Glucosylceramide in the nervous system - A mini-review

Radin, Norman S.

doi:10.1007/bf00971327

Cited by 14 publications

(14 citation statements)

References 37 publications

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“…2) (D’Angelo et al, 2007; Ichikawa et al, 1996; Jeckel et al, 1992). Unlike GalCer, GlcCer is a precursor for more than 3,000 GSLs, the majority of all GSLs that can be produced by mammalian cells, and GCS is the first rate-limiting enzyme in the synthesis of these GSLs (Merrill, 2011; Radin, 1994). Ceramide substrate is transported by vesicles from the ER or by CERT (see section II.…”

Section: Ceramide Glycosylation and Glycosphingolipid-enriched MImentioning

confidence: 99%

Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance

Liu

Hill

2013

Advances in Cancer Research

140

118

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Glucosylceramide synthase (GCS), converting ceramide to glucosylceramide, catalyzes the first reaction of ceramide glycosylation in sphingolipid metabolism. This glycosylation by GCS is a critical step regulating the modulation of cellular activities by controlling ceramide and glycosphingolipids (GSLs). An increase of ceramide in response to stresses, such as chemotherapy, drives cells to proliferation arrest and apoptosis or autophagy; however, ceramide glycosylation promptly eliminates ceramide and consequently, these induced processes, thus protecting cancer cells. Furthermore, persistently enhanced ceramide glycosylation can increase GSLs, participating in selecting cancer cells to drug resistance. GCS is overexpressed in diverse drug-resistant cancer cells and in tumors of breast, colon, and leukemia that display poor response to chemotherapy. As ceramide glycosylation by GCS is a rate-limiting step in GSL synthesis, inhibition of GCS sensitizes cancer cells to anticancer drugs and eradicates cancer stem cells. Mechanistic studies indicate that uncoupling ceramide glycosylation can modulate gene expression, decreasing MDR1 through the cSrc/β-catenin pathway and restoring p53 expression via RNA splicing. These studies not only expand our knowledge in understanding how ceramide glycosylation affects cancer cells, but also provide novel therapeutic approaches for targeting refractory tumors.

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Section: Ceramide Glycosylation and Glycosphingolipid-enriched MImentioning

confidence: 99%

Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance

Liu

Hill

2013

Advances in Cancer Research

140

118

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“…How ever, a gradual decline in enzyme activity with develop ment and maturation agrees with the previous study [33], Although HFA GicCer has not previously been identi fied as a significant brain MGC component, it is note worthy that the GlcT:HFA-ceramide is more active than GlcT: NFA-ceramide during development. GalTLNFAceramide has previously been reported to require lecithin [34] and to have a low activity in brain [35]. We assumed that a single transferase mediated the synthesis of both NFA and HFA cerebrosides and employed iden tical assay conditions.…”

Section: Discussionmentioning

confidence: 99%

Neutral Monoglycosylceramides in Rat Brain: Occurrence, Molecular Expression and Developmental Variation

Dasgupta¹,

Everhart²,

Bhat³

et al. 1997

Dev Neurosci

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Developmental expression of neutral monoglycosylceramides (MGCs) has been examined in rat brain from embryonic day 15 (E15) to postnatal day 30 (P30) and adulthood. To this point, glucosylceramide (GlcCer) is the only MGC that has been characterized in embryonic brain. Galactosylceramide (GalCer) appears at PI, increases with age until P25 and remains constant thereafter. The developmental occurrence of GlcCer and GalCer agrees well with their respective glucosyl- and galactosyltransferase activities. Cerebroside fatty-acid and base compositions, examined by gas chromatography, also change during development. Several alkali-labile fast-migrating cerebrosides (FMCs) with a higher thin-layer chromatography RF than GalCer/GlcCer are expressed early at P10, increase in concentration with age (P25–P30) and are unchanged until maturity. They are derivatives of GalCer. By employing a newly developed neutral methylation procedure, we have confirmed the structure of one of the FMCs as 6-acylGalCer. A reduction in brain FMC concentrations along with GalCer in murine genetic dysmyelinating disorders (jimpy and quaking) further supports the conclusion that they are myelin constituents.

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“…Oligodendrocytes have an active α-hydroxylation machinery [42]. Interestingly, the α-hydroxylation of fatty acids seems to be closely linked to the synthesis of HFA-ceramide and HFA-GalCer, as free hydroxy fatty acids and HFA-ceramide have not been detected in brain [42,43] or kidney [11] ; the latter apparently also displays α-hydroxylation as its GalCer contains mainly HFA [11,12]. Although the kidney-derived MDCK cells contain only low levels of HFA-GalCer [10], their CGalT displays the same preference for HFA-ceramide as the myelin enzyme (Table 2) and is localized in the ER [35], suggesting that epithelial cells and myelin express the same CGalT.…”

Section: Cgalt Substrate-specificity and Products In Vivomentioning

confidence: 99%

Synthesis of non-hydroxy-galactosylceramides and galactosyldiglycerides by hydroxy-ceramide galactosyltransferase

Bijl¹,

Strous²,

Lopes‐Cardozo³

et al. 1996

Biochemical Journal

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Galactosylceramide (GalCer) is the major glycolipid in brain. In order to characterize the activity of brain UDPgalactose: ceramide galactosyltransferase (CGalT), it has been stably expressed in CGalT-negative Chinese hamster ovary (CHO) cells. After fractionation of transfected cells, CHO-CGT, on sucrose gradients, the activity resides at the density of endoplasmic reticulum and not of Golgi. A lipid chromatogram from CHO-CGT cells revealed two new iodine-staining spots identified as GalCer, since they comigrate with GalCer standards, can be metabolically labelled with [3H]galactose, are recognized by anti-GalCer antibodies, and are resistant to alkaline hydrolysis. A third [3H]galactose lipid was identified as galactosyldiglyceride. In the homogenate CGalT displays a 25-fold preference for hydroxy fatty acid-containing ceramides. Remarkably, endogenous GalCer of transfected cells contains exclusively non-hydroxy fatty acids: fast atom bombardment and collision-induced dissociation mass spectrometric analysis revealed mainly C16:0 in the lower GalCer band on TLC and mainly C22:0 and C24:0 in the upper band. Our results suggest that CGalT galactosylates both hydroxy- and non-hydroxy fatty acid-containing ceramides and diglycerides, depending on their local availability. Thus, CGalT alone may be responsible for the synthesis of hydroxy- and non-hydroxy-GalCer, and galactosyldiglyceride in myelin.

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Glucosylceramide in the nervous system - A mini-review

Abstract: A reviewer of this manuscript has recommended that I warn the reader that the hypotheses offered here do not have enough experimental support to make them widely accepted.

Cited by 14 publications

References 37 publications

Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance

Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance

Neutral Monoglycosylceramides in Rat Brain: Occurrence, Molecular Expression and Developmental Variation

Synthesis of non-hydroxy-galactosylceramides and galactosyldiglycerides by hydroxy-ceramide galactosyltransferase

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