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Review
. 2019;95(3):136-149.
doi: 10.2183/pjab.95.011.

Elucidation of the enigma of glycosphingolipids in the regulation of inflammation and degeneration - Great progress over the last 70 years

Koichi Furukawa  1   2 , Yuhsuke Ohmi  1 , Yuji Kondo  2 , Robiul H Bhuiyan  1 , Orie Tajima  1 , Pu Zhang  1   2 , Yuki Ohkawa  1 , Keiko Furukawa  1
Affiliations
Review

Elucidation of the enigma of glycosphingolipids in the regulation of inflammation and degeneration - Great progress over the last 70 years

Koichi Furukawa et al. Proc Jpn Acad Ser B Phys Biol Sci. 2019.

Abstract

Since globotetraosylceramide was defined as a major glycosphingolipid in human erythrocytes, various glycolipids have been found in normal cells and diseased organs. However, the implications of their polymorphic structures in the function of individual cells and tissues have not been clarified. Genetic manipulation of glycosphingolipids in cultured cells and experimental animals has enabled us to substantially elucidate their roles. In fact, great progress has been achieved in the last 70 years in revealing that glycolipids are essential in the maintenance of integrity of nervous tissues and other organs. Furthermore, the correct composition of glycosphingolipids has been shown to be critical for the protection against inflammation and degeneration. Here, we summarized historic information and current knowledge about glycosphingolipids, with a focus on their involvement in inflammation and degeneration. This topic is significant for understanding the biological responses to various stresses, because glycosphingolipids play roles in the interaction with various intrinsic and extrinsic factors. These findings are also important for the application of therapeutic interventions of various diseases.

Keywords: carbohydrate; degeneration; glycosphingolipids; glycosyltransferase; inflammation; knockout.

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Figures

Figure 1.
Figure 1.
Synthetic pathway of glycosphingolipids. The majority of glycosphingolipids are synthesized from Glc-Cer through lactosyl ceramide (LacCer) along several pathways.1,2) Glycolipid structures deleted in individual KO lines are indicated by squares.–7,17,54,57)
Figure 2.
Figure 2.
Globo-series glycosphingolipids. Globo-series glycosphingolipids are generated via Gb3 with the A4galt enzyme.14) Extended forms of globo-series glycolipids are expressed in restricted cells and organs such as erythrocytes (human),,–18) kidney,19) endothelial cells,6,19) B lymphocytes (some differentiation stages),–28,34) early developmental stages of embryonal cells,28,30,31) and some malignant tumor cells.23,24) Cytosolically located GlcCer is converted to lactosyl ceramide (LacCer) by B4galt5/B4galt6 in the Golgi,13) and then Gb3 is synthesized in the Golgi by A4galt. It is transferred and expressed in the outer leaflet of membranes.
Figure 3.
Figure 3.
Globo-series glycolipids interact with exogenous and endogenous factors on the cell surface. Gb3 specifically binds the B subunit of verotoxins, playing a role as a receptor for exogenous bacterial toxins,19,38,41) whereas Gb4 binds TLR4/MD2 as an endogenous ligand. Gb4 with saturated FAs binds the gap region in MD2 molecules, competing with LPS in the binding of its receptor.6)
Figure 4.
Figure 4.
Function of globo-series glycosphingolipids elucidated in Gb3 synthase (A4galt)-KO mice. A, Gb3 synthase KO mice were resistant to verotoxins. These KO mice were resistant to VT-2 at more than a 100 times higher dose than is lethal for WT mice.19) B, Gb3 synthase KO mice were more sensitive to LPS (Shwartzman, R), as shown by the percentage survival after the injection of LPS. Particularly when LPS was injected at 25 mg/kg mouse, a significantly lower survival rate was observed in Gb3 synthase KO mice than in WT mice.6)
Figure 5.
Figure 5.
DKO mice exhibited refractory skin lesions on the face and tips of the fingers. A, TLC pattern of gangliosides from the brains of WT and DKO mice. Degeneration of sciatic nerve in DKO (lower) compared with WT (upper) mice. Skin lesions on the face and the tips of the fingers in DKO mice.61) Arrows indicate injured and bleeding fingers. B, Progressive inflammatory reactions with aging as detected using the mRNA expression levels of inflammatory cytokines (IL-1β) and complement. RNA was extracted from the cerebella of DKO mice (GM2/GD2 synthase and GD3 synthase) as shown by - ◆ -, and by - ● - for WT.62,67,68) C, A scheme to summarize the effects of ganglioside deficiency on inflammation and neurodegeneration, and rescue of these pathological processes by the loss of complements (TKO).
Figure 6.
Figure 6.
Glycosphingolipids play roles in the maintenance of the integrity of nervous tissues. A, Lipid/rafts (GEM/rafts) consist of sphingomyelin, glycosphingolipids, and GPI-anchored proteins.65,66) Various growth factor receptors and adhesion receptors are frequently localized in lipid/rafts depending on the cellular situation. B, Shifts in raft-resident molecules to non-raft fractions due to ganglioside deficiency. Neurodegeneration is induced by disordered GEM/rafts in ganglioside-deficient mice.,–69)
Figure 7.
Figure 7.
Hereditary spastic paraplegia (HSP) and abnormal phenotypes in B4galnt1-deficient mice. Patients with HSP with a mutated B4GANT1 gene exhibited relatively mild neurological disorders.–74) These clinical features were similar to the phenotypes of B4galnt1 KO mice.57,58) Including male infertility, B4galnt1 KO mice might be good models for HSP.75)
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