Glycosphingolipid Storage in Fabry Mice Extends Beyond Globotriaosylceramide and is Affected by ABCB1 Depletion

Kamani, Mustafa; Provençal, Philippe; Boutin, Michel; Pacienza, Natalia; Fan, Xueli; Novak, Anton; Huang, Tonny C; Binnington, Beth; Au, Bryan; Auray‐Blais, Christiane; Lingwood, Clifford A.; Medin, Jeffrey A.

doi:10.4155/fsoa-2016-0027

Cited by 6 publications

(4 citation statements)

References 78 publications

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“…Furthermore, there were some differences between Fabry disease and age-related CSVD: in Fabry disease, it was dominated by glycosphingolipid changes, while in age-related CSVD ceramide changes were more prominent. Our study showed there were not statistically significant differences of ceramides in Fabry disease compared with control, consistent with previous reports [39,40]. It is currently believed that the vascular involvement of Fabry disease is related to the deposition of glycosphingolipids in endothelial cells and smooth muscle cells, probably due to induction of oxidative stress [41,42].…”

Section: Fabry Diseasesupporting

confidence: 91%

“…It has been shown different trihexosylceramides are deposited in different organs, leading to different pathophysiological changes. Levels of dihexosylceramides varied in our study, consistent with previous reports [39]. More research are still needed in the future to help us understand properties of different glycosphingolipids and their mechanism of regulation.…”

Section: Fabry Diseasesupporting

confidence: 91%

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Plasma lipidomic analysis of sphingolipids in patients with large artery atherosclerosis cerebrovascular disease and cerebral small vessel disease

You

Peng

et al. 2020

Bioscience Reports

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Background Sphingolipids mainly consist of ceramides(Cer), sphingomyelins(SM) and glycosphingolipids. Sphingolipids are related with coronary heart disease and metabolic disease, but there’re few studies about cerebrovascular disease. The purpose was to detect sphingolipids in plasma of patients with large artery atherosclerosis (LAA) cerebrovascular disease and cerebral small vessel disease (CSVD) to explore the similarities and differences of pathogenesis of the two subtypes. Methods 20 patients with LAA cerebrovascular disease, 20 patients with age-related CSVD, 10 patients with Fabry disease and 14 controls were enrolled from October 2017 to January 2019. Ultra-high performance liquid chromatography-quadruple-time-of-flight mass spectrometry/mass spectrometry was used to determine sphingolipids. Univariate combined with multivariate analysis were used for comparison. Receiver operating characteristic curves were used to determine sensitivities and specificities. Results 276 sphingolipids were detected, including 39 Cer, 3 ceramide phosphates, 72 glycosphingolipids, and 162 SM. ①Cer(d36:3), Cer(d34:2), Cer(d38:6), Cer(d36:4) and Cer(d16:0/18:1) were increased in LAA; SM(d34:1), Cer(d34:2), Cer(d36:4), Cer(d16:0/18:1), Cer(d38:6), Cer(d36:3), Cer(d32:0) were increased in age-related CSVD.②Cer(d36:4), SM(d34:1) were increased in age-related CSVD compared with LAA. ③Total trihexosyl ceramides were increased in Fabry group compared with control(p<0.05); SM(d34:1) was increased in Fabry group. Conclusions Ceramides are increased in both LAA and age-related CSVD, which may be related to similar risk factors and pathophysiological process of arteriosclerosis; SM is increased in both age-related CSVD and Fabry disease, suggesting that increased SM may be associated with CSVD. Glycosphingolipids, trihexosylceramides in particular, are increased in Fabry disease.

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Section: Fabry Diseasesupporting

confidence: 91%

Section: Fabry Diseasesupporting

confidence: 91%

Plasma lipidomic analysis of sphingolipids in patients with large artery atherosclerosis cerebrovascular disease and cerebral small vessel disease

You

Peng

et al. 2020

Bioscience Reports

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“…Mouse mdr1a/b knockdown results in decreased GSL levels in skin fibroblasts, but brain GSLs are unaltered ( 100 ), further indicating a cell-type-dependent role of ABCB1 in GSL synthesis. In cross-breeding of Fabry and ABCB1 knockout mice, we found that only the heart and spleen showed reduced GlcCer, whereas LacCer was generally elevated in these tissues and Gb 3 was not affected ( 101 ). It has been argued that lack of a clear phenotype for MDR knockout mice is not consistent with a physiological function ( 102 ); however, we show in this study that there is a marked overlap and redundancy for ABC proteins in GSL biosynthesis, possibly as GlcCer flippases.…”

Section: Discussionmentioning

confidence: 99%

ATP-binding cassette transporters mediate differential biosynthesis of glycosphingolipid species

Budani

Auray‐Blais

Lingwood

2021

Journal of Lipid Research

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Another difficulty in the pathogenesis studies of Fabry disease is the lack of appropriate experimental models, in which the effect of storage compounds on the disease phenotype can be investigated. Kamani et al robustly characterized GSLs in Fabry mice vs. WT mice, and demonstrated differential accumulation of Gb 3 species in Fabry mouse tissues, and a unique fold-change of Gb 3 in each tissue in Fabry mice relative to WT (18). However, because all the Gb 3 isoforms are increased in Fabry mice compared to WT controls, it remains unclear which Gb 3 species are responsible for the disease.…”

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confidence: 99%

Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model

Jabbarzadeh-Tabrizi

Boutin

Day

et al. 2020

Journal of Lipid Research

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Fabry disease is caused by deficient activity of α-galactosidase A—an enzyme that hydrolyses the terminal α-galactosyl moieties from glycolipids and glycoproteins—and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3) and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney and dorsal root ganglion (DRG) were similar in two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared to Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in non-peptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of non-peptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types.

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Glycosphingolipid Storage in Fabry Mice Extends Beyond Globotriaosylceramide and is Affected by ABCB1 Depletion

Cited by 6 publications

References 78 publications

Plasma lipidomic analysis of sphingolipids in patients with large artery atherosclerosis cerebrovascular disease and cerebral small vessel disease

Plasma lipidomic analysis of sphingolipids in patients with large artery atherosclerosis cerebrovascular disease and cerebral small vessel disease

ATP-binding cassette transporters mediate differential biosynthesis of glycosphingolipid species

Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model

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