The sphingolipid salvage pathway in ceramide metabolism and signaling

Abstract

Sphingolipids are important components of eukaryotic cells, many of which function as bioactive signaling molecules. Of these, ceramide is a central metabolite and plays key roles in a variety of cellular responses, including regulation of cell growth, viability, differentiation, and senescence. Ceramide is composed of the long-chain sphingoid base, sphingosine, in N-linkage to a variety of acyl groups. Sphingosine serves as the product of sphingolipid catabolism, and it is mostly salvaged through reacylation, resulting in the generation of ceramide or its derivatives. This recycling of sphingosine is termed the "salvage pathway", and recent evidence points to important roles for this pathway in ceramide metabolism and function. A number of enzymes are involved in the salvage pathway, and these include sphingomyelinases, cerebrosidases, ceramidases, and ceramide synthases. Recent studies suggest that the salvage pathway is not only subject to regulation, but it also modulates the formation of ceramide and subsequent ceramide-dependent cellular signals. This review focuses on the salvage pathway in ceramide metabolism, its regulation, its experimental analysis, and emerging biological functions.

Figure 1. Ceramide synthesis

The scheme shows metabolic pathways for ceramide synthesis composed of the sphingomyelinase pathway, the de novo pathway, the exogenous ceramide-recycling pathway, and the salvage pathway. Dotted lines indicate the pathway of ceramide synthesis resulting from recycling/salvaging sphingosine.

Figure 2. Regulation of the salvage pathway and function of ceramide signals

PKC, protein kinase C; CAPP, ceramide-activated protein phosphatase