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PubMed1991

PAF-like activity of O-acetylated sphingomyelin.

O-acetylated sphingomyelin (Ac-SM) was found to cause aggregation of rabbit platelets in vitro. The Ac-SM-induced aggregation was accompanied by subsequent desensitisation of platelets to platelet-activating factor (PAF). The activity of Ac-SM exceeded that of acyl-PAF by about fourfold. BN 52021, a specific PAF-receptor antagonist, was found to inhibit the Ac-SM-induced aggregation. These results, together with earlier reports that sphingomyelin can inhibit the effects of PAF, suggest a new physiological function for sphingomyelin as a regulator of PAF-receptor binding. A search for enzymes to catalyse specifically the acetylation and deacetylation of sphingomyelin is required to confirm the physiological existence of sphingomyelin derivatives.

Acetylation↗
PubMed1984

Correlation of ultrasonic epiphyseal centers and the lecithin: sphingomyelin ratio.

Ossification centers about the fetal knee were identified and measured by ultrasound in 133 nondiabetic patients who underwent amniocentesis for determination of the amniotic fluid lecithin:sphingomyelin ratio (L:S ratio) between 28 and 42 weeks' gestation. A distal femoral epiphysis measuring greater than or equal to 5 mm and a proximal tibial epiphysis measuring 3 mm or greater was seen at 34 to 35 weeks' gestation. A mature lecithin: sphingomyelin ratio (lecithin: sphingomyelin greater than or equal to 2.0) was present with 66, 94, and 100% of proximal tibial epiphysis measuring 0 to 2, 3 to 4, and 5 to 7 mm, respectively. A mature lecithin: sphingomyelin ratio was present with 39, 76, and 95% of distal femoral epiphysis measuring 0 to 2, 3 to 4, and 5 to 7 mm, respectively. These results suggest that in nondiabetic patients, the ossification centers about the fetal knee as measured by ultrasound correlate well with amniotic fluid lecithin: sphingomyelin ratio.

Amniocentesis↗
PubMed1984

Effects of high erucic acid diet on sphingomyelin biosynthesis in rat lung microsomes.

The amount of fatty acids in free ceramides and sphingomyelins and the biosynthesis of sphingomyelins were measured in lung microsomes of rats fed either a stock diet or semisynthetic diets containing 15% by weight of sunflower oil or rapeseed oil (48% erucic acid). The rapeseed oil diet increased the amount of 24 : 1 in free ceramides and decreased that of 24 : 0 in both fractions as compared to the other reference diets. Incubations of lyophilized microsomes with [14C acyl] ceramides (16 : 0, 18 : 1 or 24 : 1) and [3H methyl] phosphatidylcholine showed that in the stock and the sunflower oil diet groups the conversion kinetics of the 18 : 1 and 24 : 1 ceramides into sphingomyelins were the same while that of the 16 : 0 ceramide showed a higher affinity for the enzymatic systems. The rapeseed oil diet enhanced the apparent kinetic constants of 24 : 1 ceramide conversion. Studies on the appearance of 3H radioactivity in sphingomyelin showed that phosphorylcholine transfer from phosphatidylcholine to a ceramide acceptor occurred during sphingomyelin biosynthesis in lung microsomes. This pathway was also influenced by the rapeseed oil diet.

Animals↗
PubMed1984

[Effect of sphingomyelin on RNA-polymerase activity in the cell nucleus of normal and regenerating rat liver].

Using a model of regenerating rat liver, it was shown that the activities of RNA polymerases I and II, and the ratio of free to template engaged form of the enzyme are correlated with the changes in the contents of sphingomyelin in chromatin isolated from cell nuclei of hepatectomized animals. Injections of sphingomyelin to intact and hepatectomized animals in doses increasing its contents in chromatin, stimulate the activity of RNA polymerases I and II and increase the ratio of free to engaged form of the enzyme. Addition of sphingomyelin as a micellar suspension to heterochromatin in vitro facilitates RNA polymerase binding to the template. Removal of sphingomyelin from the intranuclear structures by its degradation with sphingomyelinase results in a loss of activities of both RNA polymerases. It is assumed that sphingomyelin plays a role in the transcriptional activity by changing the structure of the template and that of the enzymes.

Animals↗
PubMed1980

Mild alkali-stable phospholipids in chicken egg yolks: characterization of 1-alkenyl and 1-alkyl-sn-glycero-3-phosphoethanolamine, sphingomyelin, and 1-alkyl-sn-glycero-3-phosphocholine.

Chicken egg yolk phospholipids were subjected to mild alkaline hydrolysis. The resulting alkali-stable phospholipids were characterized by chemical chromatographic, and enzymatic methods. Two major phospholipids, 1 - O - alkyl - sn - glycero - 3 - pohosphoethanolamine and sphingomyelin; and two minor phospholipids, 1-O-alkenyl-sn-glycero-3-phosphoethanolamine and 1-O-alkyl-sn-glycero-3-phosphocholine; were identified. The sphingomyelins were converted into ceramides by enzymatic hydrolysis with phospholipase C. Ceramides derived from sphingomyelins with non-hydroxy fatty acids (99% of total ceramides) consisted predominantly of the N-palmitoyl, N-stearoyl, and N-nervonyl species. Ceramides derived from sphingomyelins with hydroxy fatty acids (1% of total ceramides) consisted almost exclusively of the N-alpha-hydroxyeicosanoyl species. The long chain bases of ceramides derived from both species of sphingomyelins (hydroxy and non-hydroxy fatty acids) consisted of 97% D-erythro-sphing-4-enine and 3% D-erythro-sphinganine, 1-O-alkyl-sn-glycero-3-phosphoethanolamine and 1-O-alkyl-sn-glycero-3-phosphocholine were converted to corresponding 1-O-alkyldiacetylglycerols. The 1-O-alkyldiacetylglycerols derived from both ether phospholipids consisted largely of the hexadecyl and octadecyl species. Smaller quantities of the heptadecyl, cis-9-octadecenyl and eicosanyl derivatives were also present.

Animals↗
PubMed1997

Effect of 27-hydroxycholesterol on cellular sphingomyelin synthesis and Ca++ content in cultured smooth muscle cells.

The relationships among sphingomyelin synthesis cytosolic free Ca++ level and cytotoxicity in the presence of 27-hydroxycholesterol were investigated by measurement of [methyl-3H] choline incorporation into sphingomyelin, phosphatidylcholine, phosphocholine and cytidine choline 5'-diphosphate, 45Ca++ uptake, cytosolic free Ca++ levels and viable cell numbers. The results indicated that 27-hydroxycholesterol at higher than normal level induced increased [3H] choline incorporation in sphingomyelin accompanied by decreased radioactivity in phosphatidylcholine but did not alter [3H] choline content in phosphocholine and cytidine choline 5'-diphosphate. The increased radioactivity in sphingomyelin by 27-hydroxycholesterol was detected first, followed by detection of the enhanced Ca++ uptake and cytosolic free Ca++. Finally, a decrease in viable cell number occurred. We suggest that the increased transfer from phosphatidylcholine to sphingomyelin by 27-hydroxycholesterol may be related to enhanced cytosolic free Ca++.

Calcium↗
PubMed1998

Comparative investigation of sphingoid bases and fatty acids in ceramides and sphingomyelins from human ovarian malignant tumors and normal ovary.

Fatty acid and sphingoid base compositions of ceramides and sphingomyelins were investigated in malignant tumors and normal tissue of human ovaries. It has been established that fatty acid compositions of ceramide and sphingomyelin isolated from one tissue are significantly different: the predominant acids are oleic (18:1) in ceramide and palmitic (16:0) in sphingomyelin, which contains much more other saturated acids. These differences are characteristic of both normal and tumor tissues. Sphingoid base compositions of ceramide and sphingomyelin in normal tissue are identical: the major component is sphingenine (over 96%), while ceramides from tumors contain, in addition to sphingenine, a significant amount of sphinganine. In sphingomyelins from tumors, sphinganine content is significantly lower than in ceramides and depends on the type of tumor.

Ceramides↗
PubMed2003

Hydration and lateral organization in phospholipid bilayers containing sphingomyelin: a 2H-NMR study.

Interfacial properties of lipid bilayers were studied by (2)H nuclear magnetic resonance spectroscopy, with emphasis on a comparison between phosphatidylcholine and sphingomyelin. Spectral resolution and sensitivity was improved by macroscopic membrane alignment. The motionally averaged quadrupolar interaction of interlamellar deuterium oxide was employed to probe the interfacial polarity of the membranes. The D(2)O quadrupolar splittings indicated that the sphingomyelin lipid-water interface is less polar above the phase transition temperature T(m) than below T(m). The opposite behavior was found in phosphatidylcholine bilayers. Macroscopically aligned sphingomyelin bilayers also furnished (2)H-signals from the amide residue and from the hydroxyl group of the sphingosine moiety. The rate of water-hydroxyl deuteron exchange could be measured, whereas the exchange of the amide deuteron was too slow for the inversion-transfer technique employed, suggesting that the amide residue is involved in intermolecular hydrogen bonding. Order parameter profiles in mixtures of sphingomyelin and chain-perdeuterated phosphatidylcholine revealed an ordering effect as a result of the highly saturated chains of the sphingolipids. The temperature dependence of the (2)H quadrupolar splittings was indicative of lateral phase separation in the mixed systems. The results are discussed with regard to interfacial structure and lateral organization in sphingomyelin-containing biomembranes.

Deuterium↗
PubMed1995

Molecular species of sphingomyelin in sphingomyelinase-sensitive and sphingomyelinase-resistant pools of HL-60 cells.

This study of sphingomyelin molecular species in undifferentiated and differentiated (granulocytic form) HL-60 cells demonstrated only minor differences in the distribution of species between the sphingomyelinase-sensitive and sphingomyelinase-resistant pools of sphingomyelin in these cells. The two most prominent species of sphingosine present in both the undifferentiated and differentiated cells were those containing 16:0 (slightly higher in the sphingomyelinase-resistant membranes) and 24:1 N-acyl moieties. Cell differentiation exerted little effect on the distribution of molecular species of sphingomyelin between the sphingomyelinase-sensitive and sphingomyelinase-resistant pools in HL-60 cells, although the levels of N-palmitoyl sphinganine were significantly lower and the N-nervonoyl sphingosine higher in both pools from the differentiated cells. Our results indicate the same species of sphingomyelin, available at both the outer layer of the plasma membrane and inner layer of the plasma membrane (plus intracellular membranes) of HL-60 cells, serve as precursors for generation of the ceramides that participate in signal transduction processes initiated by cell activation.

Cell Differentiation↗
PubMed1988

Endovesiculation of human erythrocytes exposed to sphingomyelinase C: a possible explanation for the enzyme-resistant pool of sphingomyelin.

When human erythrocytes are treated with Staphylococcus aureus sphingomyelinase C at 37 degrees C they become susceptible to cold lysis and appear to endovesiculate. Endovesiculation has been confirmed by showing that in parallel with sphingomyelin breakdown, the cells accumulate [3H]inulin or [14C]sucrose (without losing intracellular K+) and also experience a loss of cell-surface acetylcholinesterase activity into a latent intracellular pool which can be revealed by treatment with detergent. On the basis of these observations it can be calculated that endovesicles account for about 2-4% of cell volume and about 25% of total cell surface. Pretreatment of cells with bee venom phospholipase A2 completely blocked sphingomyelinase-induced endovesiculation but this effect was related to a concomitant decrease in sphingomyelin breakdown which was reduced by about 90%. These results indicate that the pool of sphingomyelin which is not susceptible to attack by sphingomyelinase C (about 15% of total sphingomyelin) may be resistant because of membrane internalisation and not because it originally resides in the inner leaflet of the plasma membrane.

Acetylcholinesterase↗
PubMed1999

Stimulation of lysosomal sphingomyelin degradation by sphingolipid activator proteins.

Lysosomal breakdown of glycosphingolipids with short hydrophilic carbohydrate headgroups is achieved by the simultaneous action of specific hydrolases and sphingolipid activator proteins (SAPs). Activator proteins are considered to facilitate the enzyme/substrate interaction between water-soluble enzymes and membrane-bound substrates. Sphingomyelin, containing the small hydrophilic phosphorylcholine moiety, is hydrolysed by acid sphingomyelinase (acid SMase). Recent experimental data on the in vivo and in vitro role of activator proteins in sphingomyelin breakdown by acid SMase are reviewed. These data combined with the results using homogenous protein preparations as well as a liposomal assay system mimicking the physiological conditions suggest that lysosomal sphingomyelin degradation is not critically dependent on any of the known activator proteins. Moreover, evidence is provided that the assumed intramolecular activator domain of acid SMase and especially the presence of negatively charged lipids in the lysosomes are sufficient for sphingomyelin turnover.

Animals↗
PubMed2003

A possible role of cholesterol-sphingomyelin/phosphatidylcholine in nuclear matrix during rat liver regeneration.

BACKGROUND/AIMS: Phospholipids and cholesterol in chromatin have been previously demonstrated. The lipid fraction changes during cell proliferation in relation to activation of enzymes of phospholipid metabolism. The aim of the present work is to clarify if chromatin lipids may derive or not from nuclear matrix and if they have different roles. METHODS: The subnuclear fractions were isolated from rat hepatocyte nuclei and the lipid fraction was extracted and analysed by chromatography in normal and regenerating liver. The phosphatidylcholine-sphingomyelin metabolism enzymes activity was assayed, by using radioactive substrates. RESULTS: In nuclear matrix, cholesterol and sphingomyelin are respectively five and three times higher than those present in chromatin; the amount of phosphatidylcholine, which it is enriched in saturated fatty acids, is lower, thus indicating a less fluid structure. The lower content in phosphatidylcholine may be justified by the phosphatidylcholine-dependent phospholipase C activity, which increases during liver regeneration, reaching a peak at the beginning of S-phase, when also cholesterol and sphingomyelin increase. CONCLUSIONS: The nuclear matrix lipids are independent from chromatin lipids; the ratio cholesterol-sphingomyelin/phosphatidylcholine is higher and, as a consequence, nuclear matrix is less fluid in relation to DNA synthesis, suggesting a specific role of nuclear matrix as a structure involved in DNA duplication.

Animals↗
PubMed1980

Enzymic hydrolysis of sphingomyelin in the presence of bile salts.

Sphingomyelin in mixed dispersion with bile salts was hydrolysed by the solubilized sphingomyelinase of rat brain lysosomes. In parallel studies, physical properties of these dispersions were determined. The kinetic curves that described the rate of hydrolysis as a function of increasing concentrations of bile salt were multiphasic. A region of very low activity was followed by an ascending portion, a peak, a descending portion, a trough and a second ascending portion. The positions of the initiation points, peaks and troughs were found to be a function of the respective ratios of the bile salt to sphingomyelin for the detergent sodium taurodeoxycholate, but of the absolute concentration of the detergent for sodium taurocholate. Turbidity studies suggested that hydrolysis of sphingomyelin begins at a bile salt concentration that solubilizes the lipid and incorporates it into a mixed micelle with the detergent. Ultracentrifugation studies suggested that the sizes of the mixed aggregates of detergent and lipid were a function of the ratio of taurodeoxycholate to sphingomyelin, but of the absolute concentration of the bile salt, for sodium taurocholate.

Animals↗
PubMed1996

Betamethasone modulation of sphingomyelin hydrolysis up-regulates CTP:cholinephosphate cytidylyltransferase activity in adult rat lung.

Glucocorticoids appear to play an integral role in stimulating surfactant synthesis by activating the rate-regulatory enzyme for phosphatidylcholine synthesis, CTP:cholinephosphate cytidylyltransferase (CT). The activity of liver CT, in vitro, has been shown to be inhibited by the sphingomyelin hydrolysis product, sphingosine. In order to investigate the mechanisms by which glucocorticoids alter CT activity, in vivo, we administered betamethasone (1 mg/kg intraperitoneally) sequentially to adult male rats for 5 days. Betamethasone increased CT activity 2-fold relative to control in whole lung. The hormone also increased membrane-bound activity, but did not affect cytosolic enzyme activity. Betamethasone modestly increased CT mRNA as determined by the reverse-transcription PCR and Southern analysis of PCR products, but did not alter the levels of immunoreactive enzyme in lung membranes as demonstrated by Western blotting. The hormone did, however, produce a nearly 3-fold increase in membrane-associated sphingomyelin, and co-ordinately a substantial decrease in the levels of sphingosine in lung membranes. Sphingosine, but not sphinganine, was a competitive, reversible inhibitor of lung CT with respect to the enzyme activator, phosphatidylglycerol. Betamethasone decreased the activities of the sphingomyelin hydrolases: acid sphingomyelinase by 33% and of alkaline ceramidase by 21%. The hormone also inhibited the generation of sphingosine from lysosphingomyelin in lung membranes. There was no significant effect of the hormone on serine palmitoyltransferase activity, the first committed enzyme for sphingolipid biosynthesis. Further, administration of L-cycloserine, an inhibitor of sphingosine formation, was shown to stimulate CT activity by 74% and increase disaturated phosphatidylcholine in alveolar lavage by 52% relative to control. These observations suggest that glucocorticoids up-regulate surfactant synthesis at the level of a key regulatory enzyme by significantly altering the availability of inhibitory metabolites resulting from sphingomyelin hydrolysis.

Amidohydrolases↗
PubMed1997

The sphingomyelin-ceramide pathway participates in cytokine regulation of C-reactive protein and serum amyloid A, but not alpha-fibrinogen.

Maximal induction of the acute-phase proteins C-reactive protein (CRP) and serum amyloid A (SAA) in the human hepatoma cell line Hep3B requires the combination of interleukin (IL)-6 and IL-1. In contrast, IL-1 inhibits fibrinogen induction by IL-6. To explore the possible participation of the sphingomyelin-ceramide pathway in the transduction of cytokine effects, the role of this pathway in expression of CRP, SAA and alpha-fibrinogen was investigated. The cell-permeable ceramide analogues C2 and C6 each greatly potentiated induction of both CRP and SAA mRNA by IL-6+IL-1beta but did not affect the responses of alpha-fibrinogen to IL-6 or to IL-6+IL-1beta. The combination of IL-6+IL-1beta led to increased turnover of sphingomyelin in Hep3B cells. D609, an inhibitor of ceramide production by acidic but not neutral sphingomyelinases, substantially inhibited induction of CRP and SAA by IL-6+IL-1beta. The ability of C2 and C6 to potentiate the effects of cytokines suggests that the sphingomyelin-ceramide pathway participates in induction of CRP and SAA by IL-6+IL-1beta under these experimental conditions, most likely by transducing the effects of IL-1beta. C2 and C6 were unable to substitute for IL-1beta in enhancing IL-6 effects on CRP and SAA, consistent with other reports indicating that the sphingomyelin-ceramide pathway is only a single component of multiple necessary converging pathways for induction of many genes. In contrast, this pathway does not appear to participate in mediating the inhibitory effects of IL-1beta on fibrinogen induction by IL-6.

Apolipoproteins↗
PubMed1998

Sphingomyelin, glycosphingolipids and ceramide signalling in cells exposed to P-fimbriated Escherichia coli.

Uropathogenic Escherichia coli attach to epithelial cells through P fimbriae that bind Galalpha1-4Galbeta-oligosaccharide sequences in cell surface glycosphingolipids. The binding of P-fimbriated E. coli to uroepithelial cells causes the release of ceramide, activation of the ceramide signalling pathway and a cytokine response in the epithelial cells. The present study examined the molecular source of ceramide in human kidney A498 cells exposed to P-fimbriated E. coli. Agonists such as TNF-alpha and IL-1beta released ceramide from sphingomyelin by the activation of endogenous sphingomyelinases and hydrolysis of sphingomyelin, and triggered an IL-6 response. P-fimbriated E. coli caused a slight increase in endogenous sphingomyelinase activity, but there was no associated sphingomyelin hydrolysis. Instead, the concentration of galactose-containing glycolipids decreased. We propose that P-fimbriated E. coli differ from other activators of the ceramide pathway, in that release of ceramide is from receptor glycolipids and not from sphingomyelin. Receptor breakdown may be an efficient host defence strategy, as it reduces the concentration of cell surface receptors, releases soluble receptor analogues and activates an inflammatory response.

Ceramides↗
PubMed1992

Toward gene therapy for Niemann-Pick disease (NPD): separation of retrovirally corrected and noncorrected NPD fibroblasts using a novel fluorescent sphingomyelin.

The neurologic (type A) and nonneurologic (type B) forms of Niemann-Pick disease (NPD) both result from deficiencies of acid sphingomyelinase (ASM) activity leading to the accumulation of sphingomyelin and other related lipids within lysosomes. Recently, the full-length cDNA and genomic sequences encoding ASM have been isolated and the nature of the molecular lesions causing NPD has been investigated. Although these developments have facilitated diagnosis for this debilitating disease, no effective treatment is currently available. Toward this latter goal, our laboratories recently reported the effectiveness of retroviral-mediated gene transfer for the in vitro correction of the cellular pathology in NPD fibroblasts (Suchi et al., 1992). In addition, novel selection procedures were developed to separate retrovirally corrected and noncorrected NPD fibroblasts based on the receptor-mediated delivery of a fluorescently (pyrene)-labeled sphingomyelin (P12-SPM) to the lysosomes of cells using liposomes coated with apolipoprotein E. In this study, we have used a different, fluorescent derivative of sphingomyelin (lissamine-rhodamine dodecanoyl sphingomyelin; LR12-SPM) to extend and improve this selection system. LR12-SPM offers a number of advantages over P12-SPM, including the facts that apolipoprotein E is not required for its efficient uptake and targeting to lysosomes and that the product of LR12-SPM degradation by ASM is efficiently transported out of cells. Thus, when analyzed in a fluorescence-activated cell sorter (FACS), there was complete separation (i.e., no overlap) of retrovirally corrected and noncorrected NPD cells after the administration of LR12-SPM.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Separation↗
PubMed1987

Sphingomyelin lipidosis in a cat.

A 7-month-old Balinese cat with progressive neurological dysfunction had histopathological lesions of brain, liver, kidney, spleen, and lung consistent with a lysosomal storage disease. Ultrastructural examination revealed lysosomal hypertrophy with membranous inclusions. Hepatic sphingomyelin and cholesterol were elevated 10 times normal, and total phospholipids were increased 3.6 fold. Sphingomyelinase activity measured with 14C labeled sphingomyelin at pH 5.0 was virtually absent in brain and liver. Other lysosomal hydrolase activities were normal or elevated. Clinical, morphological, and biochemical findings suggest that this cat had sphingomyelin lipidosis similar to human Niemann-Pick disease type A, and that feline sphingomyelin lipidosis provides another model of human lysosomal storage disease.

Animals↗