Ceramide

Ceramides 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. Perhaps one of the most fascinating aspects of ceramide is the fact that it can be released from the cell membrane by enzymes and then 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. Due to this function, ceramides are sometimes called "messengers of cell death".

Pathways for ceramide synthesis
There are two known means of generating ceramide. 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. Regardless of which pathway is used, the generation of pools of ceramide serve to signal the cell towards a programmed cell death.

Hydrolysis
Hydrolysis of sphingomyelin - catalyzed by enzyme sphingomyelinase. Because sphingomyelin is one of the four common phospholipids found in the lipid bilayer 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 pathway - catalyzed by the enzyme ceramide synthase. De novo synthesis of ceramide occurs in the endoplasmic reticulum. Ceramide is subsequently transported to the Golgi. In the Golgi apparatus, ceramide can be further metabolized to other sphingolipids, such as sphingomyelin and the glycosphingolipids.  Ceramide accumulation due to induction of the de novo pathway has been implicated in chemotherapy-induced apoptosis of some cancer cells.

Implications in apoptotic signaling
Ceramide was first implicated in being a signal for programmed cell death when patients with the genetic disorder Niemann-Pick Disease were found to have certain cell types that were resistant to apoptosis. Niemann-Pick Disease is a disease in which there is a deficiency in acid sphingomyelinase, the enzyme that leads to the production of ceramide. Over time, series of experiments at multiple institutions have shown that ceramide is a pro-apoptotic signal that, itself, can induce apoptosis in many cell types. Currently, research is being done on the role that ceramide plays in apoptosis that is induced by ionizing radiation. An acid-sphingomyelinase knock-out mouse has been genetically engineered, and various cell types from this mouse are resistant to signals that would otherwise cause apoptosis.

Substances known to induce ceramide generation
(also heat and ionizing radiation)
 * TNF-alpha
 * Endotoxin
 * Chemotherapeutic agents
 * 1,25 dihydroxy vitamin D
 * gamma interferon
 * 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 signaling occurs
It is hypothesized that after ceramide is generated in the lipid bilayer in the plasma membrane in response to one of the aforementioned stress signals, ceramide clusters onto lipid platforms known as lipid rafts. It has been postulated that these lipid rafts are transmembrane structures that serve as platforms for signaling molecules to be brought together. Because the rafts 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.