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 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, and apoptosis 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 spingomyelinase 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 of sphingomyelin - catalyzed by enzyme sphingomyelinase. As sphingomyelin is one of the four most common phospholipids found in the lipid bilayer of cells, the implications of the reaction catayzed by sphingomyelinase is that the cellular membrane is a site of ceramide-mediated signalling. There has been research that suggests that the apoptotic signals in some cells originate with the activation of acid spingomyelinase in the lipid membrane and the generation of ceramide. PMID 8046331

• 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 and then to the lipid bilayer. This 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:

• TNF-alpha
• Endotoxin
• Chemotherapeutic agents
• 1,25 dihydroxy vitamin-D
• gamma interferon

(also heat and ionizing radiation)