Ceramide and Insulin Resistance: How Should the Issue Be Approached?

Abstract

There is a growing amount of data indicating that ceramide is involved in the generation of insulin resistance (1–3). However, investigation into the biological function of ceramide is a complex issue. First, there are no ceramide receptors on the plasma membrane. Second, the membrane is impermeable for ceramides containing long-chain fatty acid residues and only such ceramides seem to exist in nature. There are 13 and 12 ceramides containing different long-chain fatty acid residues that have been identified in human and rat skeletal muscle, respectively (4,5). This means that none of them can be used to study a biological role of extracellular ceramide. Therefore, there remain two other options: 1 ) use short-chain (C2 or C6) ceramides, which penetrate the cell membrane or 2 ) manipulate with the level of intracellular ceramide. In the latter case, the activity of selected enzymes of its metabolism may be influenced either by different compounds or by genetic manipulations with the expression of the enzymes. However, there are several pathways of feeding into the ceramide pool in the cell. They are de novo synthesis, hydrolysis of sphingomyelin, catabolism of complex sphingolipids, acylation of sphingosine, and dephosphorylation of ceramide-1-phosphate (Fig. 1). Moreover, most reactions involved in ceramide metabolism are reversible (6,7). Ceramide is on the crossroads of sphingolipid metabolism. However, so far the contributions of different pathways to the ceramide pool have not been quantified in detail. Certainly, the most important source of ceramide for the balance of sphingolipids in the cell is its de novo synthesis. This pathway supplies, through ceramide, all other sphingolipid metabolic pathways (6,7). FIG. 1. The pathways of …