Glucosylceramide and galactosylceramide, small glycosphingolipids with significant impact on health and disease

Abstract

Numerous clinical observations and exploitation of cellular and animal models indicate that glucosylceramide (GlcCer) and galactosylceramide (GalCer) are involved in many physiological and pathological phenomena. In many cases, the biological importance of these monohexosylcermides has been shown indirectly as the result of studies on enzymes involved in their synthesis and degradation. Under physiological conditions, GalCer plays a key role in the maintenance of proper structure and stability of myelin and differentiation of oligodendrocytes. On the other hand, GlcCer is necessary for the proper functions of epidermis. Such an important lysosomal storage disease as Gaucher disease (GD) and a neurodegenerative disorder as Parkinson's disease are characterized by mutations in the GBA1 gene, decreased activity of lysosomal GBA1 glucosylceramidase and accumulation of GlcCer. In contrast, another lysosomal disease, Krabbe disease, is associated with mutations in the GALC gene, resulting in deficiency or decreased activity of lysosomal galactosylceramidase and accumulation of GalCer and galactosylsphingosine. Little is known about the role of both monohexosylceramides in tumor progression; however, numerous studies indicate that GlcCer and GalCer play important roles in the development of multidrug-resistance by cancer cells. It was shown that GlcCer is able to provoke immune reaction and acts as a self-antigen in GD. On the other hand, GalCer was recognized as an important cellular receptor for HIV-1. Altogether, these two molecules are excellent examples of how slight differences in chemical composition and molecular conformation contribute to profound differences in their physicochemical properties and biological functions.

Keywords: biological functions; galactosylceramide; glucosylceramide; glycosphingolipids; neurological diseases.

Fig. 1

The synthesis and degradation of GlcCer and GalCer and their metabolites referred to in the review.

Fig. 2

Intracellular localization and transport of GlcCer and GalCer. In the “classical” model (shown in blue), GlcCer, synthesized on the cytosolic side of the cis-Golgi, is transported to the trans-Golgi and translocated to the luminal side, where synthesis of complex GSLs takes place. In the alternative model (shown in violet), ceramide is transported from the ER to the cytosol with the help of CERT (1), then GlcCer is synthesized on the cytosolic side of the trans-Golgi (2), from there most GlcCer is transported back to the cytoplasmic leaflet of ER with the help of the FAPP2 (3). There, GlcCer is translocated to the luminal side and transported again to the trans-Golgi apparatus, where complex GSLs are synthesized (4). Remaining GlcCer is transported by FAPP2 from the cytosolic surface of the trans-Golgi to the cytosolic surface of the plasma membrane (5). GalCer is synthesized on the luminal side of the ER (shown in red). From there, it is transported to the trans-Golgi compartment, where complex galactosphingolipids and sulfatides are synthesized. FAPP2—4-phosphate adaptor protein-2, CERT—ceramide transport protein.

Fig. 3

Lysosomal degradation of GlcCer and GalCer. GlcCer and GalCer degradation is initiated by the invagination of the plasma membrane. During endocytosis, GSLs are assimilated as vesicles into early and late endosome. These vesicles reach the lysosome compartment after the fusion of late endosome with primary lysosome. GlcCer and GalCer are then degraded to ceramide by lysosomal enzymes, which are further hydrolyzed by ceramidase to spingoid base and fatty acid.

Fig. 4

GlcCer and epidermal functions. Lamellar bodies after fusion with the apical plasma membrane of the uppermost granular cells release GlcCer into the intercellular spaces by exocytosis. There, GlcCer is hydrolyzed and the released ceramide becomes a part of stratum corneum consisting of dead keratinocytes embedded with extracellular lipids such as cholesterol, ceramides and fatty acids.