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 that it can 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.
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.
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.
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 maintenace 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. .
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.
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.