatty acid chain length and that cholesterol mixes more ideally in sphingomyelins than in phosphatidylcholines of equal chain length. It is found that at approximately 20 mol % cholesterol the cholesterol-rich areas suddenly become connected, forming a network that extends over the entire bilayer. This change in the lateral connectivity of the cholesterol-rich domains occurs over a narrow concentration interval and is presumably responsible for the abrupt change in the lateral diffusion coefficient observed at this concentration.

Cholesterol↗

PubMed1995

Sphingolipid biosynthesis de novo by rat hepatocytes in culture. Ceramide and sphingomyelin are associated with, but not required for, very low density lipoprotein secretion.

Sphingolipids are constituents of liver and lipoproteins, but relatively little is known about their synthesis and secretion. Incubation of rat hepatocytes with [14C]- or [3H]serine labeled the long-chain base backbones of mainly ceramide and sphingomyelin. Most of the labeled sphingolipids were associated with the cells; however, 1-5% (the majority of which was ceramide) was released into the medium as part of very low density lipoproteins (VLDL). Since this is the first report that lipoproteins contain ceramide, lipoproteins were isolated from rat plasma, and the ceramide contents were (per mg of protein): 6.5 nmol for VLDL (d < 1.018), 0.6 nmol for low density lipoproteins (1.018 < d < 1.063), 0.2 nmol for high density lipoproteins (1.063 < d < 1.18), and 0.1 nmol for the albumin fraction; the lipoproteins also contained 0.1-0.4 nmol of free sphingosine/mg of protein. A number of factors affected the secretion of radiolabeled sphingolipids: 1) addition of palmitic acid, but not stearic or oleic acid, enhanced secretion due to an increase in long-chain base synthesis de novo. 2) Choline deficiency caused a 42% reduction in the secretion of radiolabeled sphingomyelin, but this was due to an effect on VLDL secretion rather than a decrease in sphingolipid synthesis. Removal of choline was examined because previous studies (Yao, Z. M., and Vance, D. E. (1988) J. Biol. Chem. 263, 2998-3004) have shown that choline deficiencies depress phosphatidylcholine synthesis and lipoprotein secretion. 3) Incubation of the cells with fumonisin B1, a mycotoxin inhibitor of sphinganine (sphingosine) N-acyltransferase, reduced overall sphingolipid synthesis and secretion by 90%, but had no effect on the secretion of apoB, phosphatidylcholine, or cholesterol. All together, these findings demonstrate that rat hepatocytes synthesize ceramide and sphingomyelin de novo and incorporate them into both cellular membranes and secreted VLDL, but normal sphingolipid synthesis is not required for lipoprotein secretion.

Animals↗

PubMed1999

Maturation of the axonal plasma membrane requires upregulation of sphingomyelin synthesis and formation of protein-lipid complexes.

Neuronal maturation is a gradual process; first axons and dendrites are established as distinct morphological entities; next the different intracellular organization of these processes occurs; and finally the specialized plasma membrane domains of these two compartments are formed. Only when this has been accomplished does proper neuronal function take place. In this work we present evidence that the correct distribution of a class of axonal membrane proteins requires a mechanism which involves formation of protein-lipid (sphingomyelin/cholesterol) detergent-insoluble complexes (DIGs). Using biochemistry and immunofluorescence microscopy we now show that in developing neurons the randomly distributed Thy-1 does not interact with lipids into DIGs (in fully developed neurons the formation of such complexes is essential for the correct axonal targeting of this protein). Using lipid mass spectrometry and thin layer chromatography we show that the DIG lipid missing in the developing neurons is sphingomyelin, but not cholesterol or glucosylceramide. Finally, by increasing the intracellular levels of sphingomyelin in the young neurons the formation of Thy-1/DIGs was induced and, consistent with a role in sorting, proper axonal distribution was facilitated. These results emphasize the role of sphingomyelin in axonal, and therefore, neuronal maturation.

4-Chloro-7-nitrobenzofurazan↗

PubMed1985

Biochemical studies in Niemann-Pick disease. III. In vitro and in vivo assays of sphingomyelin degradation in cultured skin fibroblasts and amniotic fluid cells for the diagnosis of the various forms of the disease.

Sphingomyelinase activities were assayed in vitro in cultured skin fibroblasts of 61 patients with Niemann-Pick disease (NPD). Residual activities found in type A and B were 1% and 4%, respectively, of the mean control values, i.e. significantly higher in type B. In 27 cases with NPD type C, the mean activity was 42% of that in controls, with residual activities ranging from 15% up to normal. Fifteen pregnancies at risk for NPD type A and B were monitored; 4 affected foetuses were found. The uptake of exogenously added radiolabelled sphingomyelin by cultured cells and metabolism of the choline moiety of this lipid were studied in 35 patients with NPD and 14 controls. No difference of uptake between normal and mutant cells was observed. Normally, 77 +/- 5% of the radioactivity taken up was converted to phosphatidylcholine after 18 h incubation, compared to 5 +/- 2% (n = 7) in NPD type A. A substantially greater hydrolysis (31 +/- 12%; n = 8) occurred in NPD type B, and the test allowed complete discrimination between these two types. In NPD type C, 16 patients showed an abnormally low rate of intracellular sphingomyelin degradation (48 +/- 5%) while 4 others were not distinguishable from controls. There was a correlation (r = 0.76) between the results of the in vitro and in vivo assays, but also between the severity of the clinical symptoms and the impairment in sphingomyelin degradation. For the diagnosis of NPD type C, the in vivo test gave more reproducible and more clearcut results than the in vitro assay.

Amniotic Fluid↗

PubMed1982

Differential study of phosphatidylcholine and sphingomyelin in human high-density lipoproteins with lipid-specific fluorescent probes.

Modified phosphatidylcholine and sphingomyelin containing an anthryl end group attached to one of the fatty acyl chains were used as fluorescent probes in an investigation of the molecular organization of human high-density lipoproteins (HDL). Monolayer experiments and NMR measurements showed the anthryl-labeled lipids to mimic closely the corresponding host phospholipids, the fluorophores being located near to the terminal CH3 groups of the fatty acid residues. The above fluorescent phospholipid probes made it possible for the first time to study differentially the behaviour of phosphatidylcholine and sphingomyelin in HDL. The probes were shown to interact in a different way with the apoprotein tryptophans and to be non-randomly distributed at the surface of the globules. The probable sphingomyelin binding site of apolipoprotein A-I was defined. Evidence was obtained suggesting the existence in high-density lipoproteins of two slowly exchanging phospholipid pools: one strongly bound to apoproteins, and the other free or loosely bound. Fluorescence parameters characterizing the fluidity of HDL phospholipids and their interaction with the apoprotein tryptophans were found to correlate with the HDL cholesterol level. The possible significance of the obtained results for a better understanding of the relation of high-density lipoproteins to coronary heart diseases is discussed.

Energy Transfer↗

PubMed1997

Changes in composition of newly synthesized sphingolipids of HeLa cells during the cell cycle -- suppression of sphingomyelin and higher-glycosphingolipid synthesis and accumulation of ceramide and glucosylceramide in mitotic cells.

Sphingolipid biosynthesis in synchronized HeLa cells was studied by pulse labeling with [14C]Ser or [14C]Gal and a simple TLC method. The major HeLa cell sphingolipids are ceramide (Cer), sphingomyelin, glucosylceramide (GlcCer), lactosylceramide (LacCer), globotriaosylceramide (Gb3Cer), N-acetylneuraminosylgangl iotriaosylceramide (GM2) and sialylparagloboside (G[M1-GlcNAc]). The sphingolipid biosynthetic profiles of HeLa cells in the G1, G1/S boundary, S and G2 phases were similar, but significant changes occurred during M phase, when incorporation of radioactivity into sphingomyelin, Gb3Cer and a mixture of GM2 and G(M1-GlcNAc) decreased, and those of Cer and GlcCer increased. These data indicate that transfer of phosphocholine and galactose to Cer and GlcCer, respectively, decreased in mitotic cells, resulting in accumulation of Cer and GlcCer. Analysis of LacCer synthase activity revealed that GlcCer accumulation was not due to reduced activity of this enzyme. The results suggest that Cer and GlcCer accumulation in mitotic cells resulted from suppression of sphingomyelin and LacCer synthesis, probably caused by vesiculation of membranous organelles, such as the endoplasmic reticulum and Golgi apparatus.

Autoradiography↗

PubMed1985

Rapid enzyme analysis of amniotic fluid phospholipids containing choline: a comparison with the lecithin to sphingomyelin ratio in prenatal assessment of fetal lung maturity.

The relation between the choline containing surfactant phospholipids lecithin and sphingomyelin in amniotic fluid and fetal lung maturity is well established. An enzymatic method that had been automated and optimised for use on a centrifugal analyser was used to measure the total choline containing phospholipids in amniotic fluid. The total time taken for this assay was 10 minutes. The results obtained from 100 patient samples, using this procedure, compared favourably with the results obtained by the thin layer chromatography procedure used to determine the lecithin to sphingomyelin ratio (r = 0.93). A clinical study of 60 patients showed that this assay predicted prenatal respiratory distress syndrome as well as the lecithin to sphingomyelin ratios. The advantage of this assay over existing procedures is that it requires minimum preparation of the specimen and no extraction, is quick, and shows a high degree of precision.

Amniotic Fluid↗

PubMedDate not supplied

The sphingomyelin signal transduction pathway mediates apoptosis for tumor necrosis factor, Fas, and ionizing radiation.

Recent evidence suggests that tumor necrosis factor alpha, Fas, and ionizing radiation employ the sphingomyelin pathway to trigger apoptosis. The sphingomyelin pathway is initiated by hydrolysis of plasma membrane sphingomyelin to generate ceramide via a sphingomyelinase. Ceramide serves as a second messenger stimulating a cascade of kinases and transcription factors that activate a final common pathway of programmed cell death. The extent to which this signaling system is used in apoptosis induced by other toxic modalities is not known, but accumulating evidence suggests that it is a commonly employed pathway that could be exploited therapeutically.

Animals↗

PubMed1996

GPI-anchored proteins, glycosphingolipids, and sphingomyelin are sequestered to caveolae only after crosslinking.

GPI-anchored proteins, glycosphingolipids, and sphingomyelin are all enriched in the detergent-insoluble complex which has been suggested to be purified caveolae. I studied the relationship of the molecules with caveolae in cultured cells by immunocytochemical methods. In cells reacted with antibodies to various membrane proteins and lipids on ice and fixed before applying secondary antibodies, labeling did not show concentration in caveolae. In contrast, when cells were incubated with the primary and secondary antibodies on ice and then transferred to 37 degrees C without fixation, labeled Thy-1.2, beta 2-microglobulin, lactosyl ceramide, ceramide tetrahexose, Forssman antigen, and sphingomyelin became concentrated in caveolae, whereas labeled transferrin receptor did not. Thy-1.2 and sphingolipids formed common patches and were sequestered in the same caveolae when crosslinked with two primary antibodies simultaneously. On the other hand, when either Thy-1.2 alone or lactosyl ceramide alone was crosslinked and sequestered to caveolae, the other antigen remained evenly distributed. Caveolar sequestration of the antigens occurred in the presence of cytochalasin D, nocodazole, or a mixture of the two reagents. The results show that not only GPI-anchored proteins but also glycosphingolipids and sphingomyelin are sequestered in caveolae only after crosslinking, and that the sequestration does not require the intact cytoskeleton.

Animals↗

PubMed1982

Adrenalectomy decreases the sphingomyelin and cholesterol content of fat cell ghosts.

Adrenalectomy produces a significant fall in the sphingomyelin and cholesterol content of ghosts isolated from rat epididymal fat cells. Previous studies from this laboratory have demonstrated an effect of dexamethasone in vitro to increase the sphingomyelin content of fat cell ghosts obtained from adrenalectomized animals. The present study demonstrates that adrenalectomy influences the membrane lipid content. Dexamethasone, in vitro, was found to increase the sphingomyelin of epididymal fat cell ghosts isolated from intact animals, as it previously had been shown to affect epididymal fat cell ghosts obtained from adrenalectomized animals. Incubation with dexamethasone for 3 h had no effect on the cholesterol content of the ghosts. Adrenalectomy, on the other hand, resulted in a significant decrease in the cholesterol content of the fat cell ghosts.

Adipose Tissue↗

PubMed1980

Studies in vitro on the biosynthesis of ceramide and sphingomyelin. A reevaluation of proposed pathways.

The postulated biosynthetic-pathways of ceramide and sphingomyelin were reinvestigated in extensive investigations by means of synthetic stereo- and radio-chemically pure substrates of high specific radioactivity. As a result, the synthesis of ceramides requires the acyl-CoA-mediated acyltransfer to the long chain bases sphingenine and sphinganine. During the biosynthesis of sphingomyelins, phosphocholine is being transferred from the donor CDP-choline to the primary alcohol group of ceramides. Neither can the free long chain sphingosine bases act as acceptor molecule for the phosphocholine group from CDP-choline, nor has a transfer of [N-14CH3]phosphocholine from [N-14CH3]phosphatidyl choline to ceramide by rat liver enzyme preparations been observed. In agreement with previous studies in vivo, the acylation of sphingenylphosphocholine by acyl-CoA or free fatty acid, ATP and CoASH as an alternative pathway in sphingomyelin biosynthesis has been excluded. Other parameters of the CDP-choline:ceramide cholinephosphotransferase reaction (pH-optimum, ion requirement, competitive inhibition by diacyl glycerols, chain length of fatty acids) are reported. Sphingenine-containing ceramide species are preferred as acceptor molecules. Ceramide species with the L-threo (2S,3S)-enantiomeric long-chain bases are better acceptors than the corresponding D-erythro (2S,3R)-isomeric compounds. The meaning of the steric arrangement for the reaction is discussed.

Acyl Coenzyme A↗