Ceramide

Ceramides (pronounced ser-A-mid) are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. For years, it was assumed that ceramides and other sphingolipids found in the bilayer cell membrane were purely structural elements. This is now known to be not completely true. Ceramide can actually act as a signaling molecule. The most well-known functions of ceramides as cellular signals include regulating the differentiation, proliferation, programmed cell death (PCD), and apoptosis (Type I PCD) of cells.

Pathways for ceramide synthesis
There are three major pathways of ceramide generation. The sphingomyelinase pathway uses an enzyme to breakdown sphingomyelin in the cell membrane and release ceramide. The de novo pathway creates ceramide from less complex molecules. Ceramide generation can also occur through breakdown of complex sphingolipids that are ultimately broken down into sphingosine, which is then reused by reacylation to form ceramide. This latter pathway is termed the Salvage pathway.

Sphingomyelin hydrolysis
Hydrolysis of sphingomyelin is catalyzed by the enzyme sphingomyelinase. Because sphingomyelin is one of the four common phospholipids found in the plasma membrane of cells, the implications of this method of generating ceramide is that the cellular membrane is the target of extracellular signals leading to programmed cell death. There has been research suggesting that when ionizing radiation causes apoptosis in some cells, the radiation leads to the activation of sphingomyelinase in the cell membrane and ultimately, to ceramide generation.

De novo
De novo synthesis of ceramide begins with the condensation of palmitate and serine to form 3-keto-dihydrosphingosine. This reaction is catalyzed by the enzyme serine palmitoyl transferase and is the rate-limiting step of the pathway. In turn, 3-keto-dihydrosphingosine is reduced to dihydrosphingosine, which is then followed by acylation by the enzyme (dihydro)ceramide synthase to produce dihydroceramide. The final reaction to produce ceramide is catalyzed by dihydroceramide desaturase. De novo synthesis of ceramide occurs in the endoplasmic reticulum. Ceramide is subsequently transported to the Golgi by either vesicular trafficking or the ceramide transfer protein CERT. Once in the Golgi apparatus, ceramide can be further metabolized to other sphingolipids, such as sphingomyelin and the complex glycosphingolipids.

The salvage pathway
Constitutive degradation of sphingolipids and glycosphingolipids takes place in the acidic subcellular compartments, the late endosomes and the lysosomes. In case of glycosphingolipids, exohydrolases, acting at acidic pH optima, cause the stepwise release of monosaccharide units from the end of the oligosaccharide chains one after the other leading to the generation of ceramide whereas sphingomyelin is converted to ceramide by acid sphingomyelinase. Ceramide can be further hydrolyzed by acid ceramidase to form sphingosine and a free fatty acid, both of which are able to leave the lysosome in contrast to ceramide. The long-chain sphingoid bases released from the lysosome may then re-enter pathways for synthesis of ceramide and/or sphingosine-1-phosphate. The salvage pathway re-utilizes long-chain sphingoid bases to form ceramide through the action of ceramide synthase. Thus, ceramide synthase family members probably trap free sphingosine released from the lysosome at the surface of the endoplasmic reticulum or in endoplasmic reticulum-associated membranes. It should also be noted that the salvage pathway has been estimated to contribute from 50% to 90% of sphingolipid biosynthesis

Physiological roles of ceramide
As a bioactive lipid, ceramide has been implicated in a variety of physiological functions including apoptosis, cell growth arrest, differentiation, cell senescence, cell migration and adhesion. Roles for ceramide and its downstream metabolites have also been suggested in a number of pathological states including cancer, neurodegeneration, diabetes, microbial pathogenesis, obesity, and inflammation.

Apoptosis
One of the most studied roles of ceramide pertains to its function as a proapoptotic molecule. Apoptosis, a form of programmed cell death, is essential for the maintenance of normal cellular homeostasis and is an important physiological response to many forms of cellular stress. Ceramide accumulation has been found following treatment of cells with a number of apoptotic agents including ionizing radiation, UV light , TNF-alpha , and chemotherapeutic agents. This suggests a role for ceramide in the biological responses of all these agents. Because of its apoptosis-inducing effects in cancer cells, ceramide has been termed the “tumor suppressor lipid”. Several studies have attempted to define further the specific role of ceramide in the events of cell death and some evidence suggests ceramide functions upstream of the mitochondria in inducing apoptosis. However, owing to the conflicting and variable nature of studies into the role of ceramide in apoptosis, the mechanism by which this lipid regulates apoptosis remains elusive. .

Substances known to induce ceramide generation

 * Anandamide
 * Tetrahydrocannabinol and other Cannabinoids
 * TNF-alpha
 * Fas ligand
 * Endotoxin
 * Chemotherapeutic agents
 * 1,25 dihydroxy vitamin D
 * gamma interferon
 * heat
 * ionizing radiation
 * Ceramidase Inhibitors

It is interesting to note that the substances that can cause ceramide to be generated tend to be stress signals that can cause the cells to go into programmed cell death. Ceramide thus acts as an intermediary signal that connects the external signal to the internal metabolism of the cells.

Mechanism by which ceramide signalling occurs
Currently, the means by which ceramide acts as a signaling molecule are not clear.

One hypothesis is that ceramide generated in the plasma membrane stabilizes smaller lipid platforms known as lipid rafts, allowing them to serve as platforms for signalling molecules. Moreover, as rafts can cross the entire lipid bilayer, they can serve as the link between signals outside of the cell to signals to be generated within the cell.

Ceramide has also been shown to form organized large channels traversing the mitochondrial outer membrane. This leads to the egress of proteins from the intermembrane space.