Ceramide in regulation of apoptosis

While the exact mechanism of ceramide-mediated regulation of most of the above proteins is still unknown, ASM-released ceramide binds directly to PLAa and cathepsin D (Huwiler et al, 2001 Heinrich et al., 1999). Binding of ceramide to cathepsin D in endosomes triggers autocatalytic cleavage of cathepsin to its active form (Heinrich et al, 1999). However, the physiological role of ceramide binding to cathepsin D and PLA2 for apoptosis stiU remains to be determined. 

There are many frontiers coming to fore where ceramide is emerging as an important intermediate. Recent findings highlight roles for ceramide in the regulation of apoptosis, oxidative stress, heat stress, and disease, and these are discussed below as examples/models of current investigations in this area of research. 

Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process. In many cases proteins and/or lipid mediators that induce changes in mitochondrial membrane permeability and calcium regulation are produced or activated. For example, the pro-apoptotic Bcl-2 family members Bax, Bad and Bid may associate with the mitochondrial membrane and modify its permeability. Membrane-derived lipid mediators such as ceramide and 4-hydroxynonenal can also induce mitochondrial membrane alterations that are critical for the execution of apoptosis. 

A variety of studies demonstrate a central role for ASM and ceramide in several forms of apoptosis. Ceramide seems to regulate the activity of certain proteins and, thus, may function, in some circumstances, as a second messenger. In addition, the concept of raft modification hy ceramide provides a comprehensive model for cellular effects of ceramide, and perhaps a biophysical explanation for the diverse functions of this lipid. 

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