Role Of Ceramide In Apoptosis Research Articles

Role of Ceramide in Apoptosis and Development of Insulin Resistance.

This review presents data on the functional biochemistry of ceramide, one of the key sphingolipids with properties of a secondary messenger. Molecular mechanisms of the involvement of ceramide in apoptosis in pancreatic β-cells and its role in the formation of insulin resistance in pathogenesis of type 2 diabetes are reviewed. One of the main predispositions for the development of insulin resistance and diabetes is obesity, which is associated with ectopic fat deposition and significant increase in intracellular concentrations of cytotoxic ceramides. A possible approach to the restoration of tissue sensitivity to insulin in type 2 diabetes based on selective reduction of the content of cytotoxic ceramides is discussed.

Ceramide: From Embryos to Tumors

Ceramides are ubiquitous lipids that have important functions integral to apoptotic signaling. Several therapeutic agents currently exist that induce ceramide-dependent apoptosis in cancerous cells, and a number of enzymes involved in ceramide metabolism are beginning to be recognized as potential targets for cancer therapy. Recent research shows that evasion of ceramide-dependent apoptosis is essential at the earliest stages of embryonic development and is an important mechanism of multidrug resistance. Although ceramide-based strategies for treating cancer are promising, current data about ceramide-resistant tumors require further understanding of the role of ceramide in apoptosis.

Apoptosis and signalling in acid sphingomyelinase deficient cells

BackgroundRecent evidence suggests that the activation of a non-specific lipid scramblase during apoptosis induces the flipping of sphingomyelin from the cell surface to the cytoplasmic leaftet of the plasma membrane. Inner leaflet sphingomyelin is then cleaved to ceramide by a neutral sphingomyelinase. The production of this non-membrane forming lipid induces blebbing of the plasma membrane to aid rapid engulfment by professional phagocytes. However contrary evidence suggests that cells which are deficient in acid sphingomyelinase are defective in apoptosis signalling. This data has been interpreted as support for the activation of acid sphingomyelinase as an early signal in apoptosis.HypothesisAn alternative explanation is put forward whereby the accumulation of intracellular sphingomyelin in sphingomyelinase deficient cells leads to the formation of intracellular rafts which lead to the sequestration of important signalling molecules that are normally present on the cell surface where they perform their function.Testing the hypothesisIt is expected that the subcellular distribution of important signalling molecules is altered in acid sphingomyelinase deficient cells, leading to their sequestration in late endosomes / lysosomes. Other sphingolipid storage diseases such as Niemann-Pick type C which have normal acid sphingomyelinase activity would also be expected to show the same phenotype.Implications of the hypothesisIf true the hypothesis would provide a mechanism for the pathology of the sphingolipid storage diseases at the cellular level and also have implications for the role of ceramide in apoptosis.

48] Synthesis and characterization of metabolically stable sphingolipids

Over the past decade, sphingolipids have become candidates of prime interest in phenomena such as cell adhesion and signal transduction, as well as programmed cell death. Studies on the importance of certain sphingolipids as second messenger molecules and receptor modulators have added ceramides, sphingomyelin, and some glycosphingolipids exogenously to cells in culture or laboratory animals. As these compounds are subject to (sometimes rapid) metabolism, it is difficult to know whether the observed effect on cell behavior is elicited by the applied sphingolipid itself or by its metabolic product(s). In addition, for a complete understanding of the role of sphingolipids, information on their intracellular transport would be essential. Thus, it would be desirable to employ metabolically stable sphingolipids or ones with a restricted metabolism in either the catabolic or the anabolic pathway of metabolism. This chapter describes the synthesis of a metabolically stable ceramide analog that proves useful in the study by fluorescence microscopy of its intracellular distribution in cultured fibroblasts and perhaps other cells. This analog carries a stable O-methyl group in place of a primary hydroxyl group and, can neither be glycosylated to glycosphingolipids nor acquire a phosphorylcholine residue to become sphingomyelin. This compound or its radioactive and nonfluorescent homo- log may be valuable for further investigation on the role of ceramide in apoptosis. The synthesis of glycosphingolipid analogs (glucosylceramide and lactosylceramide) that are totally resistant to the action of glycohydrolases is also discussed in this chapter. These compounds feature a thioglycosidic bond that cannot be split in detectable amounts by mammalian glycohydrolases. These analogs of glycosphingolipids are becoming valuable tools in studies on their intracellular transport.

Differential responses of oligodendrocytes to tumor necrosis factor and other pro‐apoptotic agents: Role of ceramide in apoptosis

Differential responses of oligodendrocytes to tumor necrosis factor and other pro‐apoptotic agents: Role of ceramide in apoptosis

Differential responses of oligodendrocytes to tumor necrosis factor and other pro-apoptotic agents: Role of ceramide in apoptosis

Staurosporine induced apoptosis in a human oligodendroglioma cell line (HOG), neonatal rat oligodendrocyte (O2A(+)) precursors, and mature rat oligodendrocytes. In all three cell culture systems, the activation of caspase-3-like activity (CPP32) coincided with the increased formation of ceramide from sphingomyelin and the onset of DNA fragmentation. Further, the addition of exogenous C(2)-ceramide induced CPP32 activation and DNA fragmentation in all three culture systems. Raising endogenous ceramide levels by the addition of the ceramidase inhibitor, oleoylethanolamine, enhanced apoptosis in both a time- and concentration-dependent manner. Inhibitors of phosphatidylinositol 3-kinase (wortmannin and LY294002) also induced caspase-3 (CPP32) activation, increased ceramide formation, induced DNA fragmentation, and reduced cell viability. In contrast, cytokines such as tumor necrosis factor-alpha (TNF-alpha) had a differential effect on the three cell cultures. Thus, TNF-alpha (160 ng/ml) induced 70% apoptosis in 24 hr in freshly isolated rat brain O2A(+) precursor cells, 60% apoptosis in 24 hr in a human oligodendroglioma (HOG) cell line, but no apoptosis in mature neonatal rat oligodendrocytes. Interferon-gamma augmented the activation of CPP32 by TNF-alpha in HOG cells and O2A(+) oligodendrocyte precursor cells but had no effect on mature oligodendrocytes. Thus, the death pathway appears to be similar in the three cell lines but the lack of coupling between TNF-alpha receptors and the apoptotic pathway leads to a lack of response to cytokines in mature oligodendrocytes.