The "sphingosin" backbone of
sphingolipids was so named by J. L. W. Thudichum in 1884 for its enigmatic ("Sphinx-like") properties. Although still an elusive class of
lipids, research on the involvement of
sphingolipids in the signal transduction pathways that mediate cell growth, differentiation, multiple cell functions, and cell death has been rapidly expanding our understanding of these compounds. In addition to the newly discovered role of
ceramide as an intracellular second messenger for
tumor necrosis factor-alpha, IL-1beta, and other
cytokines,
sphingosine,
sphingosine-1-phosphate, and other
sphingolipid metabolites have recently been demonstrated to modulate cellular
calcium homeostasis and cell proliferation. Perturbation of
sphingolipid metabolism using synthetic and naturally occurring inhibitors of key
enzymes of the biosynthetic pathways is aiding the characterization of these processes; for examples, inhibition of cerebroside synthase has indicated a role for
ceramide in cellular stress responses including heat shock, and inhibition of
ceramide synthase (by
fumonisins) has revealed the role of disruption of
sphingolipid metabolism in several
animal diseases.
Fumonisins are currently the focus of a FDA long-term
tumor study. This review summarizes recent research on (i) the role of
sphingolipids as important components of the diet, (ii) the role of sphingoid base metabolites and the
ceramide cycle in expression of genes regulating cell growth, differentiation, and apoptosis, (iii) the use of cerebroside synthase inhibitors as tools for understanding the role of
sphingolipids as mediators of cell cycle progression, renal disease, and stress responses, and (iv) the involvement of disrupted
sphingolipid metabolism in animal disease and cellular deregulation associated with exposure to inhibitors of
ceramide synthase and
serine palmitoyltransferase, key
enzymes in de novo
sphingolipid biosynthesis. These findings illustrate how an understanding of the function of
sphingolipids can help solve questions in toxicology and this is undoubtedly only the beginning of this story.