Ceramide

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

sphingomyelinase in the cell membrane and ultimately, to ceramide generation.^[1]

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 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)

• 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 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. ^[2][3][4]

References

1. ^ Haimovitz-Friedman A, Kan CC, Ehleiter D, et al (1994). "Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis". J. Exp. Med. 180 (2): 525-35. PMID 8046331.
2. ^ Siskind LJ, Kolesnick RN, Colombini M (2002). "Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins". J. Biol. Chem. 277 (30): 26796-803. doi:10.1074/jbc.M200754200. PMID 12006562.
3. ^ Stiban J, Fistere D, Colombini M (2006). "Dihydroceramide hinders ceramide channel formation: Implications on apoptosis". Apoptosis 11 (5): 773-80. doi:10.1007/s10495-006-5882-8. PMID 16532372.
4. ^ Siskind LJ, Kolesnick RN, Colombini M (2006). "Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations". Mitochondrion 6 (3): 118-25. doi:10.1016/j.mito.2006.03.002. PMID 16713754.