SPHINGOLIPIDS - THE ENIGMATIC LIPID CLASS - BIOCHEMISTRY, PHYSIOLOGY,AND PATHOPHYSIOLOGY

The ''sphingosin'' backbone of sphingolipids was so named by J. L. W. Thudichum in 1884 for its enigmatic (''Sphinx-like'') properties. Alth ough still an elusive class of lipids, research on the involvement of sphingolipids in the signal transduction pathways that mediate cell gr owth, differentiation, multiple cell functions, and cell death has bee n rapidly expanding our understanding of these compounds. In addition to the newly discovered role of ceramide as an intracellular second me ssenger for tumor necrosis factor-alpha, IL-1 beta, and other cytokine s, sphingosine, sphingosine-1-phosphate, and other sphingolipid metabo lites have recently been demonstrated to modulate cellular calcium hom eostasis and cell proliferation. Perturbation of sphingolipid metaboli sm using synthetic and naturally occurring inhibitors of key enzymes o f the biosynthetic pathways is aiding the characterization of these pr ocesses; for examples, inhibition of cerebroside synthase has indicate d a role for ceramide in cellular stress responses including heat shoc k, and inhibition of ceramide synthase (by fumonisins) has revealed th e role of disruption of sphingolipid metabolism in several animal dise ases. Fumonisins are currently the focus of a FDA long-term tumor stud y. This review summarizes recent research on (i) the role of sphingoli pids as important components of the diet, (ii) the role of sphingoid b ase metabolites and the ceramide cycle in expression of genes regulati ng cell growth, differentiation, and apoptosis, (iii) the use of cereb roside synthase inhibitors as tools for understanding the role of sphi ngolipids as mediators of cell cycle progression, renal disease, and s tress responses, and (iv) the involvement of disrupted sphingolipid me tabolism in animal disease and cellular deregulation associated with e xposure to inhibitors of ceramide synthase and serine palmitoyltransfe rase, 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 be ginning of this story. (C) 1997 Academic Press