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At least 19 recordsLinked to original sources
PubMed1999

Preparation of fluorescence-labeled GM1 and sphingomyelin by the reverse hydrolysis reaction of sphingolipid ceramide N-deacylase as substrates for assay of sphingolipid-degrading enzymes and for detection of sphingolipid-binding proteins.

Sphingolipid ceramide N-deacylase is an enzyme capable of hydrolyzing the N-acyl linkages of ceramides of various sphingolipids. Recently, it was found that the enzyme catalyzes the reverse hydrolysis reaction in which free fatty acids are condensed to lyso-sphingolipids to produce sphingolipids. This paper describes a simple method for the synthesis of fluorescence-labeled sphingolipids utilizing the condensation reaction of the enzyme. N-TFAc-aminododecanoic acids were efficiently condensed by the enzyme to the lyso-forms of GM1 and sphingomyelin in glycine buffer (pH 10). The reaction products, N-TFAc-amino-GM1 and sphingomyelin, were obtained with overall yields of 60%. The purified products were identified to be omega-amino-GM1 and omega-amino-sphingomyelin, respectively, by TLC and FAB-MS or ESI-LC/MS analysis after removal of the N-TFAc by mild alkaline treatment. NBD-labeled GM1 and sphingomyelin were prepared from omega-amino-GM1 and omega-amino-sphingomyelin by coupling with 4-fluoro-NBD. These fluorescence-labeled substrates, C12-NBD-GM1 and C12-NBD-sphingomyelin, were hydrolyzed by endoglycoceramidase and sphingomyelinase, respectively, to produce NBD-dodecanoylsphingosines, but were resistant to hydrolysis by sphingolipid ceramide N-deacylase. C12-NBD-sphingomyelin was found to be a better substrate than the commercially available C6-NBD-sphingomyelin for the assay of sphingomyelinase from various sources. We also describe a new method to detect GM1-binding proteins using fluorescence-labeled GM1.

Amidohydrolases↗
PubMed2004

Sphingolipid uptake by cultured cells: complex aggregates of cell sphingolipids with serum proteins and lipoproteins are rapidly catabolized.

Human fibroblasts, rat neurons, and murine neuroblastoma cells, cultured in the presence of fetal calf serum, were fed with [1-(3)H]sphingosine to radiolabel sphingolipids. The fate of cell sphingolipids, the release of sphingolipids in the culture medium, the interaction of sphingolipids with the proteins and lipoproteins of fetal calf serum, and the fate of sphingolipids taken up by the cells were investigated. For this latter purpose, the culture medium containing radioactive sphingolipids was delivered to nonlabeled cells. The presence of tritium at position 1 of sphingosine allowed us to follow the extent of sphingolipid catabolism by measuring the production of radioactive phosphatidylethanolamine and proteins by recycling the radioactive ethanolamine formed during sphingosine catabolism and the production of tritiated water. We confirmed that in cells the recycling of sphingosine occurred to a high extent and that only a minor portion of cell sphingolipids was catabolized to the small fragments of ethanolamine and water. Cell sphingolipids were released in the culture medium, where they formed large lipoproteic aggregates at a rate of about 12% per day. Released sphingolipids were taken up by the cells and catabolized to the sphingosine and then to ethanolamine, and recycling of sphingosine was not observed. This suggests that in the presence of fetal calf serum in the culture medium, exogenous sphingolipids directly reach the lysosomes, were they are entirely catabolized. Thus, the trafficking of sphingolipids from cells to the extracellular environment and from this to other cells does not allow the modification of the plasma membrane composition.

Animals↗
PubMed1991

Sphingolipids are required for mammalian epidermal barrier function. Inhibition of sphingolipid synthesis delays barrier recovery after acute perturbation.

Stratum corneum lipids comprise an approximately equimolar mixture of sphingolipids, cholesterol, and free fatty acids, arranged as intercellular membrane bilayers that are presumed to mediate the epidermal permeability barrier. Prior studies have shown that alterations in epidermal barrier function lead to a rapid increase in cholesterol and fatty acid synthesis which parallels the early stages of the repair process. Despite an abundance of indirect evidence for their role in the barrier, the importance of sphingolipids has yet to be demonstrated directly. Whereas sphingolipid synthesis also increases during barrier repair, this response is delayed in comparison to cholesterol and fatty acid synthesis (Holleran, W.M., et al. 1991. J. Lipid Res. 32:1151-1158). To further delineate the role of sphingolipids in barrier homeostasis, we assessed the impact of inhibition of sphingolipid synthesis on epidermal barrier recovery. A single topical application of beta-chloro-L-alanine (beta-CA), an irreversible inhibitor of serine-palmitoyl transferase (SPT), applied to acetone-treated skin of hairless mice resulted in: (a) greater than 75% inhibition of SPT activity at 30 min (P less than 0.001); (b) a global decrease in sphingolipid synthesis between 1 and 3 h (P less than 0.02); (c) reduction of epidermal sphingolipid content at 18 h (P less than 0.01); (d) delayed reaccumulation of histochemical staining for sphingolipids in the stratum corneum; and (e) reduced numbers and contents of lamellar bodies in the stratum granulosum. Finally, despite its immediate, marked diminution of sphingolipid synthesis, beta-CA slowed barrier recovery only at late time points (greater than 6 h) after acetone treatment. This inhibition was overridden by coapplications of ceramides (the distal SPT product), indicating that the delay in repair was not due to non-specific toxicity. These studies demonstrate a distinctive role for epidermal sphingolipids in permeability barrier homeostasis.

Acyltransferases↗
PubMed1999

Sphingolipids in food and the emerging importance of sphingolipids to nutrition.

Eukaryotic organisms as well as some prokaryotes and viruses contain sphingolipids, which are defined by a common structural feature, i.e. , a "sphingoid base" backbone such as D-erythro-1,3-dihydroxy, 2-aminooctadec-4-ene (sphingosine). The sphingolipids of mammalian tissues, lipoproteins, and milk include ceramides, sphingomyelins, cerebrosides, gangliosides and sulfatides; plants, fungi and yeast have mainly cerebrosides and phosphoinositides. The total amounts of sphingolipids in food vary considerably, from a few micromoles per kilogram (fruits) to several millimoles per kilogram in rich sources such as dairy products, eggs and soybeans. With the use of the limited data available, per capita sphingolipid consumption in the United States can be estimated to be on the order of 150-180 mmol (approximately 115-140 g) per year, or 0.3-0.4 g/d. There is no known nutritional requirement for sphingolipids; nonetheless, they are hydrolyzed throughout the gastrointestinal tract to the same categories of metabolites (ceramides and sphingoid bases) that are used by cells to regulate growth, differentiation, apoptosis and other cellular functions. Studies with experimental animals have shown that feeding sphingolipids inhibits colon carcinogenesis, reduces serum LDL cholesterol and elevates HDL, suggesting that sphingolipids represent a "functional" constituent of food. Sphingolipid metabolism can also be modified by constituents of the diet, such as cholesterol, fatty acids and mycotoxins (fumonisins), with consequences for cell regulation and disease. Additional associations among diet, sphingolipids and health are certain to emerge as more is learned about these compounds.

Cell Division↗
PubMed1995

Role of dietary sphingolipids and inhibitors of sphingolipid metabolism in cancer and other diseases.

Sphingolipids are found in all eukaryotic and some prokaryotic organisms and participate in the regulation of cell growth, differentiation, and diverse cell functions including cell-cell communication, cell-substratum interactions and intracellular signal transduction. Nonetheless, the field of nutrition has given scant attention to these compounds so that little is known about the following fundamental questions: What is the fate of sphingolipids that are consumed in food? Does consumption of dietary sphingolipids affect the behavior of cells in the gastrointestinal tract or other organs? How do other factors in the diet affect sphingolipid metabolism? Several recent findings underscore the importance of these questions, for examples: 1) Sphingolipids are digested throughout the GI tract to ceramide and sphingosine, which are highly bioactive compounds that affect cellular regulatory pathways; 2) addition of sphingomyelin to a standard AIN diet (which is essentially devoid of sphingolipids) reduces the appearance of aberrant colonic crypts, and perhaps the number of tumors, in mice treated with a colon carcinogen; and 3) an enzyme of sphingolipid metabolism has been discovered to be the target of a class of toxic and carcinogenic mycotoxins called fumonisins. Given these recent findings, it is possible that some of the confusion that has arisen regarding the relationships between dietary fat and disease might be due to the lack of consideration of the sphingolipids that are also present.

Animals↗
PubMed1993

Mutant strains of Saccharomyces cerevisiae lacking sphingolipids synthesize novel inositol glycerophospholipids that mimic sphingolipid structures.

Mutant strains of Saccharomyces cerevisiae, termed SLC, make no detectable sphingolipids when cultured without a sphingolipid long chain base such as phytosphingosine (Dickson, R.C., Wells, G.B., Schmidt, A., and Lester, R.L. (1990) Mol. Cell. Biol. 10, 2176-2181). When grown with phytosphingosine they make sphingolipids in normal amounts. SLC strains carry a secondary suppressor mutation that bypasses the need to synthesize a long chain base. Hypothetically, the suppressor mutation could function by mutating a gene whose protein product required a sphingolipid for function, by increasing the level of one or more endogenous lipids, or by making new lipid(s). Here we demonstrate that SLC strains make novel inositol glycerophospholipids when cultured without a long chain base. The novel lipids are phosphatidylinositol (PI), mannosyl-PI, and inositol-P-(mannosyl-PI), containing 1 mol of C26 fatty acid, ordinarily found in yeast sphingolipids but not usually found in glycerophospholipids; the C26 fatty acid appears to be located at the SN-2 position of the glycerol. In addition, mono-fattyacyl versions of these three compounds were also identified. The polar head groups and hydrophobic portions of these novel lipids are strikingly similar to S. cerevisiae sphingolipids found in wild-type cells. We speculate that the novel lipids structurally mimic sphingolipids and thereby compensate for some sphingolipid function(s) necessary for growth.

Chromatography, High Pressure Liquid↗
PubMed2005

Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids.

Sphingolipids and glycosphingolipids are membrane components of eukaryotic cell surfaces. Their constitutive degradation takes place on the surface of intra-endosomal and intra-lysosomal membrane structures. During endocytosis, these intra-lysosomal membranes are formed and prepared for digestion by a lipid-sorting process during which their cholesterol content decreases and the concentration of the negatively charged bis(monoacylglycero)phosphate (BMP)--erroneously also called lysobisphosphatidic acid (LBPA)--increases. Glycosphingolipid degradation requires the presence of water-soluble acid exohydrolases, sphingolipid activator proteins, and anionic phospholipids like BMP. The lysosomal degradation of sphingolipids with short hydrophilic head groups requires the presence of sphingolipid activator proteins (SAPs). These are the saposins (Saps) and the GM2 activator protein. Sphingolipid activator proteins are membrane-perturbing and lipid-binding proteins with different specificities for the bound lipid and the activated enzyme-catalyzed reaction. Their inherited deficiency leads to sphingolipid- and membrane-storage diseases. Sphingolipid activator proteins not only facilitate glycolipid digestion but also act as glycolipid transfer proteins facilitating the association of lipid antigens with immunoreceptors of the CD1 family.

Animals↗
PubMed1998

Functional involvement of proteins, interacting with sphingolipids, in sphingolipid transport to the canalicular membrane in the human hepatocytic cell line, HepG2?

A photoreactive sphingolipid precursor was used to investigate the potential involvement of protein-lipid interactions that may convey specificity to sphingolipid transport in the human hepatoma cell line, HepG2. A 125I-labeled, photoreactive ceramide, 125I-N3-Cer, was incubated with the cells and became incorporated into two sphingolipid products. The major product was photoreactive sphingomyelin (125I-N3-SM) (25% of total radioactivity), while only minor amounts of photoreactive glucosylceramide (125I-N3-GlcCer) were formed (< 2%). After photoactivation, a restricted number of proteins was labeled. Given the absolute amounts of the newly synthesized, photoreactive lipids and their precursor present in the cells, labeling of the proteins can be assumed to be derived from interaction with either ceramide (Cer) or sphingomyelin (SM), or both. To discriminate between these possibilities, photoactivation and protein analysis was performed in cells treated with D-threo-1-phenyl-2-decanoyl amino-3-morpholino-1-propanol (PDMP), an inhibitor of sphingolipid biosynthesis. In treated cells, the radioactive SM pool was reduced by approximately 80%. Concomitantly, labeling of a 60-kd protein, seen in control cells, decreased. Furthermore, the 60-kd protein is membrane-associated and insoluble in detergent at low temperature. Moreover, when cells containing photoreactive sphingolipids after a preincubation with the photoreactive Cer were photoactivated and subsequently incubated with fluorescent sphingolipid analogs, transport of the latter to the bile canalicular membrane, as observed in control cells, was inhibited. Taken together, the data suggest that distinct proteins, among them a 60-kd protein, may play a specific and functional role in sphingolipid transport to the bile canalicular membrane.

Bile Canaliculi↗
PubMed1992

Sphingolipids are essential for the growth of Chinese hamster ovary cells. Restoration of the growth of a mutant defective in sphingoid base biosynthesis by exogenous sphingolipids.

We previously isolated a temperature-sensitive Chinese hamster ovary cell mutant (strain SPB-1) with thermolabile serine palmitoyltransferase, which is involved in the first step of sphingolipid synthesis (Hanada, K., Nishijima, M., and Akamatsu, Y. (1990) J. Biol. Chem. 265, 22137-22142). In this study, sphingolipid-deficient culture medium was used to examine the effect of exogenous sphingolipids on the cell growth of SPB-1. When cultivated in the sphingolipid-deficient medium, SPB-1 cells ceased growing at non-permissive temperatures. Under these conditions, de novo sphingolipid synthesis ceased in the SPB-1 cells, resulting in a decrease in levels of sphingomyelin and ganglioside sialyl lactosylceramide (GM3), whereas the parental CHO-K1 cells grew logarithmically with normal sphingolipid synthesis. Exogenous sphingosine restored the contents of both sphingomyelin and GM3 in the SPB-1 cells near to the parental levels through metabolic utilization and allowed the mutant cells to grow even at the non-permissive temperature. Similarly, exogenous sphingomyelin restored the sphingomyelin levels and only partly the GM3 levels and also suppressed the temperature-sensitivity of the SPB-1 cell growth. In contrast, exogenous glucosylceramide, which restored the GM3 levels but not the sphingomyelin levels, failed to suppress the temperature sensitivity of the SPB-1 cell growth. Combination of exogenous sphingomyelin with ceramide, glucosylceramide, GM3, or sphingoid bases did not show any synergistic or additive effect on the SPB-1 cell growth enhancement, compared with sphingomyelin alone. The results indicated that the temperature sensitivity of the SPB-1 cell growth was due to the lack of cellular sphingolipids, possibly that of sphingomyelin.

Acyltransferases↗
PubMed2004

Fluorescent analogues of plasma membrane sphingolipids are sorted to different intracellular compartments in astrocytes; Harmful effects of chronic ethanol exposure on sphingolipid trafficking and metabolism.

Sphingolipids are basic constituents of cellular membranes and are essential for numerous functions such as intracellular signalling. They are transported along the exocytic and endocytic pathways in eukaryotic cells. After endocytosis, fluorescent-labelled sphingolipids are sorted to distinct intracellular organelles prior to recycling (via early/recycling endosomes) or degradation (late endosomes/lysosomes). Here we examine, in primary cultures of rat astrocytes, the internalisation routes followed by C(6)-NBD-glucosylceramide (NBD-GlcCer) and C(6)-NBD-sphingomyelin (NBD-SM) and the effects of ethanol on their endocytic trafficking. Endocytosed plasma membrane NBD-GlcCer and NBD-SM are diverted to the Golgi apparatus and lysosomes, respectively. These different internalisation pathways are maintained regardless of the differentiation stage of astrocytes. Chronic ethanol exposure did not alter this endocytic sorting, but delayed the internalisation of both NBD-sphingolipids. Moreover, ethanol also stimulated the in situ metabolism of NBD-ceramide to NBD-GlcCer and NBD-SM. We conclude that in rat astrocytes internalised plasma membrane NBD-sphingolipids are sorted to different subcellular compartments. The exposure to chronic ethanol perturbed the lipid endocytic process and stimulated the de novo synthesis of NBD-sphingolipids, shifting the balance of sphingolipid metabolism in favour of the sphingomyelin pathway.

Animals↗
PubMedDate not supplied

New approaches to the study of sphingolipid enriched membrane domains: the use of electron microscopic autoradiography to reveal metabolically tritium labeled sphingolipids in cell cultures.

This paper is the first report on the use of the electron microscopy autoradiography technique to detect metabolically tritium labeled sphingolipids in intact cells in culture. To label cell sphingolipids, human fibroblasts in culture were fed by a 24 hours pulse, repeated 5 times, of 3 x 10(-7) M [1-(3)H]sphingosine. [1-(3)H]sphingosine was efficently taken up by the cells and very rapidly used for the biosynthesis of complex sphingolipids, including neutral glycolipids, gangliosides, ceramide and sphingomyelin. The treatment with [1-(3)H]sphingosine did not induce any morphological alteration of cell structures, and well preserved cells, plasma membranes, and intracellular organelles could be observed by microscopy. Ultrathin sections from metabolic radiolabeled cells were coated with autoradiographic emulsion. One to four weeks of exposition resulted in pictures where the location of radioactive sphingolipids was evidenced by the characteristic appearance of silver grains as irregular coiled ribbons of metallic silver. Radioactive sphingolipids were found at the level of the plasma membranes, on the endoplasmic reticulum and inside of cytoplasmic vesicles. Thus, electron microscopy autoradiography is a very useful technique to study sphingolipid-enriched membrane domain organization and biosynthesis.

Autoradiography↗
PubMed1997

Importance of sphingolipids and inhibitors of sphingolipid metabolism as components of animal diets.

Sphingolipids are highly bioactive compounds that participate in the regulation of cell growth, differentiation, diverse cell functions, and apoptosis. They are present in both plant and animal foods in appreciable amounts, but little is known about their nutritional significance. Recent studies have shown that feeding sphingomyelin to female CF1 mice treated with a colon carcinogen (1,2-dimethylhydrazine) reduced the number of aberrant colonic crypt foci; longer-term feeding also affected the appearance of colonic adenocarcinomas. Therefore, dietary sphingolipids should be considered in studies of the relationships between diet and cancer. Sphingolipids have also surfaced as important factors in understanding the mechanism of action of a recently discovered family of mycotoxins, termed fumonisins. Fumonisins are produced by fungi commonly found on maize and a few related foods, and their consumption can result in equine leukoencephalomalacia, porcine pulmonary edema and a number of other diseases of veterinary animals and, perhaps, humans. A cellular target of fumonisins is the enzyme ceramide synthase, and disruption of sphingolipid metabolism by fumonisins has been established by studies with both cells in culture and animals that have consumed these toxic mycotoxins. These findings underscore the ways in which sphingolipids and agents that affect sphingolipid utilization should be given consideration in selecting animal diets for nutritional and toxicological studies.

Animal Feed↗
PubMed1992

Use of N-([1-14C]hexanoyl)-D-erythro-sphingolipids to assay sphingolipid metabolism.

An advantage of using N-([1-14C]hexanoyl)sphingolipids to assay sphingolipid metabolism is their ability to rapidly and spontaneously transfer into biological membranes without destroying membrane integrity. This property allows analysis of the activity of enzymes of sphingolipid metabolism under conditions in which the rate of product formation is not limited by availability of substrate, as is often the case with naturally occurring lipids whose rates of spontaneous transfer are extremely slow. Thus, the use of N-([1-14C]hexanoyl)sphingolipids provides an alternative means for studying sphingolipid metabolism in vitro.

Animals↗
PubMed2002

The role of sphingolipids in neuronal development: lessons from models of sphingolipid storage diseases.

The study of sphingolipids has undergone a renaissance over the past decade due to the realization that these lipids are involved in a variety a biological processes, such as differentiation, apoptosis, cell growth, and cell migration. In the nervous system, sphingolipids, particularly gangliosides, have attracted particular attention as they occur at high levels and their levels change in a developmentally regulated program. Despite the fact that a large body of data has accumulated on the expression and metabolism of individual gangliosides within specific brain regions, the role of individual gangliosides in neuronal development is still poorly understood, and their specific functions are only now beginning to be elucidated. In the present article, we discuss various aspects of our current knowledge concerning the involvement of sphingolipids and gangliosides in neuronal development, and then discuss some recent findings that shed light on the role of sphingolipids and gangliosides obtained with animal models of sphingolipid and other lysosomal storage diseases.

Animals↗
PubMed1995

A regulatory role for sphingolipids in neuronal growth. Inhibition of sphingolipid synthesis and degradation have opposite effects on axonal branching.

Sphingolipids, particularly gangliosides, are enriched in neuronal membranes where they have been implicated as mediators of various regulatory events. We recently provided evidence that sphingolipid synthesis is necessary to maintain neuronal growth by demonstrating that in hippocampal neurons, inhibition of ceramide synthesis by Fumonisin B1 (FB1) disrupted axonal outgrowth (Harel, R. and Futerman, A. H. (1993) J. Biol. Chem. 268, 14476-14481). We now analyze further the relationship between neuronal growth and sphingolipid metabolism by examining the effect of an inhibitor of glucosylceramide synthesis, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1- propanol (PDMP) and by examining the effects of both FB1 and PDMP at various stages of neuronal development. No effects of FB1 or PDMP were observed during the first 2 days in culture, but by day 3 axonal morphology was significantly altered, irrespective of the time of addition of the inhibitors to the cultures. Cells incubated with FB1 or PDMP had a shorter axon plexus and less axonal branches. FB1 appeared to cause a retraction of axonal branches between days 2 and 3, although long term incubation had no apparent effect on neuronal morphology or on the segregation of axonal or dendritic proteins. In contrast, incubation of neurons with conduritol B-epoxide, an inhibitor of glucosylceramide degradation, caused an increase in the number of axonal branches and a corresponding increase in the length of the axon plexus. A direct correlation was observed between the number of axonal branch points per cell and the extent of inhibition of either sphingolipid synthesis or degradation. These results suggest that sphingolipids play an important role in the formation or stabilization of axonal branches.

Animals↗
PubMed1995

Sphingolipid-dependent fusion of Semliki Forest virus with cholesterol-containing liposomes requires both the 3-hydroxyl group and the double bond of the sphingolipid backbone.

Low-pH-induced membrane fusion of Semliki Forest virus (SFV) in a model system is mediated by sphingolipids in the target membrane; ceramide is the sphingolipid minimally required (J. L. Nieva, R. Bron, J. Corver, and J. Wilschut, EMBO J. 13:2797-2804, 1994). Here, using various ceramide analogs, we demonstrate that sphingolipid-dependent fusion of SFV with cholesterol-containing liposomes exhibits remarkable molecular specificity, the 3-hydroxyl group and the 4,5-trans carbon-carbon double bond of the sphingosine backbone being critical for the sphingolipid to mediate the process. This observation supports the notion that sphingolipids act as a cofactor in SFV fusion, interacting directly with the viral fusion protein to induce its ultimate fusion-active conformation.

Ceramides↗
PubMed1996

Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids.

The four established or putative sphingolipid activator proteins derive from a large precursor protein encoded by a single gene. In addition to generating the four sphingolipid activator proteins, the precursor protein is suspected of having functions of its own, as, for example, a lipid binding/transport protein or a neurotrophic factor. The gene also appears to encode the Sertoli cell major sulfated glycoprotein. Sequence similarities have been noted with many other proteins of diverse functions. One patient and a fetus in a single family with a complete defect of this gene due to a mutation in the initiation codon exhibited complex pathological and biochemical abnormalities. Mutant mice homozygous for an inactivated gene of the sphingolipid activator protein precursor exhibit two distinct clinical phenotypes-neonatally fatal and later-onset. The latter develop rapidly progressive neurological signs around 20 days and die by 35-38 days. At 30 days, severe hypomyelination and periodic acid-Schiff-positive materials throughout the nervous system and in abnormal cells in the liver and spleen are the main pathology. Most prominently lactosylceramide, and additionally ceramide, glucosylceramide, galactosylceramide, sulfatide, and globotriaosylceramide are abnormally increased in the brain, liver, kidney, and their catabolism abnormally slow in cultured fibroblasts. Brain gangliosides are generally increased, particularly the monosialogangliosides. The clinical, pathological and biochemical phenotype closely resembles that of the human disease. This model not only allows further clarification of the physiological functions of the four individual sphingolipid activator proteins but also should be useful to explore putative functions of the precursor protein.

Animals↗
PubMed1998

Sphingolipid metabolism. Sphingoid analogs, sphingolipid activator proteins, and the pathology of the cell.

Sphingolipid metabolism and function was investigated using sphingoid analogs, cells from human sphingolipidoses patients, and knockout animals. Treatment of primary cultured murine cerebellar cells with the structurally modified sphingosine base cis-4 methylsphingosine resulted in decreased sphingolipid biosynthesis accompanied by significant morphological changes. Plasma-membrane-derived glycosphingolipids (GSLs) destined for digestion are internalized through the endocytic pathway and delivered to lysosomes. There, GSLs are degraded by the action of exohydrolases, which are supported, in the case of GSLs with short oligosaccharide chains, by sphingolipid activator proteins (SAPs or saposins). The inherited deficiency of activators give rise to sphingolipid storage diseases. The analysis of cultured fibroblasts from corresponding patients suggests a new model for the topology of endocytosis and lysosomal digestion. Mice with disrupted genes for activator proteins and for GM2 degrading hexosaminidases turned out to be useful models for human diseases.

Animals↗