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ReviewCeramide and ceramide 1-phosphate in health and disease

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. Introduction Sphingolipids play essential roles in normal cell and tissue homeostasis as well as in the establishment and progression of numerous diseases. In particular, ceramide is the central core in sphingolipid metabolism, but has also been involved in the regulation of signal transduction processes. Specifically, ceramides induce cell cycle arrest and promote apoptosis, a form of programmed cell death [1,2]. Also, ceramides play important roles in the regulation of autophagy, cell differentiation, survival, and inflammatory responses [3-11], and have been associated with insulin resistance through activation of protein phosphatase 2A and the subsequent dephosphorylation and inactivation of Akt (also known as protein kinase B (PKB)) [12-14]. Cell ceramides typically have long N-acyl chains ranging from 16 to 26 carbons in length [15-17]. However, in many studies short-chain analogs (N-acetylsphingosine, or C2-ceramide, N-hexanoylsphingosine, or C6-ceramide, and N-octanoylsphingosine, or C8-ceramide) have been used in experiments because these are more water soluble than long-chain ceramides. Formation of ceramide is also relevant because it is the precursor of important bioactive sphingolipids that can also regulate cellular functions, as discussed below. A major metabolite of ceramide is ceramide-1-phosphate (C1P), which is generated through direct phosphorylation of ceramide by ceramide kinase (CerK) (Fig. 1). There is increasing evidence suggesting that C1P can regulate cell proliferation and apoptosis [7,18], and Chalfant and co-workers have elegantly demonstrated that C1P is a potent pro-inflammatory agent (Reviewed in [19,20]). In addition, C1P plays an important role in phagocytosis [21,22], and we have recently demonstrated that is a key factor in the regulation of macrophage chemotaxis. The aim of the present review is to discuss recent progress in C1P biology with especial emphasis in the context of health and disease. Synthesis of Bioactive Sphingolipids Although sphingosine is the simplest sphingolipid, ceramide is considered to be the central structure in sphingolipid metabolism. Fig. 1 shows that ceramide can be generated by three major mechanisms: 1) the de novo synthesis pathway is an anabolic route that begins with condensation of the amino acid serine and palmitoylCoA to form 3-ketosphinganine in a reaction that is catalyzed by serine palmitoyltransferase (SPT); reduction of 3-ketosphinganine to sphinganine follows immediately; acylation of sphinganine by dihydroceramide synthase * Correspondence: antonio.gomez@ehu.es 1 Department of Biochemistry and Molecular Biology. Faculty of Science and Technology. University of the Basque Country (UPV/EHU). P.O. Box 644. 48080 -