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PubMed1997

An apparent association between glycosylphosphatidylinositol-anchored proteins and a sphingolipid in Tetrahymena mimbres.

Sphingolipids are thought to stabilize glycosylphosphatidylinositol (GPI)-anchored protein-rich membrane domains of yeast and polarized higher animal cells during the processing and targeting of these proteins to the plasma membrane. A widely used criterion for identifying the stable sphingolipid- and GPI-anchored protein-enriched membrane domains is the resistance of these lipid-modified proteins to solubilization by the detergent Triton X-100 (TX-100) at low temperature. Surprisingly, there have been no reports of sphingolipid/GPI-anchored protein association in protozoans, despite the fact that these cells contain considerably higher levels of GPI-anchored proteins than does any other organism. We report here the presence in Tetrahymena mimbres of a significant pool of GPI-anchored proteins which resisted extraction by 1% TX-100 at 4 degrees C but not at 37 degrees C. Of the total cellular complement of GPI-anchored proteins, which together accounted for more than 2% of whole-cell protein and were especially enriched in surface membranes, 10% of the major 63kDa component (gpi63) and 23% of a somewhat less abundant component (gpi23) were insoluble in TX-100 at 4 degrees C. A substantial proportion of the cell's only abundant sphingolipid, ceramideaminoethylphosphonate (CAEP), was also insoluble in 1% TX-100 at 4 degrees C. Radiolabelling studies involving [3H]leucine incorporation into proteins and [3H]palmitic acid incorporation into lipids revealed that the TX-100-resistant gpi63, gpi23 and CAEP molecules were all metabolically distinct from their TX-100-soluble counterparts in other compartments of the cell. The presence of detergent-resistant sphingolipid/GPI-anchored protein domains in non-polarized ciliate and trypanosomatid cells was probably obscured in previous studies by the profusion of accompanying detergent-soluble molecules.

Animals↗
PubMed1999

Internalization and sorting of plasma membrane sphingolipid analogues in differentiating oligodendrocytes.

We studied the formation of early endosomes in differentiating oligodendrocytes and type-2 astrocytes, which are derived from common precursor cells in rat neonates, using fluorescent analogues of lactosylceramide (LacCer) and sulfatide labeled with 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene++ +-3-pentanoic acid (BODIPY FL C5). These sphingolipid analogues exhibit a concentration-dependent shift in their fluorescence emission maximum from green to red wavelengths that can be used to estimate the relative concentration of an analogue in the intracellular membranes of living cells by quantitative fluorescence microscopy. When oligodendrocytes at various stages of differentiation were incubated with 1 microM BODIPY-sphingolipid at 10 degrees C and washed, yellow/green plasma membrane fluorescence was observed. Quantitative studies confirmed that the amount of BODIPY-LacCer or -sulfatide incorporated into the plasma membrane of a given cell type was identical. When these cells were subsequently warmed to 37 degrees C for 2-10 min to allow internalization to occur, the BODIPY-sphingolipid analogues were distributed in a punctate pattern throughout the cytoplasm. Within individual cells labeled with BODIPY-sulfatide, some endosomes exhibited green fluorescence, whereas others emitted red/orange fluorescence. In contrast, when BODIPY-LacCer was used, only green endosomes were observed. Although this phenomenon could be observed at earlier stages of differentiation, it was most obvious in mature oligodendrocytes, where quantitative measurements of the red/green ratio of individual endosomes suggested about a threefold difference between the concentration of the LacCer and sulfatide analogues in endosomes. These results suggest that "lipid sorting" takes place during endocytosis in mature oligodendrocytes, resulting in selective exclusion of certain lipid species during the internalization process. This sorting event may result in the net addition of lipids to the differentiated oligodendrocyte plasma membrane.

Animals↗
PubMed1999

Sphingolipids stimulate cell growth via MAP kinase activation in osteoblastic cells.

Ceramide, ceramide-1-phosphate (C1P) sphingosine (SPH) and sphingosine-1-phosphate (S1P) effects on proliferation and extracellular-signal regulated kinases, ERKs (also known as MAPKs), activation were investigated in human and rat osteoblastic cells. MAPK activation was sphingolipid-specific in cells from both species. In human osteoblastic cells, S1P and C1P markedly stimulated ERK2 phosphorylation with a slight increase in phosphorylation of ERK1. SPH nor ceramide induced phosphorylation of either ERK isoform. In rat osteoblastic cells, SIP, ceramide and SPH stimulated phosphorylation of both isoforms. C1P did not induce phosphorylation of ERK1 but produced a mild increase in phosphorylation of ERK2. In human cells, only S1P significantly (P<0.05) increased osteoblastic cell proliferation, while in the rat cells all four sphingolipids significantly (P<0.05) induced proliferation. The calcium channel blocker verapamil blocked (P<0.05) these effects in both cell types. The MAPK inhibitor, PD98059, inhibited (P<0.05) the mitogenic effect of SIP in human cells. In rat cells, PD98059 effects were less substantial but significant for S1P and C1P. This study demonstrates that sphingolipids are mitogens for both human and rat osteoblastic cells with the MAPK pathway and calcium mediating in part these effects in a species specific manner.

Animals↗
PubMed1983

Sphingolipid metabolism in cultured fibroblasts: microscopic and biochemical studies employing a fluorescent ceramide analogue.

A fluorescent analogue of ceramide, N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-epsilon-aminocaproyl sphingosine (C6-NBD-ceramide), was used to investigate sphingolipid metabolism in Chinese hamster fibroblasts. C6-NBD-ceramide was incorporated into small unilamellar dioleoyl phosphatidylcholine vesicles and incubated with cells in monolayer culture at 2 degrees C, resulting in rapid and preferential transfer of the labeled ceramide from vesicles to cells. The cells were then washed and subsequently incubated at 37 degrees C for various intervals. The metabolism of C6-NBD-ceramide was monitored by lipid extraction and analysis, and the intracellular distribution of the labeled molecule was followed by fluorescence microscopy. Initially, fluorescence was detected almost exclusively in mitochondria, with over 90% of the extractable lipid fluorescence due to C6-NBD-ceramide. After 30 min at 37 degrees C, intense fluorescence appeared in the Golgi apparatus. This organelle was identified by colocalization of NBD fluorescence with a Golgi-apparatus-specific stain. At later times the plasma membrane became visibly labeled as well, at which point 90% of the cell-associated fluorescence was recovered as NBD-labeled sphingomyelin and NBD-labeled cerebroside. These metabolites were identified by enzymatic and biochemical analysis and by thin-layer chromatography of the fluorescent lipid extracts. The finding that C6-NBD-ceramide is used by these cells in standard pathways of sphingolipid biosynthesis suggests that this fluorescent precursor will be a valuable tool for correlating the metabolism of sphingolipids with their intracellular distribution and translocation. In addition, during its metabolism by Chinese hamster fibroblasts, this compound acts as a vital stain for the Golgi apparatus.

4-Chloro-7-nitrobenzofurazan↗
PubMed1998

Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response.

The sphingolipid metabolites ceramide and sphingosine-1-phosphate are second messengers with opposing roles in mammalian cell growth arrest and survival; their relative cellular level has been proposed to be a rheostat that determines the fate of cells. This report demonstrates that this rheostat is an evolutionarily conserved stress-regulatory mechanism that influences growth and survival of yeast. Although the role of sphingosine-1-phosphate in yeast was not previously examined, accumulation of ceramide has been shown to induce G1 arrest and cell death. We now have identified a gene in Saccharomyces cerevisiae, LBP1, that regulates the levels of phosphorylated sphingoid bases and ceramide. LBP1 was cloned from a yeast mutant that accumulated phosphorylated long-chain sphingoid bases and diverted sphingoid base intermediates from sphingolipid pathways to glycerophospholipid biosynthesis. LBP1 and its homolog, LBP2, encode very hydrophobic proteins that contain a novel-conserved sequence motif for lipid phosphatases, and both have long-chain sphingoid base phosphate phosphatase activity. In vitro characterization of Lbp1p shows that this phosphatase is Mg2+-independent with high specificity for phosphorylated long-chain bases, phytosphingosine and sphingosine. The deletion of LBP1 results in the accumulation of phosphorylated long-chain sphingoid bases and reduced ceramide levels. Moreover, deletion of LBP1 and LBP2 results in dramatically enhanced survival upon severe heat shock. Thus, these phosphatases play a previously unappreciated role in regulating ceramide and phosphorylated sphingoid base levels in yeast, and they modulate stress responses through sphingolipid metabolites in a manner that is reminiscent of their effects on mammalian cells.

Amino Acid Sequence↗
PubMed1996

Complete removal of sphingolipids from the plasma membrane disrupts cell to substratum adhesion of mouse melanoma cells.

GM-95, a mutant cell line derived from mouse melanoma MEB-4 cells, is deficient in glycosphingolipids (GSLs) due to the lack of ceramide glucosyltransferase-1 activity (Ichikawa, S., Nakajo, N., Sakiyama, H., and Hirabayashi, Y. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 2703-2707). In this study, we examined the involvement of the complex sphingolipids in cell to substratum adhesion. Immunofluorescent and chemical analyses revealed that the complex sphingolipids were significantly concentrated in the detergent-insoluble substrate attachment matrix of both GM-95 and MEB-4 cells. In spite of the absence of GSLs, GM-95 cells retained the ability to adhere to extracellular matrix (ECM) proteins such as fibronectin, collagen, and laminin. When both GM-95 and MEB-4 cells were treated with neutral sphingomyelinase, GM-95 cells were rounded up and detached from all ECM proteins examined. In contrast, neither the morphology nor the adherence of MEB-4 cells was altered. Under this treatment, sphingomyelin (SM) became undetectable in both cells. A similar inhibition was observed upon pretreatment of cells with fumonisin B1 or ISP-1, both of which block the synthesis of ceramide, a common precursor of both GSLs and SM. Stable transfectants expressing GSLs, which were established by transfection of glucosyltransferase-1 cDNA into GM-95 cells, became resistant to neutral sphingomyelinase-mediated rounding up and detachment from ECM proteins. In conclusion, the complex sphingolipids play critical roles in cell to substratum adhesion, and the presence of either GSLs or SM is sufficient for the adhesion.

Animals↗
PubMed1996

Dual roles of sphingolipids in signaling of the escape from and onset of apoptosis in a mouse cytotoxic T-cell line, CTLL-2.

In our previous study, the sphingosine-like immunosuppressant, ISP-1, was found to suppress the proliferation of an interleukin-2-dependent cytotoxic T cell line, CTLL-2, through the inhibition of serine palmitoyltransferase, which catalyzes the committed step of sphingolipid biosynthesis. Analysis of the effect of ISP-1 by flow cytometry revealed that the ISP-1-dependent decrease in cell number was not due to inhibition of the cell cycle progression of CTLL-2 cells but to the induction of apoptosis of the cells. The ISP-1-induced apoptosis was inhibited by the addition of sphingosine (2 microM), suggesting that this ISP-1-induced apoptosis is triggered by the decrease in the intracellular levels of sphingolipids caused by the inhibition of serine palmitoyltransferase. However, another interleukin-2-dependent cell line, F7, which was derived from a mouse pro-B cell line, did not show ISP-1-dependent apoptosis, indicating that the effect of ISP-1 may be specific for a certain type of T cell lineage such as CTLL-2. On the other hand, a high dose of sphingosine (5 microM) by itself induced the apoptosis of CTLL-2 cells. This sphingosine-dependent apoptosis was also observed with F7 cells. These results provide evidence that the intracellular levels of sphingolipids play an important role in the signaling of the escape from and onset of apoptosis of CTLL-2 cells.

Acyltransferases↗
PubMed1997

A mammalian homolog of the yeast LCB1 encodes a component of serine palmitoyltransferase, the enzyme catalyzing the first step in sphingolipid synthesis.

Serine palmitoyltransferase (SPT; EC 2.3.1.50) catalyzes the initial step dedicated to sphingolipid biosynthesis and is thought to be a key enzyme for regulating cellular sphingolipid content. For SPT activity, the yeast Saccharomyces cerevisiae requires two genes, LCB1 and LCB2. We isolated mammalian LCB1 cDNA homologs from mouse and Chinese hamster ovary (CHO) cells and an LCB2 cDNA homolog from CHO cells. The mammalian LCB1 proteins are predicted to have about 35% amino acid identity to the yeast Lcb1 protein, whereas the CHO LCB2 protein is predicted to have about 40% amino acid identity to the yeast Lcb2 protein. Northern blot analysis of mRNA isolated from various mouse tissues revealed that the tissue distribution of both LCB1 and LCB2 messengers followed a similar pattern. Transfection of an SPT-defective CHO mutant strain with a CHO LCB1-expressing plasmid restored both SPT activity and de novo sphingolipid synthesis to the wild type levels, whereas transfection of the mutant strain with a CHO LCB2-expressing plasmid did not exhibit any recovery effects, indicating that the SPT defect in the mutant cells is specifically complemented by the CHO LCB1 homolog. Furthermore, when the SPT-defective mutant cells were transfected with a plasmid encoding a His6-tagged CHO LCB1 protein, SPT activity bound to a Ni2+-immobilized resin. These results indicate that the CHO LCB1 homolog encodes a component of SPT.

Acyltransferases↗
PubMed1998

Rustmicin, a potent antifungal agent, inhibits sphingolipid synthesis at inositol phosphoceramide synthase.

Rustmicin is a 14-membered macrolide previously identified as an inhibitor of plant pathogenic fungi by a mechanism that was not defined. We discovered that rustmicin inhibits inositol phosphoceramide synthase, resulting in the accumulation of ceramide and the loss of all of the complex sphingolipids. Rustmicin has potent fungicidal activity against clinically important human pathogens that is correlated with its sphingolipid inhibition. It is especially potent against Cryptococcus neoformans, where it inhibits growth and sphingolipid synthesis at concentrations <1 ng/ml and inhibits the enzyme with an IC50 of 70 pM. This inhibition of the membrane-bound enzyme is reversible; moreover, rustmicin is nearly equipotent against the solubilized enzyme. Rustmicin was efficacious in a mouse model for cryptococcosis, but it was less active than predicted from its in vitro potency against this pathogen. Stability and drug efflux were identified as two factors limiting rustmicin's activity. In the presence of serum, rustmicin rapidly epimerizes at the C-2 position and is converted to a gamma-lactone, a product that is devoid of activity. Rustmicin was also found to be a remarkably good substrate for the Saccharomyces cerevisiae multidrug efflux pump encoded by PDR5.

Animals↗
PubMed1999

Sphingolipid activator proteins are required for epidermal permeability barrier formation.

The epidermal permeability barrier is maintained by extracellular lipid membranes within the interstices of the stratum corneum. Ceramides, the major components of these multilayered membranes, derive in large part from hydrolysis of glucosylceramides mediated by stratum corneum beta-glucocerebrosidase (beta-GlcCerase). Prosaposin (pSAP) is a large precursor protein that is proteolytically cleaved to form four distinct sphingolipid activator proteins, which stimulate enzymatic hydrolysis of sphingolipids, including glucosylceramide. Recently, pSAP has been eliminated in a mouse model using targeted deletion and homologous recombination. In addition to the extracutaneous findings noted previously, our present data indicate that pSAP deficiency in the epidermis has significant consequences including: 1) an accumulation of epidermal glucosylceramides together with below normal levels of ceramides; 2) alterations in lipids that are bound by ester linkages to proteins of the cornified cell envelope; 3) a thickened stratum lucidum with evidence of scaling; and 4) a striking abnormality in lamellar membrane maturation within the interstices of the stratum corneum. Together, these results demonstrate that the production of pSAP, and presumably mature sphingolipid activator protein generation, is required for normal epidermal barrier formation and function. Moreover, detection of significant amounts of covalently bound omega-OH-GlcCer in pSAP-deficient epidermis suggests that deglucosylation to omega-OH-Cer is not a requisite step prior to covalent attachment of lipid to cornified envelope proteins.

Animals↗
PubMed1999

Sphingolipid depletion increases formation of the scrapie prion protein in neuroblastoma cells infected with prions.

Sphingolipid-rich rafts play an essential role in the posttranslational (Borchelt, D. R., Scott, M., Taraboulos, A., Stahl, N., and Prusiner, S. B. (1990) J. Cell Biol. 110, 743-752)) formation of the scrapie prion protein PrP(Sc) from its normal conformer PrP(C) (Taraboulos, A., Scott, M., Semenov, A., Avrahami, D., Laszlo, L., Prusiner, S. B., and Avraham, D. (1995) J. Cell Biol. 129, 121-132). We investigated the importance of sphingolipids in the metabolism of the PrP isoforms in scrapie-infected ScN2a cells. The ceramide synthase inhibitor fumonisin B(1) (FB(1)) reduced both sphingomyelin (SM) and ganglioside GM1 in cells by up to 50%, whereas PrP(Sc) increased by 3-4-fold. Whereas FB(1) profoundly altered the cell lipid composition, the raft residents PrP(C), PrP(Sc), caveolin 1, and GM1 remained insoluble in Triton X-100. Metabolic radiolabeling demonstrated that PrP(C) production was either unchanged or slightly reduced in FB(1)-treated cells, whereas PrP(Sc) formation was augmented by 3-4-fold. To identify the sphingolipid species the decrease of which correlates with increased PrP(Sc), we used two other reagents. When cells were incubated with sphingomyelinase for 3 days, SM levels decreased, GM1 was unaltered, and PrP(Sc) increased by 3-4-fold. In contrast, the glycosphingolipid inhibitor PDMP reduced PrP(Sc) while increasing SM. Thus, PrP(Sc) seems to correlate inversely with SM levels. The effects of SM depletion contrasted with those previously obtained with the cholesterol inhibitor lovastatin, which reduced PrP(Sc) and removed it from detergent-insoluble complexes.

Animals↗
PubMed2001

Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide.

Ordered lipid domains enriched in sphingolipids and cholesterol (lipid rafts) have been implicated in numerous functions in biological membranes. We recently found that lipid domain/raft formation is dependent on the sterol component having a structure that allows tight packing with lipids having saturated acyl chains (Xu, X., and London, E. (2000) Biochemistry 39, 844-849). In this study, the domain-promoting activities of various natural sterols were compared with that of cholesterol using both fluorescence quenching and detergent insolubility methods. Using model membranes, it was shown that, like cholesterol, both plant and fungal sterols promote the formation of tightly packed, ordered lipid domains by lipids with saturated acyl chains. Surprisingly ergosterol, a fungal sterol, and 7-dehydrocholesterol, a sterol present in elevated levels in Smith-Lemli-Opitz syndrome, were both significantly more strongly domain-promoting than cholesterol. Domain formation was also affected by the structure of the sphingolipid (or that of an equivalent "saturated" phospholipid) component. Sterols had pronounced effects on domain formation by sphingomyelin and dipalmitoylphosphatidylcholine but only a weak influence on the ability of cerebrosides to form domains. Strikingly it was found that a small amount of ceramide (3 mol %) significantly stabilized domain/raft formation. The molecular basis for, and the implications of, the effects of different sterols and sphingolipids (especially ceramide) on the behavior and biological function of rafts are discussed.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2004

Genetic, biochemical, and transcriptional responses of Saccharomyces cerevisiae to the novel immunomodulator FTY720 largely mimic those of the natural sphingolipid phytosphingosine.

Sphingolipids are signaling molecules that influence diverse cellular functions from control of the cell cycle to degradation of plasma membrane proteins. The synthetic sphingolipid-like compound FTY720 is an immunomodulating agent in clinical trials for transplant graft maintenance. In this report, we compare the effects of the natural yeast sphingolipid phytosphingosine with FTY720 in Saccharomyces cerevisiae. We show that the multicopy suppressor genes that induce growth resistance to FTY720 also confer resistance to growth-inhibitory concentrations of phytosphingosine. In addition, mutants for ubiquitination pathway proteins are shown to be resistant to the growth-inhibiting effect of both FTY720 and phytosphingosine. We observe fewer similarities between sphingosine and FTY720 than between FTY720 and phytosphingosine as revealed by genetic studies. Yeast cells lacking the specific sphingosine kinase LCB4 are sensitive to phytosphingosine and FTY720 but resistant to sphingosine, suggesting that FTY720 and phytosphingosine have a more related mechanism of action. Gene expression profile comparisons of sensitive and resistant yeast cells exposed to FTY720 and phytosphingosine highlight a number of similarities. In response to treatment with these compounds, approximately 77% of the genes that are regulated >2-fold by FTY720 also respond to phytosphingosine in the same direction in the parent strain. In addition, a close inspection of TAT1 and TAT2 transporters following exposure to phytosphingosine indicates that TAT1 protein is degraded in a similar fashion upon treatment with FTY720 and phytosphingosine. There were differences, however, with respect to the TAT2 protein level and the expression profiles of a subset of genes. The genetic, transcriptional, and biochemical data together indicate that FTY720 and phytosphingosine influence similar pathways in yeast cells. These findings offer further insights into the physiological pathways influenced by these compounds in all eukaryotic cells and help us to understand the therapeutic consequences of FTY720 in humans.

Amino Acids↗
PubMedDate not supplied

Dexamethasone and sphingolipids inhibit concanavalin A stimulated glucose uptake in 3T3-L1 fibroblasts.

Studies were carried out in 3T3-L1 fibroblasts to determine the effect of sphingolipids and corticosteroids on concanavalin A stimulated glucose uptake. Sphinganine (40 microM) and sphingosine (40 AND 100 microM) significantly inhibited concanavalin A stimulated glucose uptake (P less than 0.025 & less than 0.005). Prior incubation with 10(-7) M dexamethasone also significantly inhibited concanavalin A stimulated glucose uptake (P less than 0.005). The known effects of corticosteroids on sphingolipid synthesis, degradation, and tissue levels, suggest inhibition by corticosteroids of glucose uptake may be through effects of the steroid on sphingolipid metabolism.

Animals↗
PubMed1999

Advances in the signal transduction of ceramide and related sphingolipids.

Recently, the sphingolipid metabolites ceramide, sphingosine, ceramide 1-P, and sphingosine 1-P have been implicated as second messengers involved in many different cellular functions. Publications on this topic are appearing at a rapidly increasing rate and new developments in this field are also appearing rapidly. It is thus important to summarize the results obtained from many different laboratories and from different fields of research to obtain a clearer picture of the importance of sphingolipid metabolites. This article reviews the studies from the last few years and includes the effects of a variety of extracellular agents on sphingolipid signal transduction pathways in different tissues and cells and on the mechanisms of regulation. Sphingomyelin exists in a number of functionally distinct pools and is composed of distinct molecular species. Sphingomyelin metabolites may be formed by many different pathways. For example, the generation of ceramide from sphingomyelin can be catalyzed by at least five different sphingomyelinases. A large variety of stimuli can induce the generation of ceramide, leading to activation or inhibition of various cellular events such as proliferation, differentiation, apoptosis, and inflammation. The effect of ceramide on these physiological processes is due to its many different downstream targets. It can activate ceramide-activated protein kinases and ceramide-activated protein phosphatases. It also activates or inhibits PKCs, PLD, PLA2, PC-PLC, nitric oxide synthase, and the ERK and SAPK/JNK signaling cascades. Ceramide activates or inhibits transcription factors, modulates calcium homeostasis and interacts with the retinoblastoma protein to regulate cell cycle progression. Most of the work in this field has involved the study of ceramide effects, but the roles of the other three sphingomyelin metabolites is now attracting much attention. The complex interactions between signaling components and ceramide and the controls regulating these interactions are now being identified and are presented in this review.

Animals↗
PubMed1979

Sphingolipid biosynthesis and vitamin K metabolism in Bacteroides melaninogenicus.

B. melaninogenicus provides a unique system for the study of the biosynthesis of an important group of lipids, the phosphosphingolipids. Sphingolipid biosynthesis can be repressed and induced by depletion and restoration of vitamin K. At least one enzyme involved in sphingolipid biosynthesis from the microorganism can be solubilized and so purified by conventional methods. Pathways involved in biosynthesis may differ from hitherto postulated pathways, for example, the incorporation of NH4+ into ethanolamine residue of ceramide phosphorylethanolamine. Moreover, the derivation of mutants defective in steps in sphingolipid biosynthesis would be of great value in these studies.

Animals↗
PubMed1989

Sphingolipid biosynthesis by rat liver cells: effects of serine, fatty acids and lipoproteins.

The effects of circulating factors that might influence de novo sphingolipid biosynthesis were examined with rat liver cells by following the incorporation of [14C]serine into sphingosine and sphinganine, the predominant long-chain base backbones of hepatic sphingolipids. The rate of long-chain base formation depended on the concentration of [14C]serine in the medium and exhibited saturation kinetics. Long-chain base formation was stimulated by another precursor, palmitic acid, but stearic, oleic, linoleic and linolenic acids were inhibitory. This kinetic behavior indicates that long-chain base formation in liver is affected by the availability of the substrates of the initial enzyme of this pathway, serine palmitoyltransferase. Since liver is also exposed to sphingolipids associated with circulating lipoproteins, the effects of various lipoprotein fractions were determined and each appeared to decrease long-chain base formation. These results suggest that hepatic long-chain base biosynthesis can be stimulated by increases in the circulating levels of the precursors serine and palmitic acid whereas some other fatty acids and lipoproteins decrease the flux through this pathway.

Acyltransferases↗
PubMed1994

Dietary fumonisin B1 induces disruption of sphingolipid metabolism in Sprague-Dawley rats: a new mechanism of nephrotoxicity.

Fumonisins are potent inhibitors of sphingolipid biosynthesis produced by several Fusarium species. Consumption of corn or corn products infected with F. moniliforme, or high levels of fumonisins, is associated with several animal diseases. In a 4-wk feeding study, the concentration of fumonisin B1 that caused nephrotoxicity in Sprague-Dawley rats was much less than that required to cause hepatotoxicity. This retrospective study shows a close correlation between the extent and severity of ultrastructural lesions and the degree of disruption of sphingolipid metabolism. The kidney was more sensitive to fumonisin B1-induced disruption of sphingolipid metabolism than liver with significant elevation of free sphingosine, free sphinganine, and the free sphinganine:free sphingosine ratio in rats fed 15, 50 and 150 micrograms/g fumonisin B1. Accumulation of free sphinganine and elevation of the free sphinganine:free sphingosine ratio in urine closely reflected the changes that occurred in kidney. The accumulated sphinganine and elevation of the free sphinganine:free sphingosine ratio was associated with accumulation of cells in urine. Thus, urine rather than serum is the fluid of choice for detecting elevated free sphingoid bases generated as a consequence of fumonisin-induced kidney damage.

Animals↗