Advances in determining signaling mechanisms of ceramide and role in disease

Abstract

Ceramide is a critical bioactive lipid involved in diverse cellular processes. It has been proposed to regulate cellular processes by influencing membrane properties and by directly interacting with effector proteins. Advances over the past decade have improved our understanding of ceramide as a bioactive lipid. Generation and characterization of ceramide-metabolizing enzyme KO mice, development of specific inhibitors and ceramide-specific antibodies, use of advanced microscopy and mass spectrometry, and design of synthetic ceramide derivatives have all provided insight into the signaling mechanisms of ceramide and its implications in disease. As a result, the role of ceramide in biological functions and disease are now better understood, with promise for development of therapeutic strategies to treat ceramide-regulated diseases.

Keywords: aging; animal models; cancer; heart disease; lipid signaling; lipidomics; membrane/fluidity; multiple sclerosis; obesity; receptors/plasma membrane.

Graphical abstract

Fig. 1.

Ceramide structure. Endogenous ceramides are comprised of a sphingoid base with 18 carbons, a 4,5-trans double bond and an acyl chain that ranges from 12 to greater than 26 carbons in length. Ceramides lacking the 4,5-trans double bond are called dihydroceramides and are an important intermediate during de novo synthesis. Both the acyl chain and sphingoid base can contain additional double bonds and can also be hydroxylated. Finally, addition of chemical groups to carbon 1 converts ceramide to more complex sphingolipids. This graphic, in black, represents the chemical structure of C16-ceramide containing an 18-carbon sphingoid base with a 4-5-trans double bond, referred to as d18:1/C16:0 ceramide.

Fig. 2.

Ceramide metabolism. Ceramide is the centerpiece of the sphingolipid metabolism and can be synthetized by different pathways. The condensation of serine and palmitoyl-CoA initiates the de novo synthesis pathway (blue box). Ceramide can be generated through the hydrolysis of sphingomyelin by the action of SMases (green box) or by hydrolysis of other complex sphingolipids (glucosylceramide and galactosylceramide) (yellow box). Different SMases have been identified according to their cation dependence and pH optima of action. Ceramide can be hydrolyzed to sphingosine and then reacylated back to ceramide in the salvage pathway (orange box). Both the de novo synthesis and the salvage pathways involve the action of CerS; six different CerSs have been described, each of them has preference for specific acyl chain length and, therefore, they synthetize a subset of ceramides. Dihydroceramide desaturase (DES); ceramidase (CDase); sphingomyelin synthase (SMS); glucosylceramide synthase (GCS); glucosylceramidase (GCase); ceramide galactosyltransferase (CGT); galactosylceramidase (GalC).