Ceramide and ceramide 1-phosphate in health and disease

Abstract

Sphingolipids are essential components of cell membranes, and many of them regulate vital cell functions. In particular, ceramide plays crucial roles in cell signaling processes. Two major actions of ceramides are the promotion of cell cycle arrest and the induction of apoptosis. Phosphorylation of ceramide produces ceramide 1-phosphate (C1P), which has opposite effects to ceramide. C1P is mitogenic and has prosurvival properties. In addition, C1P is an important mediator of inflammatory responses, an action that takes place through stimulation of cytosolic phospholipase A2, and the subsequent release of arachidonic acid and prostaglandin formation. All of the former actions are thought to be mediated by intracellularly generated C1P. However, the recent observation that C1P stimulates macrophage chemotaxis implicates specific plasma membrane receptors that are coupled to Gi proteins. Hence, it can be concluded that C1P has dual actions in cells, as it can act as an intracellular second messenger to promote cell survival, or as an extracellular receptor agonist to stimulate cell migration.

Figure 1

Formation of bioactive sphingolipids in mammalian cells. Ceramide can be produced by degradation of sphingomyelin (SM) by sphingomyelinases (SMase), or by de novo synthesis through the concerted action of serine palmitoyltransferase and dihydroceramide synthase. It can also be generated through metabolism of more complex sphingolipids. Ceramide can be metabolized to ceramide-1-phosphate by ceramide kinase, or to glucosylceramide by glucosylceramide synthase (GCS). The reverse reaction is catalyzed by ceramide-1-phosphate phosphatase, or by lipid phosphate phosphatases. Alternatively, ceramide can be degraded by ceramidases to form sphingosine, which can, in turn, be phosphorylated to sphingosine-1-phosphate by sphingosine kinase. The reverse reaction is catalyzed by sphingosine-1-phosphate phosphatases, or by lipid phosphate phosphatases. Sphingomyelin N-deacylase generates sphingosylphosphorylcholine.