A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

Abstract

Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer's and Parkinson's disease, and lysosomal storage disorders.

Keywords: biosynthesis; ceramide; glycosphingolipids; glycosyl hydrolase; inflammation; lysosomal storage disorder; neurodegeneration; sphingolipid; sphingosine-1-phosphate.

Figure 1

a-series ganglioside family structure similarity. All share the similarity of possessing a single sialic acid residue (shown as Neu5Ac) attached to the β-D-galactose (Gal) at position II. Note that ceramide ((2S,3R,4E)-2-(Acetylamino)-4-octadecene-1,3-diol) is composed of the sphingoid base, sphingosine (highlighted in orange), along with the saturated 18-carbon fatty acyl, stearic acid (highlighted in blue). Each ganglioside structure is divided based on its carbohydrate head group: β-D-glucose is the first sugar group, linked to the ceramide tail during the production of complex GSLs, shown highlighted in pink. β-D-glucose conjugated with ceramide alone would produce glucosylceramide (GlcCer); however, this is not depicted above. The addition of Gal and sialylation of the 3-OH of position of Gal (as highlighted in green) yields GM3 ganglioside. Note that although the green rectangle intends to highlight the Gal residues of gangliosides, Neu5Ac is conjugated to the second Gal of GM3, GM2, GM1, and GD1a ganglioside, as well as the terminal Gal residue of GD1a. The structure of the most common sialic acid in mammalian cells, N-acetyl-α-D-neuraminic acid (Neu5Ac), is depicted in the top left corner. The addition of N-acetyl-β-D-galactosamine (GalNAc) to the second Gal through a β-1,4 linkage produces GM2. The subsequent conjugation of a terminal Gal through a β-1,3 linkage to the GalNac moiety yields GM1, which can then be sialylated to form GD1a.

Figure 2

Summary of Ceramide Synthesis Pathways. A summarized schematic of the biosynthesis pathways which may produce ceramide, including the de novo pathway (right) and the salvage pathway (bottom). All sphingoid bases are depicted in blue. The de novo pathway begins with synthesis of the sphingoid base sphinganine and ends with ceramide desaturation. Sphinganine is also capable of producing phytosphingosine or sphinganine-1-phosphate. The salvage pathway consists of two streams: SM hydrolysis and GSL recycling. SM is converted to ceramide through the hydrolysis of the phosphocholine unit. The components of complex GSLs can also be recycled to reform ceramide through stepwise hydrolysis of carbohydrate units, eventually leaving a simple GSL such as GlcCer, depicted above. GlcCer is then converted to ceramide by glucocerebrosidase. GSL: glycosphingolipid; SM: sphingomyelin; aSMAase: acid sphingomyelinase; GlcCer: glucosylceramide; GBA: glucocerebrosidase; CoA: acyl coenzyme-A; CoA SH: coenzyme A; SphK; sphingosine kinase; CerS: ceramide synthase.

Figure 3

Summary of Complex GSL Biosynthesis. Ceramide is a major branching point in the biosynthetic pathway for several structures, including SM, C1P, and the simple GSLs GlcCer and GalCer. Ceramide glucosyltransferase (UGCG) is responsible for the addition of a glucose molecule to ceramide, whereas ceramide galactosyltransferase (CGT) adds a galactosyl molecule to ceramide. GalCer can be sialylated by the sialyltransferase ST3Gal V to produce GM4. In addition, GalCer may be sulfated by cerebroside sulfotransferase to form sulfatide. GlcCer is converted to LacCer by the addition of Gal onto the Glc head group. LacCer is another major branching point for complex GSL biosynthesis; however, only two synthetic pathways are illustrated above, which are the a- and b-series gangliosides (left and right, respectively).