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PubMed2005

Identification of fungal sphingolipid C9-methyltransferases by phylogenetic profiling.

Fungal glucosylceramides play an important role in plant-pathogen interactions enabling plants to recognize the fungal attack and initiate specific defense responses. A prime structural feature distinguishing fungal glucosylceramides from those of plants and animals is a methyl group at the C9-position of the sphingoid base, the biosynthesis of which has never been investigated. Using information on the presence or absence of C9-methylated glucosylceramides in different fungal species, we developed a bioinformatics strategy to identify the gene responsible for the biosynthesis of this C9-methyl group. This phylogenetic profiling allowed the selection of a single candidate out of 24-71 methyltransferase sequences present in each of the fungal species with C9-methylated glucosylceramides. A Pichia pastoris knock-out strain lacking the candidate sphingolipid C9-methyltransferase was generated, and indeed, this strain contained only non-methylated glucosylceramides. In a complementary approach, a Saccharomyces cerevisiae strain was engineered to produce glucosylceramides suitable as a substrate for C9-methylation. C9-methylated sphingolipids were detected in this strain expressing the candidate from P. pastoris, demonstrating its function as a sphingolipid C9-methyltransferase. The enzyme belongs to the superfamily of S-adenosylmethionine-(SAM)-dependent methyltransferases and shows highest sequence similarity to plant and bacterial cyclopropane fatty acid synthases. An in vitro assay showed that sphingolipid C9-methylation is membrane-bound and requires SAM and Delta4,8-desaturated ceramide as substrates.

Amino Acid Sequence↗
PubMed2004

Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C-related protein reveals a primordial role in subcellular sphingolipid distribution.

Lipid movement between organelles is a critical component of eukaryotic membrane homeostasis. Niemann Pick type C (NP-C) disease is a fatal neurodegenerative disorder typified by lysosomal accumulation of cholesterol and sphingolipids. Expression of yeast NP-C-related gene 1 (NCR1), the orthologue of the human NP-C gene 1 (NPC1) defective in the disease, in Chinese hamster ovary NPC1 mutant cells suppressed lipid accumulation. Deletion of NCR1, encoding a transmembrane glycoprotein predominantly residing in the vacuole of normal yeast, gave no phenotype. However, a dominant mutation in the putative sterol-sensing domain of Ncr1p conferred temperature and polyene antibiotic sensitivity without changes in sterol metabolism. Instead, the mutant cells were resistant to inhibitors of sphingolipid biosynthesis and super sensitive to sphingosine and C2-ceramide. Moreover, plasma membrane sphingolipids accumulated and redistributed to the vacuole and other subcellular membranes of the mutant cells. We propose that the primordial function of these proteins is to recycle sphingolipids and that defects in this process in higher eukaryotes secondarily result in cholesterol accumulation.

Amino Acid Sequence↗
PubMed2006

Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis in APOE*3Leiden mice.

BACKGROUND: The prevalence of dyslipidemia and obesity resulting from excess energy intake and physical inactivity is increasing. The liver plays a pivotal role in systemic lipid homeostasis. Effective, natural dietary interventions that lower plasma lipids and promote liver health are needed. OBJECTIVE: Our goal was to determine the effect of dietary sphingolipids on plasma lipids and liver steatosis. DESIGN: APOE*3Leiden mice were fed a Western-type diet supplemented with different sphingolipids. Body cholesterol and triacylglycerol metabolism as well as hepatic lipid concentrations and lipid-related gene expression were determined. RESULTS: Dietary sphingolipids dose-dependently lowered both plasma cholesterol and triacylglycerol in APOE*3Leiden mice; 1% phytosphingosine (PS) reduced plasma cholesterol and triacylglycerol by 57% and 58%, respectively. PS decreased the absorption of dietary cholesterol and free fatty acids by 50% and 40%, respectively, whereas intestinal triacylglycerol lipolysis was not affected. PS increased hepatic VLDL-triacylglycerol production by 20%, whereas plasma lipolysis was not affected. PS increased the hepatic uptake of VLDL remnants by 60%. Hepatic messenger RNA concentrations indicated enhanced hepatic lipid synthesis and VLDL and LDL uptake. The net result of these changes was a strong decrease in plasma cholesterol and triacylglycerol. The livers of 1% PS-fed mice were less pale, 22% lighter, and contained 61% less cholesteryl ester and 56% less triacylglycerol than livers of control mice. Furthermore, markers of liver inflammation (serum amyloid A) and liver damage (alanine aminotransferase) decreased by 74% and 79%, respectively, in PS-fed mice. CONCLUSION: Sphingolipids lower plasma cholesterol and triacylglycerol and protect the liver from fat- and cholesterol-induced steatosis.

Animals↗
PubMed2001

GPI anchoring leads to sphingolipid-dependent retention of endocytosed proteins in the recycling endosomal compartment.

Glycosylphosphatidylinositol (GPI) anchoring is important for the function of several proteins in the context of their membrane trafficking pathways. We have shown previously that endocytosed GPI-anchored proteins (GPI-APs) are recycled to the plasma membrane three times more slowly than other membrane components. Recently, we found that GPI-APs are delivered to endocytic organelles, devoid of markers of the clathrin-mediated pathway, prior to their delivery to a common recycling endosomal compartment (REC). Here we show that the rate-limiting step in the recycling of GPI-APs is their slow exit from the REC; replacement of the GPI anchor with a transmembrane protein sequence abolishes retention in this compartment. Depletion of endogenous sphingolipid levels using sphingolipid synthesis inhibitors or in a sphingolipid-synthesis mutant cell line specifically enhances the rate of endocytic recycling of GPI-APs to that of other membrane components. We have shown previously that endocytic retention of GPI-APs is also relieved by cholesterol depletion. These findings strongly suggest that functional retention of GPI-APs in the REC occurs via their association with sphingolipid and cholesterol-enriched sorting platforms or 'rafts'.

Animals↗
PubMed1994

Uptake and metabolism of sphingolipids in isolated intestinal loops of mice.

Sphingolipids are found in all eukaryotic organisms. However, little is known about the digestion, uptake and subsequent metabolism of these constituents of food. In this study, radiolabeled sphingolipids were placed in isolated intestinal segments of female CF1 mice, and the metabolism and distribution of the radiolabel were followed. Most of the sphingomyelin was degraded to ceramide and other products in all regions of the intestine, and increasing amounts of several [3H]-labeled sphingolipids appeared in the tissues. Small amounts of the radiolabel disappeared from the intestinal loops and appeared in liver within the first 30 to 60 min implying that neither intact sphingomyelin nor its metabolites are transported very efficiently from the intestine to other organs. There were different degrees of uptake and metabolism of sphingomyelin, [4,5-3H-sphinganyl]ceramide, and [3H]sphingosine. The [3H]sphingomyelin was also administered by gavage and the appearance along the intestine measured. After 90 min, 12% was found in the cecum and colon. These results establish that some of the sphingomyelin that enters the gastrointestinal tract is hydrolyzed and taken up by the intestine, with the lipid backbone being degraded or reutilized for complex sphingolipid synthesis; however, at least a portion passes into the large intestine. The appearance of bioactive compounds throughout the gastrointestinal tract may alter the behavior of intestinal cells.

Administration, Oral↗
PubMed1997

Functional roles of sphingosine, sphingosine 1-phosphate, and methylsphingosines: in regard to membrane sphingolipid signaling pathways.

The signaling roles of ceramide and sphingosine produced through the degrading processes of membrane sphingolipids are currently receiving hot attention in the biochemical and biomedical research fields. For these 9 years at the Biomembrane Institute in Seattle, we have studied functional roles of various sphingolipids such as ceramide, sphingosine, methylsphingosines, and sphingosine 1-phosphate in a variety of biomedical systems. In this article, first, the recent conceptual developments on sphingolipid signaling pathways is outlined. Next, our recent findings on the functional roles of sphingolipids are described focusing on (i) functional roles of sphingosine 1-phosphate in cell motility regulation and platelet activation (ii) involvement of sphingosine in cell signaling (iii) effects of methylsphingosines in cancer cell apoptosis induction and in the regulation of inflammatory processes. Based upon these findings from our studies and others, the perspective of future sphingosine research (sphingology or sphingophysiology) is briefly discussed.

Animals↗
PubMed1986

Characterization of neutral sphingolipids and gangliosides from chicken liver.

The neutral sphingolipids and gangliosides were isolated from 62- and 63-day-old chicken livers and characterized. The total concentration of neutral sphingolipids was 59 nmol/g of liver, and that of gangliosides was 330 nmol/g of liver. The major neutral sphingolipids were free ceramide, galactosylceramide, glucosylceramide, lactosylceramide, galabiosylceramide, and Forssman glycolipid. Galactosylceramide was the most abundant and free ceramide was the second most abundant. The major gangliosides were sialosylgalactosylceramide (GM4) and sialosyllactosylceramide (GM3), each of which contained only N-acetylneuraminic acid as a sialic acid. Sphingosine (d18:1) was a major long-chain base in all the sphingolipids. Considerable amounts of 2-hydroxy fatty acids were present in free ceramide, galactosylceramide, and GM4.

Animals↗
PubMed1993

Inhibition of cholesterol and sphingolipid synthesis causes paradoxical effects on permeability barrier homeostasis.

Cholesterol, fatty acid, and sphingolipid synthesis are required for barrier homeostasis, as demonstrated by studies where synthesis of these species is stimulated in parallel with barrier repair. Moreover, blockade of synthesis of these lipids with inhibitors of two of the rate-limiting enzymes, HMGCoA reductase (lovastatin, fluvastatin) and serine palmitoyl transferase (beta-chloroalanine), alters the kinetics of barrier repair. Whereas these studies demonstrated a requirement for these lipids individually, we asked here whether these lipids are required in either an additive or cooperative fashion. We applied each class of inhibitor alone or the two classes of inhibitors together to acetone-treated skin, or each class separately to essential fatty acid deficient murine skin. When fluvastatin or beta-chloroalanine was applied individually to acetone-treated skin, each caused a delay in the early or late stages of barrier recovery, respectively (assessed as transepidermal water loss). However, when applied together they caused no further worsening at the early time point and a paradoxical improvement at the later time points. This improvement correlated with an accelerated return of sphingolipids, which was perhaps due to a global stimulation of lipid synthesis induced by HMGCoA reductase inhibitors. In essential fatty acid deficient animals, inhibition of HMGCoA reductase caused drastic worsening of both clinical appearance and barrier function, but beta-chloroalanine caused a paradoxical improvement, which correlated with a significant reduction in epidermal sphingolipids. These results are consistent with a requirement for both cholesterol and sphingolipids for barrier homeostasis, and also with the suggestion that both of these lipids must be present (with free fatty acids) for optimal barrier function.

Acetone↗
PubMed2005

Vitamin K and sphingolipid metabolism: evidence to date.

The brain is enriched with sphingolipids, which are important membrane constituents and major lipid signaling molecules that have a role in motor and cognitive behavior. Vitamin K has been implicated in brain sphingolipid metabolism for more than 30 years. The in vitro and in vivo studies to date suggest a role of vitamin K in the regulation of multiple enzymes involved in sphingolipid metabolism within the myelin-rich regions in the brain. However, the precise mechanisms of action are not well understood. Further, the physiological consequences of the observed effects of vitamin K on sphingolipid metabolism have not been systematically studied.

Animals↗
PubMedDate not supplied

[Biologically active sphingolipids in transplantable tumors of different histogenesis].

The composition of biologically active sphingolipids in hepatoma 22, breast adenocarcinoma, Lewis lung carcinoma, large intestine adenocarcinoma, cervical carcinoma, and melanomas M3 and B16 was compared to elucidate the similarity and differences in sphingolipids of subcutaneously transplantable murine tumors. The sphingolipid composition of the tumors was found to widely vary. The sphingomyelin, ceramide, glucosyl- and lactosylceramide, and ganglioside GD3 contents in hepatoma 22 are higher than those in normal tissue. No common regularities for tumors of different origin were observed in the ratios of bioeffectors inhibiting proliferation and stimulating apoptosis and bioeffectors stimulating cell growth and survival. However, the Cer/(GlcCer + LacCer) ratios were very low and practically equal in two melanoma strains, which probably indicates the degree of tumor malignancy. The results suggest that the content and composition of sphingolipids in tumors depend on their histogenesis.

Animals↗
PubMed2002

Expression and functional characterization of SCaMPER: a sphingolipid-modulated calcium channel of cardiomyocytes.

Calcium channels are important in a variety of cellular events including muscle contraction, signaling, proliferation, and apoptosis. Sphingolipids have been recognized as mediators of intracellular calcium release through their actions on a calcium channel, sphingolipid calcium release-mediating protein of the endoplasmic reticulum (SCaMPER). The current study investigates the expression and function of SCaMPER in cardiomyocytes. Northern analyses and RT-PCR cloning and sequencing revealed SCaMPER expression in both human and rat cardiac tissue. Immunofluorescence and Western blot analyses demonstrated that SCaMPER is abundant in cardiac tissue and is localized to the sarcotubular junction. This was confirmed by the colocalization of SCaMPER with dihydropyridine and ryanodine receptors by confocal microscopy. Purified T tubules were shown to contain SCaMPER and immunoelectron micrographs suggested that SCaMPER is located to the junctional T tubules, but a junctional SR localization cannot be ruled out. The sphingolipid ligand for SCaMPER, sphingosylphosphorylcholine (SPC), initiated calcium release from the cardiomyocyte SR. Importantly, antisense knockdown of SCaMPER mRNA produced a substantial reduction of sphingolipid-induced calcium release, suggesting that SCaMPER is a potentially important calcium channel of cardiomyocytes.

Animals↗
PubMed2001

Sphingolipid mediators in cardiovascular cell biology and pathology.

Sphingolipids have emerged as a new class of lipid mediators. In response to various extracellular stimuli, sphingolipid turnover can be stimulated in vascular cells and cardiac myocytes. Subsequent generation of sphingolipid molecules such as ceramide, sphingosine, and sphingosine-1-phosphate, is followed by regulation of ion fluxes and activation of various signaling pathways leading to smooth muscle cell proliferation, endothelial cell differentiation or apoptotic cell death, cell contraction, retraction, or migration. The importance of sphingolipids in cardiovascular signaling is illustrated by recent observations implicating them in physiological processes such as vasculogenesis as well as in frequent pathological conditions, including atherosclerosis and its complications.

Animals↗
PubMed2006

The role of cholesterol and sphingolipids in chemokine receptor function and HIV-1 envelope glycoprotein-mediated fusion.

BACKGROUND: HIV-1 entry into cells is a multifaceted process involving target cell CD4 and the chemokine receptors, CXCR4 or CCR5. The lipid composition of the host cell plays a significant role in the HIV fusion process as it orchestrates the appropriate disposition of CD4 and co-receptors required for HIV-1 envelope glycoprotein (Env)-mediated fusion. The cell membrane is primarily composed of sphingolipids and cholesterol. The effects of lipid modulation on CD4 disposition in the membrane and their role in HIV-1 entry have extensively been studied. To focus on the role of lipid composition on chemokine receptor function, we have by-passed the CD4 requirement for HIV-1 Env-mediated fusion by using a CD4-independent strain of HIV-1 Env. RESULTS: Cell fusion mediated by a CD4-independent strain of HIV-1 Env was monitored by observing dye transfer between Env-expressing cells and NIH3T3 cells bearing CXCR4 or CCR5 in the presence or absence of CD4. Chemokine receptor signaling was assessed by monitoring changes in intracellular [Ca2+] mobilization induced by CCR5 or CXCR4 ligand. To modulate target membrane cholesterol or sphingolipids we used Methyl-beta-cyclodextrin (MbetaCD) or 1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP), respectively. Treatment of the target cells with these agents did not change the levels of CD4 or CXCR4, but reduced levels of CCR5 on the cell surface. Chemokine receptor signalling was inhibited by cholesterol removal but not by treatment with PPMP. HIV-1 Env mediated fusion was inhibited by >50% by cholesterol removal. Overall, PPMP treatment appeared to slow down the rates of CD4-independent HIV-1 Env-mediated Fusion. However, in the case of CXCR4-dependent fusion, the differences between untreated and PPMP-treated cells did not appear to be significant. CONCLUSION: Although modulation of cholesterol and sphingolipids has similar effects on CD4-dependent HIV-1 Env-mediated fusion, sphingolipid modulation had little effect on CD4-independent HIV-1 Env-mediated fusion. Chemokine receptor function remained intact following treatment of cells with PPMP. Therefore such treatment may be considered a more suitable agent to inhibit CD4 dependent HIV-1 infection.

Animals↗
PubMed2005

Drug resistance-associated changes in sphingolipids and ABC transporters occur in different regions of membrane domains.

We have recently shown that two ATP binding cassette (ABC) transporters are enriched in Lubrol-resistant noncaveolar membrane domains in multidrug-resistant human cancer cells [Hinrichs, J. W. J., K. Klappe, I. Hummel, and J. W. Kok. 2004. ATP-binding cassette transporters are enriched in non-caveolar detergent-insoluble glycosphingolipid-enriched membrane domains (DIGs) in human multidrug-resistant cancer cells. J. Biol. Chem. 279: 5734-5738]. Here, we show that aminophospholipids are relatively enriched in Lubrol-resistant membrane domains compared with Triton X-100-resistant membrane domains, whereas sphingolipids are relatively enriched in the latter. Moreover, Lubrol-resistant membrane domains contain more protein and lipid mass. Based on these results, we postulate a model for detergent-insoluble glycosphingolipid-enriched membrane domains consisting of a Lubrol-insoluble/Triton X-100-insoluble region and a Lubrol-insoluble/Triton X-100-soluble region. The latter region contains most of the ABC transporters as well as lipids known to be necessary for their efflux activity. Compared with drug-sensitive cells, the detergent-insoluble glycosphingolipid-enriched membrane domains (DIGs) in drug-resistant cells differ specifically in sphingolipid content and not in protein, phospholipid, or cholesterol content. In drug-resistant cells, sphingolipids with specific fatty acids (especially C24:1) are enriched in these membrane domains. Together, these data show that multidrug resistance-associated changes in both sphingolipids and ABC transporters occur in DIGs, but in different regions of these domains.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Sply regulation of sphingolipid signaling molecules is essential for Drosophila development.

Sphingosine-1-phosphate is a sphingolipid metabolite that regulates cell proliferation, migration and apoptosis through specific signaling pathways. Sphingosine-1-phosphate lyase catalyzes the conversion of sphingosine-1-phosphate to ethanolamine phosphate and a fatty aldehyde. We report the cloning of the Drosophila sphingosine-1-phosphate lyase gene (Sply) and demonstrate its importance for adult muscle development and integrity, reproduction and larval viability. Sply expression is temporally regulated, with onset of expression during mid-embryogenesis. Sply null mutants accumulate both phosphorylated and unphosphorylated sphingoid bases and exhibit semi-lethality, increased apoptosis in developing embryos, diminished egg-laying, and gross pattern abnormalities in dorsal longitudinal flight muscles. These defects are corrected by restoring Sply expression or by introduction of a suppressor mutation that diminishes sphingolipid synthesis and accumulation of sphingolipid intermediates. This is the first demonstration of novel and complex developmental pathologies directly linked to a disruption of sphingolipid catabolism in metazoans.

Aldehyde-Lyases↗
PubMed2025

Genome-wide identification of modulators of Chlamydia trachomatis parasitophorous vacuole stability highlights an important role for sphingolipid supply.

A mechanistic understanding of how intracellular pathogens evade the intrinsic defenses of their host cells could open up intriguing therapeutic opportunities. Here, we applied a genome-wide genetic screening approach to investigate the nature of the defensive host cell death response suppressed by the membrane trafficking modulator CpoS, an effector protein secreted by the obligate intracellular bacterial pathogen Chlamydia trachomatis. Initially, this work revealed a CpoS-deficient mutant to exhibit a markedly increased dependence on host cellular synthesis of ceramides, the precursors of complex sphingolipids. Using novel microscopic reporters, we then established CpoS' role in defense evasion to occur by preserving the integrity of Chlamydia's parasitophorous vacuole (the inclusion) via ensuring an adequate sphingolipid supply. More specifically, we observed CpoS deficiency to destabilize inclusions, initially characterized by a release of individual bacteria into the host cell cytosol, then followed by inclusion rupture concomitant with host cell death. Exogenous addition of sphingosine stabilized CpoS-deficient inclusions, whereas disruption of host cellular ceramide synthesis destabilized wild-type inclusions. In combination, CpoS deficiency and impaired ceramide synthesis - presumably disrupting both Chlamydia's vesicular and non-vesicular sphingolipid supply routes - destabilized inclusions even earlier, resulting in infection clearance and host cell survival rather than host cell death. Overall, this study highlights how the vacuolar pathogen C. trachomatis maintains vacuole integrity by ensuring a steady sphingolipid supply, potentially offering inspiration and directions for future therapeutic strategies targeting parasitophorous vacuoles.

Chlamydia trachomatis↗
PubMed2005

Fungal sphingolipids as targets for the development of selective antifungal therapeutics.

Sphingolipids are essential membrane components, present in all eukaryotic cells, but structurally distinct in mammalian and fungal cells. Therefore, they represent an attractive new target for the development of novel antimycotics. This review will briefly highlight sphingolipid biosynthesis and functions in the yeast Saccharomyces cerevisiae. In addition, naturally occurring antifungal compounds that interact with fungal-specific sphingolipids, resulting in fungal growth arrest, will be discussed regarding their mode of action, and therapeutic value. These compounds include plant and insect defensins, syringomycin E and antifungal antibodies to sphingolipids.

Antifungal Agents↗
PubMed2003

[Sphingolipid and apoptosis].

Over the last decade, considerable progress has been made in the study of sphingolipids with the development of biological techniques. Sphingolipids play important roles in diverse physiological process, including cytoskeleton migration, angiogenesis, embryonic development and signal transduction. Except for this, the lastest evidence has suggested that sphingolipids and their metabolite (ceramide, sphingosine, sphingosine 1-phosphate) can induce apoptosis in a wide variety of tumor cell lines such as LoVo HT29, Bel7402, A549, CNE2 cells. This paper is attempted to review the recent advances of investigation into the relationship between sphingolipids and apoptosis.

Animals↗