Lactosylceramides
Sphingomyelin Phosphodiesterase
Niemann-Pick Diseases
Niemann-Pick Disease, Type C
Niemann-Pick Disease, Type A
Niemann-Pick Disease, Type B
Sphingomyelins
Expression of c-series gangliosides in rat hepatocytes and liver tissues. (1/160)
C-series gangliosides in rat hepatocytes and liver tissues were analyzed by thin-layer chromatographic (TLC) immunostaining with the specific monoclonal antibody A2B5. Primary cultures of hepatocytes isolated from adult rats were immunostained positively by A2B5. TLC immunostaining with A2B5 of gangliosides from the cells suggested that rat hepatocytes express c-series gangliosides including GT3, GT1c, GQ1c, and GP1c. Expression of c-series gangliosides in cultured hepatocytes was modulated by growth conditions of cells. The amount of GT3 was increased significantly by epidermal growth factor, while the contents of polysialo species such as GT1c, GQ1c, and GP1c were enhanced by higher cell density in culture. Examination of c-series gangliosides in rat liver tissues showed a unique developmental profile with a shift from GT3-dominant to polysialo species-dominant composition in late embryonic stages. These results suggest that the expression of c-series gangliosides in rat hepatocytes is regulated in a growth- and development-dependent manner. (+info)Bilayer properties of totally synthetic C16:0-lactosyl-ceramide. (2/160)
Differential scanning calorimetry (DSC) and x-ray diffraction have been used to study the structural and thermal properties of totally synthetic D-erythro-N-palmitoyl-lactosyl-C(18)-sphingosine (C16:0-LacCer). Over the temperature range 0-90 degrees C, fully hydrated C16:0-LacCer shows complex thermal transitions characteristic of polymorphic behavior of exclusively bilayer phases. On heating at 5 degrees C/min, hydrated C16:0-LacCer undergoes a complex two-peak endothermic transition with maxima at 69 degrees C and 74 degrees C and a total enthalpy of 14.6 kcal/mol C16:0-LacCer. At a slower heating rate (1.5 degrees C/min), two endothermic transitions are observed at 66 degrees C and 78 degrees C. After cooling to 0 degrees C, the subsequent heating run shows three overlapping endothermic transitions at 66 degrees C, 69 degrees C, and 71.5 degrees C, followed by a chain-melting endothermic transition at 78 degrees C. Two thermal protocols were used to completely convert C16:0-LacCer to its stable, high melting temperature (78 degrees C) form. As revealed by x-ray diffraction, over the temperature range 20-78 degrees C this stable phase exhibits a bilayer structure, periodicity d approximately 65 A with an ordered chain packing mode. At the phase transition (78 degrees C) chain melting occurs, and C16:0-LacCer converts to a liquid crystalline bilayer (L(alpha)) phase of reduced periodicity d approximately 59 A. On cooling from the L(alpha) phase, C16:0-LacCer converts to metastable bilayer phases undergoing transitions at 66-72 degrees C. These studies allow comparisons to be made with the behavior of the corresponding C16:0-Cer (. J. Lipid Res. 36:1936-1944) and C16:0-GluCer and C16:0-GalCer (. J. Lipid Res. 40:839-849). Our systematic studies are aimed at understanding the role of oligosaccharide complexity in regulating glycosphingolipid structure and properties. (+info)Common architecture of the primary galactose binding sites of Erythrina corallodendron lectin and heat-labile enterotoxin from Escherichia coli in relation to the binding of branched neolactohexaosylceramide. (3/160)
The heat-labile enterotoxin from Escherichia coli (LT) is responsible for so-called traveller's diarrhea and is closely related to the cholera toxin (CT). Toxin binding to GM1 at the epithelial cell surface of the small intestine initiates the subsequent diarrheal disease. However, LT has a broader receptor specificity than CT in that it also binds to N-acetyllactosamine-terminated structures. The unrelated lectin from Erythrina corallodendron (ECorL) shares this latter binding property. The findings that both ECorL and porcine LT (pLT) bind to lactose as well as to neolactotetraosylceramide suggests a common structural theme in their respective primary binding sites. Superimposing the terminal galactose of the lactoses in the respective crystal structures of pLT and ECorL reveals striking structural similarities around the galactose despite the lack of sequence and folding homology, whereas the interactions of the penultimate GlcNAcb3 in the neolactotetraosylceramide differ. The binding of branched neolactohexaosylceramide to either protein reveals an enhanced affinity relative to neolactotetraosylceramide. The b3-linked branch is found to bind to the primary Gal binding pocket of both proteins, whereas the b6-linked branch outside this site provides additional interactions in accordance with the higher binding affinities found for this compound. While the remarkable architectural similarities of the primary galactose binding sites of pLT and ECorL point to a convergent evolution of these subsites, the distinguishing structural features determining the overall carbohydrate specificities are located in extended binding site regions. In pLT, Arg13 is thus found to play a crucial role in enhancing the affinity not only for N-acetyllactosamine-terminated structures but also for GM1 as compared to human LT (hLT) and CT. The physiological relevance of the binding of N-acetyllactosamine-containing glycoconjugates to LT and ECorL is briefly discussed. (+info)Evidence supporting a late Golgi location for lactosylceramide to ganglioside GM3 conversion. (4/160)
Ganglioside GM2 synthase and other enzymes required for complex ganglioside synthesis were localized recently to the trans Golgi network (TGN). However, there are conflicting reports as to the location of GM3 synthase; originally this enzyme was detected in the early Golgi of rat liver but a recent report localized it to the late Golgi. We have used chimeric forms of ganglioside GM2 synthase to determine if the location of lactosylceramide (LacCer) to GM3 conversion in Chinese hamster ovary (CHO) cells was the early or late Golgi. Our approach tested whether GM3 could be utilized as a substrate by GM2 synthase chimeras which were targeted to compartments earlier than the trans Golgi, i.e., GM3 produced in the cis Golgi should be utilized by GM2 synthase located anywhere in the Golgi whereas GM3 produced in the trans Golgi should only be used by GM2 synthase located in the trans Golgi or TGN. Comparison of cell lines stably expressing these chimeras revealed that the in vivo functional activity of GM2 synthase decreased progressively as the enzyme was targeted to earlier compartments; specifically, the percentage of GM3 converted to GM2 was 83-86% for wild type enzyme, 70% for the medial Golgi targeted enzyme, 13% for the ER and cis Golgi targeted enzyme, and only 1.7% for the ER targeted enzyme. Thus, these data are consistent with a late Golgi location for LacCer to GM3 conversion in these cells. (+info)Isolectins from Solanum tuberosum with different detailed carbohydrate binding specificities: unexpected recognition of lactosylceramide by N-acetyllactosamine-binding lectins. (5/160)
Glycosphingolipid recognition by two isolectins from Solanum tuberosum was compared by the chromatogram binding assay. One lectin (PL-I) was isolated from potato tubers by affinity chromatography, and identified by MALDI-TOF mass spectrometry as a homodimer with a subunit molecular mass of 63,000. The other (PL-II) was a commercial lectin, characterized as two homodimeric isolectins with subunit molecular masses of 52,000 and 55,000, respectively. Both lectins recognized N-acetyllactosamine-containing glycosphingolipids, but the fine details of their carbohydrate binding specificities differed. PL-II preferentially bound to glycosphingolipids with N-acetyllactosamine branches, as Galbeta4GlcNAcbeta6(Galbeta4GlcNAcbeta3)Galbeta4Glcbeta1C er. PL-I also recognized this glycosphingolipid, but bound equally well to the linear glycosphingolipid Galbeta4GlcNAcbeta3Galbeta4GlcNAcbeta3Galbeta4Glcbeta1Cer. Neolactotetraosylceramide and the B5 pentaglycosylceramide were also bound by PL-I, while other glycosphingolipids with only one N-acetyllactosamine unit were non-binding. Surprisingly, both lectins also bound to lactosylceramide, with an absolute requirement for sphingosine and non-hydroxy fatty acids. The inhibition of binding to both lactosylceramide and N-acetyllactosamine-containing glycosphingolipids by N-acetylchitotetraose suggests that lactosylceramide is also accomodated within the N-acetylchitotetraose/N-acetyllactosamine-binding sites of the lectins. Through docking of glycosphingolipids onto a three-dimensional model of the PL-I hevein binding domain, a Galbeta4GlcNAcbeta3Galbeta4 binding epitope was defined. Furthermore, direct involvement of the ceramide in the binding of lactosylceramide was suggested. (+info)Structural determination of glycosphingolipids as lithiated adducts by electrospray ionization mass spectrometry using low-energy collisional-activated dissociation on a triple stage quadrupole instrument. (6/160)
Structural characterization of glycosphingolipids as their lithiated adducts using low-energy collisional-activated dissociation (CAD) tandem mass spectrometry with electrospray ionization (ESI) is described. The tandem mass spectra contain abundant fragment ions reflecting the long chain base (LCB), fatty acid, and the sugar constituent of the molecule and permit unequivocal identification of cerebrosides, di-, trihexosyl ceramides and globosides. The major fragmentation pathways arise from loss of the sugar moiety to yield a lithiated ceramide ion, which undergoes further fragmentation to form multiple fragment ions that confirm the structures of the fatty acid and LCB. The mechanisms for the ion formation and the possible configuration of the fragment ions, resulting from CAD of the lithiated molecular ions ([M + Li]+) of monoglycosylceramides are proposed. The mechanisms were supported by CAD and source CAD tandem mass spectra of various cerebrosides and of their analogous molecules prepared by H-D exchange. Constant neutral loss and precursor ion scannings to identify galactosylceramides with sphingosine or sphinganine LCB subclasses, and with specific N-2-hydroxyl fatty acid subclass in mixtures are also demonstrated. (+info)Occurrence of ceramides and neutral glycolipids with unusual long-chain base composition in purified rat liver mitochondria. (7/160)
The free ceramide content of rat liver mitochondria was found to be 1.7 nmol/mg protein and outer membranes contained a three-fold higher concentration than inner membranes. The mitochondrial content in neutral glycolipids was 0.6 nmol/mg protein. The long-chain bases found in free ceramides were d18:1 sphingosine, d18:0 3-ketosphinganine and t21:1 phytosphingosine in increasing order. In contrast, 3-ketosphinganine was the only base of glucosylceramide and lactosylceramide of inner membranes, whereas d18:1 sphingosine was the major long-chain base of glucosylceramide of outer membranes. (+info)A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. (8/160)
A fatal infantile storage disorder with hepatosplenomegaly and severe neurological disease is described. Sphingolipids, including monohexosylceramides (mainly glucosylceramide), dihexosylceramides (mainly lactosylceramide), globotriaosyl ceramide, sulphatides, ceramides and globotetraosyl ceramide, were stored in the tissues. In general, cholesterol and sphingomyelin levels were unaltered. The storage process was generalized and affected a number of cell types, with histiocytes, which infiltrated a number of visceral organs and the brain, especially involved. The ultrastructure of the storage lysosomes was membranous with oligolamellar, mainly vesicular, profiles. Infrequently, there were Gaucher-like lysosomes in histiocytes. The neuropathology was severe and featured neuronal storage and loss with a massive depopulation of cortical neurons and pronounced fibrillary astrocytosis. There was a paucity of myelin and stainable axons in the white matter with signs of active demyelination. Immunohistochemical investigations indicated that saposins A, B, C and D were all deficient. The patient was homozygous for a 1 bp deletion (c.803delG) within the SAP-B domain of the prosaposin gene which leads to a frameshift and premature stop codon. In the heterozygous parents, mutant cDNA was detected by amplification refractory mutation analysis in the nuclear, but not the cytoplasmic, fraction of fibroblast RNA, indicating that the mutant mRNA was rapidly degraded. The storage process in the proband resembled that of a published case from an unrelated family. Saposins were also deficient in this case, leading to its reclassification as prosaposin deficiency, and her mother was found to be a carrier for the same c.803delG mutation. Both of the investigated families came from the same district of eastern Slovakia. (+info)Lactosylceramides are a type of glycosphingolipid, which are complex lipids found in the outer layer of cell membranes. They consist of a ceramide molecule (a fatty acid and sphingosine) with a lactose sugar (glucose and galactose) attached. Lactosylceramides play important roles in various cellular processes, including cell recognition, signal transduction, and adhesion. They are also involved in the development and progression of certain diseases, such as cancer and neurological disorders.
Sphingomyelin phosphodiesterase is an enzyme that catalyzes the hydrolysis of sphingomyelin, a sphingolipid found in animal tissues, into ceramide and phosphorylcholine. This enzyme plays a crucial role in the metabolism of sphingomyelin and the regulation of cellular processes such as apoptosis, differentiation, and inflammation.
There are several isoforms of this enzyme, including acid sphingomyelinase (ASM) and neutral sphingomyelinase (NSM), which differ in their subcellular localization, regulation, and physiological functions. Deficiencies or dysfunctions in sphingomyelin phosphodiesterase activity have been implicated in various diseases, such as Niemann-Pick disease, atherosclerosis, and cancer.
Niemann-Pick diseases are a group of inherited metabolic disorders characterized by the accumulation of lipids, particularly sphingomyelin and cholesterol, within cells due to deficiencies in certain enzymes. These diseases are caused by mutations in the SMPD1, NPC1, or NPC2 genes, among others. There are four main types of Niemann-Pick disease (Types A, B, C, and D), each with varying severity and symptoms.
Type A and Type B diseases, also known as Acid Sphingomyelinase Deficiency or ASMD, result from mutations in the SMPD1 gene leading to a deficiency of acid sphingomyelinase enzyme. This causes excessive accumulation of sphingomyelin in various tissues, particularly in the liver, spleen, lungs, and brain.
Type A is the most severe form, typically presenting in infancy with symptoms such as developmental delay, feeding difficulties, enlarged liver and spleen, lung infection, and progressive neurological degeneration, which often leads to early death, usually before age 3.
Type B has a broader range of severity and onset, from infancy to adulthood. Symptoms may include enlarged liver and spleen, lung disease, poor growth, and varying degrees of neurological impairment. Type B patients can survive into adolescence or adulthood, depending on the severity of their symptoms.
Type C and Type D diseases, also known as Niemann-Pick Type C Disease (NPC), are caused by mutations in either the NPC1 or NPC2 genes, leading to defective intracellular lipid transport. This results in excessive accumulation of cholesterol and other lipids within cells, particularly in the brain, liver, spleen, and lungs.
Type C typically presents in childhood but can also manifest in adolescence or adulthood. Symptoms include progressive neurological degeneration, ataxia, seizures, dementia, problems with speech and swallowing, and yellowish skin (jaundice) at birth or during infancy due to liver involvement. Type C patients usually have a shorter life expectancy, often surviving into their teens, twenties, or thirties.
Type D is a subtype of NPC that affects people of Nova Scotian descent and has similar symptoms to Type C but with an earlier onset and faster progression.
Niemann-Pick Disease, Type C (NPC) is a rare, progressive, and fatal neurovisceral lipid storage disorder caused by mutations in the NPC1 or NPC2 genes. These genetic defects result in impaired intracellular transport of cholesterol and other lipids, leading to excessive accumulation within lysosomes of various tissues, particularly in the brain, liver, spleen, and lungs.
The disease primarily affects children, although late-onset forms have been reported in adults. The symptoms and severity can vary widely among patients but often include neurological manifestations such as ataxia, dysarthria, dysphagia, cognitive decline, seizures, and vertical supranuclear gaze palsy (VSGP). Other features may involve visceral involvement like hepatosplenomegaly, jaundice, or pulmonary complications.
There is currently no cure for NPC, but treatments aim to manage symptoms, slow disease progression, and improve quality of life. Miglustat and cyclodextrin (HPβCD) are two FDA-approved therapeutic options that have shown some promise in stabilizing or delaying neurological decline in NPC patients. Early diagnosis and intervention are crucial for optimizing outcomes and providing appropriate supportive care.
Niemann-Pick Disease, Type A (NPD A) is a rare inherited metabolic disorder caused by a deficiency of the enzyme acid sphingomyelinase (ASM). This enzyme defect results in the accumulation of lipids, particularly sphingomyelin and cholesterol, within various cells of the body, including brain cells, liver cells, and white blood cells.
The accumulation of these lipids leads to progressive damage to these organs, causing a range of symptoms such as an enlarged liver (hepatomegaly), anemia, jaundice, and neurological problems like developmental delay, seizures, loss of muscle tone, and difficulty with swallowing. NPD A is typically diagnosed in infancy or early childhood and is often fatal by around two to three years of age due to severe neurological complications. It is an autosomal recessive disorder, meaning that an individual must inherit two copies of the defective gene (one from each parent) to develop the condition.
Niemann-Pick Disease, Type B (ASMD B) is a rare inherited metabolic disorder caused by a deficiency of the enzyme acid sphingomyelinase (ASM). This enzyme defect results in the accumulation of lipids, particularly sphingomyelin and cholesterol, within various cells of the body, including cells of the liver, spleen, lungs, and brain.
The symptoms and severity of Niemann-Pick Disease, Type B can vary widely among individuals. Common features include enlarged liver (hepatomegaly) and spleen (splenomegaly), lung disease, poor growth, and decreased muscle tone (hypotonia). Some people with this condition may also develop neurological symptoms such as ataxia, tremors, or speech and learning difficulties.
Niemann-Pick Disease, Type B is typically diagnosed through a combination of clinical evaluation, imaging studies, and enzyme assays. Molecular genetic testing can confirm the diagnosis by identifying mutations in the SMPD1 gene that cause the disease. Treatment for Niemann-Pick Disease, Type B is supportive and may include medications to manage liver and lung symptoms, physical therapy, and special education services. In some cases, bone marrow transplantation or enzyme replacement therapy may be considered as treatment options.
Sphingomyelins are a type of sphingolipids, which are a class of lipids that contain sphingosine as a backbone. Sphingomyelins are composed of phosphocholine or phosphoethanolamine bound to the ceramide portion of the molecule through a phosphodiester linkage. They are important components of cell membranes, particularly in the myelin sheath that surrounds nerve fibers. Sphingomyelins can be hydrolyzed by the enzyme sphingomyelinase to form ceramide and phosphorylcholine or phosphorylethanolamine. Abnormalities in sphingomyelin metabolism have been implicated in several diseases, including Niemann-Pick disease, a group of inherited lipid storage disorders.
Hepatomegaly is a medical term that refers to an enlargement of the liver beyond its normal size. The liver is usually located in the upper right quadrant of the abdomen and can be felt during a physical examination. A healthcare provider may detect hepatomegaly by palpating (examining through touch) the abdomen, noticing that the edge of the liver extends past the lower ribcage.
There are several possible causes for hepatomegaly, including:
- Fatty liver disease (both alcoholic and nonalcoholic)
- Hepatitis (viral or autoimmune)
- Liver cirrhosis
- Cancer (such as primary liver cancer, metastatic cancer, or lymphoma)
- Infections (e.g., bacterial, fungal, or parasitic)
- Heart failure and other cardiovascular conditions
- Genetic disorders (e.g., Gaucher's disease, Niemann-Pick disease, or Hunter syndrome)
- Metabolic disorders (e.g., glycogen storage diseases, hemochromatosis, or Wilson's disease)
Diagnosing the underlying cause of hepatomegaly typically involves a combination of medical history, physical examination, laboratory tests, and imaging studies like ultrasound, CT scan, or MRI. Treatment depends on the specific cause identified and may include medications, lifestyle changes, or, in some cases, surgical intervention.