Sphingolipids, a family of membrane lipids, are bioactive molecules that participate in diverse functions controlling fundamental cellular processes such as cell division, differentiation, and cell death. Given that most of these cellular processes form the basis for several pathologies, it is not surprising that sphingolipids are key players in several pathological processes. This review discusses the role of the sphingolipid metabolic pathway in diabetes, Alzheimer’s disease, and hepatocellular carcinoma, with a special emphasis on the changes in gene expression pattern in these disease conditions. For convenience, the sphingolipid metabolic pathway is divided into hypothetical compartments (modules) with each compartment representing a physiological process and changes in gene expression pattern are mapped to each of these modules. It appears that alterations in the gene expression pattern in these disease conditions are biased to manipulate the system in order to result in a particular disease. 1. Introduction Sphingolipids are a class of natural lipids comprised of a sphingoid base backbone, sphingosine. Sphingosine N-acylated with fatty acids forms ceramide [1], a central molecule in the sphingolipid biology. A variety of charged, neutral, phosphorylated, or glycosylated moieties are attached to ceramide further forming complex sphingolipids [2] (see Figure 1 for details). For example, phosphoryl choline attached to ceramide makes the most abundant mammalian sphingolipid, sphingomyelin. These moieties result in both polar and nonpolar regions giving the molecules an amphipathic character which accounts for their tendency to aggregate into membranous structures. Furthermore, such variations found in their chemical structures allow them to play diverse roles in cellular metabolism. Research in the past decade has clearly indicated that sphingolipids are not just the structural components of cell membrane but also act as signaling molecules controlling a majority of cellular events including signal transduction, cell growth, differentiation, and apoptosis [3–5]. Ceramide, sphingosine, sphingosine-1-phosphate (S1P), and ceramide-1-phosphate (C1P) have emerged as chief bioactive mediators in the context of sphingolipid biology. Figure 1: Structure of key sphingolipid molecules. All sphingolipids are comprised of a sphingoid base, and in mammals sphingosine (mainly C-18) is the major sphingoid base (a). A long chain fatty acid attached to sphingosine through amide linkage forms ceramide (b). Complex sphingolipids are obtained by replacement of hydrogen
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