membrane may have different roles compared to ceramide that is formed in the inner leaflet by the action of neutral SMase enzymes. Ceramide mediates many cell-stress responses, including the regulation of programmed cell death (apoptosis) and cell aging (senescence). Numerous research works have focused interest on defining the direct protein targets of action of ceramide. These include enzymes called ceramide-activated Ser-Thr phosphatases (CAPPs), such as protein phosphatase 1 and 2A (PP1 and PP2A), which were found to interact with ceramide in studies done in a controlled environment outside of a living organism (in vitro). On the other hand, studies in cells have shown that ceramide-inducing agents such as tumor necrosis factor-alpha α (TNFα) and palmitate induce the ceramide-dependent removal of a phosphate group (dephosphorylation) of the retinoblastoma gene product RB and the enzymes, protein kinases B (AKT protein family) and C α (PKB and PKCα). Moreover, there is also sufficient evidence which implicates ceramide to the activation of the kinase suppressor of Ras (KSR), PKCζ, and cathepsin D. Cathepsin D has been proposed as the main target for ceramide formed in organelles called lysosomes, making lysosomal acidic SMase enzymes one of the key players in the mitochondrial pathway of apoptosis. Ceramide was also shown to activate PKCζ, implicating it to the inhibition of AKT, regulation of the voltage difference between the interior and exterior of the cell (membrane potential) and signaling functions that favor apoptosis. Chemotherapeutic agents such as daunorubicin and etoposide enhance the de novo synthesis of ceramide in studies done on mammalian cells. The same results were found for certain inducers of apoptosis particularly stimulators of receptors in a class of lymphocytes (a type of white blood cell) called B-cells. Regulation of the de novo synthesis of ceramide by palmitate may have a key role in diabetes and the metabolic syndrome. Experimental evidence shows that there is substantial increase of ceramide levels upon adding palmitate. Ceramide accumulation activates PP2A and the subsequent dephosphorylation and inactivation of AKT, a crucial mediator in metabolic control and insulin signaling. This results in a substantial decrease in insulin responsiveness (i.e. to glucose) and in the death of insulin-producing cells in the pancreas called islets of Langerhans. Inhibition of ceramide synthesis in mice via drug treatments or gene-knockout techniques prevented insulin resistance induced by fatty acids, glucocorticoids or obesity. An increase in in vitro activity of acid SMase has been observed after applying