The therapeutic potential of modulating the ceramide/sphingomyelin pathway.

Abstract

Membrane lipids of the sphingolipid class contain a long-chain sphingoid base backbone (such as sphingosine), an amide-linked, long-chain fatty acid, and one of various polar head groups. The structure of these head groups defines the various sphingolipid subtypes, with a hydroxyl group found in ceramide, phosphorylcholine in sphingomyelin (SM), and carbohydrates in glycosphingolipids (Figure ​(Figure11 and not shown). Because SM is concentrated in the outer leaflet of the plasma membrane and provides a barrier to the extracellular environment (1), it was long assumed to serve only structural roles. However, in 1987 our laboratory reported for the first time rapid sphingomyelinase (SMase) activation in response to 1,2-diacylglycerols but not phorbol esters (2), and proposed the existence of an SM-based signaling pathway (3, 4). Subsequently, Hannun and coworkers showed that this pathway can be activated by receptor-mediated mechanisms (5) and provided evidence that ceramide is a second messenger (6). Indeed, sphingolipid metabolism has proved to be a dynamic process, and sphingolipid metabolites — including ceramide, sphingosine, and sphingosine 1-phosphate (S1P) — are now recognized as messengers playing essential roles in cell growth, survival, and death (7, 8). Figure 1 Schematic representation of sphingolipid intermediary metabolism.