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PubMed1988

The properties of brain galactocerebroside monolayers.

Using a Langmuir film balance we have compared the properties of films of the brain galactocerebrosides at 37 degrees C. There are two types of cerebroside in brain, those with an alpha-hydroxy substituent on the acyl chain (HFA) and those without (NFA). At equivalent pressures the areas of both cerebroside films are significantly less than the areas of films of the brain glycerolipids, the choline and ethanolamine phosphatides. The isotherm of NFA galactocerebrosides has two discontinuities, one at low and one at high film pressure, while the isotherm of HFA galactocerebrosides is a smooth curve at all film pressures. Below the high-pressure transition the area of the NFA film is significantly larger than the area of the HFA film. When compressed beyond the high-pressure transition there is a marked hysteresis between compression and expansion isotherms of the NFA galactocerebrosides. The pressures of both films continue to rise steeply when they are compressed into areas which are too small for them to exist as simple monolayers. We conclude that under compression cerebroside films form bilayer structures; that bilayer formation starts at low pressure and occurs progressively as the HFA cerebroside monolayer is compressed, but occurs more abruptly in the NFA cerebroside monolayer at the high-pressure-transition region of the isotherm. A study of pure cerebrosides with a single defined acyl chain shows that there is a correlation between the relative volumes of the hydrophobic and hydrophilic parts of the molecule and the ease of bilayer formation. The larger the relative volume of the hydrophilic group the more readily the cerebroside forms a bilayer film. Other brain lipids added to cerebroside monolayers have sharply differing effects on their areas. The areas of films containing cholesterol are less than the areas calculated by adding the areas of the pure components multiplied by their mole fractions. On the other hand, the area of phosphatidylcholine-containing films is much larger than calculated.

Animals↗
PubMed2003

Digestion of maize sphingolipids in rats and uptake of sphingadienine by Caco-2 cells.

We investigated the digestion of cerebrosides of plant origin prepared from maize, focusing especially on the digestive fates of trans-4, cis-8- and trans-4, trans-8-sphingadienine, which are common in higher plants. In the small intestinal mucosa and cecal contents of rats, the cerebrosidase activity at pH 5.2 toward the glucosyl linkage in maize cerebrosides (glucosylceramides) was similar to that in cerebrosides of mammalian origin. Similarly, the ceramidase activity toward the amide linkage in ceramides prepared from maize cerebrosides at pH 7.0 was the same as that toward ceramides of mammalian origin. In addition, maize cerebrosides were hydrolyzed to ceramide and free sphingoid bases in the digestive tract of rats after oral administration. To further evaluate the uptake by enterocytes of 4,8-sphingadienine, we used differentiated Caco-2 cells, derived from human colonic carcinoma, as a model of intestinal epithelial cells. The accumulation of sphingoid bases in Caco-2 cells incubated with each isomer of sphingadienine was lower than that after incubation with sphingosine (P < 0.05). Verapamil, a P-glycoprotein inhibitor, increased the accumulation of each sphingadienine but not of sphingosine, suggesting that the efflux of sphingadienine of plant origin, but not sphingosine of mammalian origin, was affected by P-glycoprotein. The digestibility of maize cerebrosides appears similar to that of cerebrosides of mammalian origin, but the metabolic fate of sphingoid bases of plant origin within enterocytes differs from that of sphingosine. Isomers of 4,8-sphingadienine degraded from dietary plant cerebrosides appear to be poorly absorbed from the digestive tract.

Animals↗
PubMed1982

The use of galactosylceramides with uniform fatty acids as substrates in the diagnosis and carrier detection of Krabbe disease.

Cerebroside-beta-galactosidase (galactosylceramidase EC 3.2.1.4.6) activity was studied using galactosylceramides of uniform fatty acid composition. The highest activity and the best discrimination between patients with Krabbe disease and controls were found with N-nervonoylgalactosylsphingosine (C 24: 1-cerebroside). As a general rule cerebrosides with a monoenoic fatty acid gave higher activity and better discrimination than the corresponding cerebroside with a saturated fatty acid, the differences being largest for the cerebrosides with the longest fatty acids. In two methods the C 24: 1 cerebroside was used as substrate in the assay of the cerebroside-beta-galactosidase activity in leukocytes from 12 Krabbe patients, 14 parents and 22 controls. In a third method lactosylceramide prepared from mammalian brain gangliosides was used as substrate. With all three methods the residual activity in the leukocytes of the Krabbe patients did not exceed 5%, there was no tendency for overlap between the activities of the patients and those of the obligate carriers, and the values of half the carriers fell within the range for the controls.

Adult↗
PubMed1985

Phase behavior of galactocerebrosides from bovine brain.

Bovine brain cerebrosides (BOV-CER) were separated by high-performance liquid chromatography into cerebroside fractions with a single acyl chain type or with a relatively homogeneous acyl chain distribution. The thermal behavior of these isolated cerebroside fractions was studied by differential scanning calorimetry. Nonhydroxy (n-acyl) fatty acid cerebrosides (NFA-CER) possessing a saturated acyl chain (C16:0, C18:0, C24:0) exhibit their major order-disorder transition temperature TM at 83 degrees C, independent of chain length. NFA-CER possessing primarily unsaturated acyl chains (C24:1) exhibits TM at 70 degrees C. 2-Hydroxy fatty acid cerebrosides (HFA-CER), which possess a saturated hydroxyacyl chain (C18:0h, C24:0h), exhibit TM at 70-72 degrees C. Thus, naturally occurring cerebrosides exhibit high TM's that do not depend significantly on acyl chain length and that depend only to a small degree on unsaturation and the presence of a 2-hydroxy branch in the amide-linked chain. Isolated NFA-CER's each exhibit metastable polymorphism of the type previously described for unfractionated NFA-CER [Curatolo, W. (1982) Biochemistry 21, 1761]. Polymorphism in HFA-CER is complex, with a different type of thermal behavior observed for each isolated acyl chain fraction studied. On prolonged storage at low temperature, unfractionated HFA-CER and unfractionated BOV-CER reach a highly ordered gel state similar to that which is readily reached by NFA-CER's. These results indicate that all cerebrosides exhibit metastable polymorphism. However, the kinetic barriers to reaching the stable gel state are greater for HFA-CER and BOV-CER than for NFA-CER.

Animals↗
PubMed2001

Parameters related to lipid metabolism as markers of myelination in mouse brain.

Myelination, during both normal development and with respect to disorders of myelination, is commonly studied by morphological and/or biochemical techniques that assay as their end-points the extent of myelination. The rate of myelination is potentially a more useful parameter, but it is difficult and time-consuming to establish, requiring a complete developmental study with labor-intensive methodology. We report herein development of methodology to assay the absolute rate of myelination at any desired time during development. This involves intraperitoneal injection of (3)H(2)O to label body water pools, followed by determination of label in the myelin-specific lipid, cerebroside. The absolute amount of cerebroside synthesized can then be calculated from the specific radioactivity of body water and knowledge of the number of hydrogens from water incorporated into cerebroside. During development, the rate of cerebroside synthesis correlated well with the rate of accumulation of the myelin-specific components, myelin basic protein and cerebroside. For purposes of control, we also tested other putative, albeit less quantitative, indices of the rate of myelination. Levels of mRNA for ceramide galactosyltransferase (rate-limiting enzyme in cerebroside synthesis) and for myelin basic protein did not closely correlate with myelination at all times. Cholesterol synthesis closely matched the rate of cholesterol accumulation but did not track well with myelination. Synthesis of fatty acids did not correlate well with accumulation of either fatty acids (phospholipids) or myelin markers. We conclude that measurement of cerebroside synthesis rates provides a good measure of the rate of myelination. This approach may be useful as an additional parameter for examining the effects of environmental or genetic alterations on the rate of myelination.

Aging↗
PubMed1984

Effects of monensin and colchicine on myelin galactolipids.

Monensin and colchicine have been used in a variety of systems to disrupt functioning of the Golgi apparatus and transport of Golgi-derived vesicles to the plasma membrane. In this study the effects of monensin and colchicine on the synthesis of cerebroside and sulfatide and their appearance in myelin were examined to determine whether these myelin components are processed through the Golgi apparatus. Brain slices from rats 17 days old were incubated with [3H]galactose and [35S]-sulfate to label cerebroside and sulfatide. Myelin was isolated on sucrose density gradients. Fractions highly enriched in cerebroside and sulfatide were prepared from homogenates and myelin fractions by lipid extraction, alkaline methanolysis, and in some cases TLC. Monensin at 0.1 microM had no significant effect on synthesis of these galactolipids as measured by incorporation of [3H]-galactose into cerebroside or [35S]sulfate into sulfatide in homogenates. However, appearance of [35S]sulfatide in the myelin fraction was reduced to 49% of control, while appearance of [3H]cerebroside was not significantly reduced. Colchicine from 1 mM to 0.1 microM had effects similar to monensin, that is, appearance of [35S]sulfatide in myelin was depressed, but again [3H]cerebroside was not affected. Incorporation of [35S]sulfate into sulfatide in homogenate was 93% of control, while appearance of [35S]sulfatide in the myelin fraction was depressed to 58% of control. The inhibition of appearance of sulfatide in myelin by colchicine and monensin is consistent with the view that sulfation of cerebroside occurs in the Golgi and that sulfatide is transported via Golgi-derived vesicles to the forming myelin membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Normal metabolism but different physical properties of myelin from mice deficient in proteolipid protein.

Proteolipid protein (PLP) is the primary protein component of CNS myelin, yet myelin from the PLP(null) mouse has only minor ultrastructural abnormalities. Might compensation for a potentially unstable structure involve increased myelin synthesis and turnover? This was not the case; neither accumulation nor in vivo synthesis rates for the myelin-specific lipid cerebroside was altered in PLP(null) mice relative to wild-type (wt) animals. However, the yield of myelin from PLP(null) mice, assayed as levels of cerebroside, was only about 55% of wt control levels. Loss of myelin occurred during initial centrifugation of brain homogenate at 20,000g for 20 min, which is sufficient to sediment almost all myelin from wt mice. Cerebroside-containing fragments from PLP(null) mice remaining in the supernatant could be sedimented by more stringent centrifugation, 100,000g for 60 min. Both the rapidly and the more slowly sedimenting cerebroside-containing membranes banded at the 0.85/0.32 M sucrose interface of a density gradient, as did myelin from wt mice. These results suggest at least some myelin from PLP(null) mice differs from wt myelin with respect to physical stability (fragmented into smaller particles during dispersion) and/or density. Alternatively, slowly sedimenting cerebroside-containing particles could be myelin precursor membranes that, lacking PLP, were retarded in their processing toward mature myelin and thus differ from mature myelin in physical properties. If this is so, recently synthesized cerebroside should be preferentially found in these "slower-sedimenting" myelin precursor fragments. Metabolic tracer experiments showed this was not the case. We conclude that PLP(null) myelin is physically less stable and/or less dense than wt myelin.

Age Factors↗
PubMed1995

Monohexosylceramides of larval and adult forms of the tapeworm, Spirometra erinacei.

The occurrence of glycosphingolipids with unique carbohydrate structures in different species of cestode, Platyhelminth, which had been shown previously, prompted us to study the molecular species of the monohexosylceramides (cerebrosides) in the pseudophyllidean cestode, Spirometra erinacei. The purpose of the study was to obtain a basis for future investigations of the physiological role of glycolipids in parasitism. Cerebrosides were isolated from S. erinacei at two growth stages, i.e., from the larval form (plerocercoid) and from the adult tapeworms (intestinal form). The cerebrosides were separated into four subfractions by silica gel column chromatography, and their constituents were analyzed by gas-liquid chromatography, gas chromatography/mass spectrometry, and high-performance liquid chromatography/mass spectrometry. The hexoses of the cerebrosides consisted primarily of galactose in both growth stages, while only a small amount of glucose was detected. The ceramides were composed of sphinganine (d18:0) and phytosphingosine (t18:0) as sphingoid bases, and of nonhydroxy fatty acids ranging from C16 to C30 and hydroxy stearic acid (18h:0). The cerebrosides of adult tapeworms contained more 18h:0 than those of plerocercoids. The combination of hexoses and ceramides in the cerebroside molecules was slightly different in the two growth stages: the glucocerebrosides of plerocercoids contained only d18:0-nonhydroxy fatty acids in their ceramide moieties, whereas those of adult tapeworms contained varying ceramide moieties. Our data indicate that the molecular species of glycolipids present were essentially homeostatic throughout growth in spite of the entirely different environmental conditions, although there were slight differences in the hexose distribution in the two growth stages.

Animals↗
PubMed2005

Structure, cellular distribution, antigenicity, and biological functions of Fonsecaea pedrosoi ceramide monohexosides.

Monohexosylceramides (CMHs, or cerebrosides) have been reported as membrane and cell wall constituents of both pathogenic and nonpathogenic fungi, presenting remarkable differences in their ceramide moiety compared to mammalian CMHs. Current evidence suggests that CMHs are involved in fungal differentiation and growth and contribute to host immune response. Here we describe a structural diversity between cerebrosides obtained from different forms of the human pathogen Fonsecaea pedrosoi. The major CMH species produced by conidial forms displayed the same structure previously demonstrated by our group for mycelia, an N-2'-hydroxyhexadecanoyl-1-beta-d-glucopyranosyl-9-methyl-4,8-sphingadienine. However, the major cerebroside species purified from sclerotic cells carries an additional hydroxyl group, bound to its long-chain base. The structural difference between cerebrosides from mycelial and sclerotic cells was apparently not relevant for their antigenicity, since they were both recognized at similar levels by sera from individuals with chromoblastomycosis and a monoclonal antibody to a conserved cerebroside structure. Preincubation of fungal cells with anti-CMH monoclonal antibodies had no effect on the interaction of F. pedrosoi sclerotic cells with murine macrophages. In contrast to what has been described for other fungal species, sclerotic bodies are resistant to the antifungal action of anti-CMH antibodies. Immunofluorescence analysis showed that recognition of sclerotic cells by these antibodies only occurs at cell wall regions in which melanization is not evident. Accordingly, melanin removal with alkali results in an increased reaction of fungal cells with anti-CMH antibodies. Our results indicate that cerebroside expression in F. pedrosoi cells is associated with dimorphism and melanin assembly on the fungal cell wall.

Animals↗
PubMed2005

The molecular relationship between deficient UDP-galactose uridyl transferase (GALT) and ceramide galactosyltransferase (CGT) enzyme function: a possible cause for poor long-term prognosis in classic galactosemia.

Classic galactosemia is an autosomal recessive disorder that is caused by activity deficiency of the UDP-galactose uridyl transferase (GALT). The clinical spectrum of classic galactosemia differs according to the type and number of mutations in the GALT gene. Short-term clinical symptoms such as jaundice, hepatomegaly, splenomegaly and E. coli sepsis are typically associated with classic galactosemia. These symptoms are often severe but quickly ameliorate with dietary restriction of galactose. However, long-term symptoms such as mental retardation and primary ovarian failure do not resolve irrespective of dietary intervention or the period of initial dietary intervention. There seem to be an association between deficient galactosylation of cerebrosides and classic galactosemia. Galactocerebrosides and glucocerebrosides are the primary products of the enzyme UDP-galactose:cerebroside galactosyl transferase (CGT). There has been an observation of deficient galactosylation coupled with over glucosylation in the brain tissue specimens sampled from deceased classic galactosemia patients. The plausible mechanism with which the association between GALT and CGT had not been explained before. Yet, UDP-galactose serves as the product of GALT as well as a substrate for CGT. In classic galactosemia, there is a consistent deficiency in cerebroside galactosylation. We postulate that the molecular link between defective GALT enzyme, which result in classic galactosemia; and the cerebroside galactosyl transferase, which is responsible for galactosylation of cerebrosides is dependent on the cellular concentrations of UDP-galactose. We further hypothesize that a threshold concentration of UDP-galactose exist below which the integrity of cerebroside galactosylation suffers.

Galactosemias↗