Principles of bioactive lipid signalling: lessons from sphingolipids

Abstract

The sphingolipids constitute an important class of bioactive lipids, including ceramide and sphingosine-1-phosphate (S1P). Ceramide can be considered to function as a hub in sphingolipid metabolism, and it mediates or regulates antiproliferative responses such as growth inhibition, apoptosis, differentiation and senescence, whereas S1P is a key regulator of cell motility and proliferation. The study of bioactive lipids in general and sphingolipids in particular presents several hurdles to molecular cell biologists. These include the hydrophobicity and biophysical properties of these molecules, the metabolic interconnections of the active metabolites, and the predominantly hydrophobic nature of the enzymes that regulate their metabolism. Enzymes of sphingolipid metabolism function as an interconnected network that regulates the levels and interconversions of the bioactive sphingolipids. Many of these enzymes, such as sphingomyelinases, sphingosine kinases and ceramide synthases, serve to couple the action of extra- and intracellular agonists to downstream effectors. Ceramide can be formed from the de novo pathway or following activation of the sphingomyelinase pathway, in which it functions in metabolic regulation and stress responses. Ceramide action is governed by the specific pathways that regulate its formation, their subcellular localization and their specific mechanisms of regulation. S1P is a product of sphingosine kinases, and acts predominantly on a family of G protein-coupled receptors that, in turn, mediate its action on cell growth, migration, transcription and signal transduction. The cellular actions of ceramide, S1P and other bioactive sphingolipids are increasingly thought to be crucial for the study of angiogenesis, inflammation, immune responses, diabetes, ageing, cancer biology and degenerative diseases.