期刊
EXPERT OPINION ON THERAPEUTIC TARGETS
卷 15, 期 9, 页码 1061-1071出版社
TAYLOR & FRANCIS LTD
DOI: 10.1517/14728222.2011.588209
关键词
amyloid; apoptosis; channels; diabetes; insulin; lipotoxicity
资金
- Deutsche Forschungsgemeinschaft (DFG)
- BMBF
Introduction: Ceramide may be synthesized de novo or generated by sphingomyelinase-dependent hydrolysis of sphingomyelin. Areas covered: The role of ceramide, ceramide-sensitive signaling and ion channels in beta-cell apoptosis, lipotoxicity and amyloid-induced beta-cell death. Expert opinion: Ceramide participates in beta-cell dysfunction and apoptosis after exposure to TNF alpha, IL-1 beta and IFN-gamma, excessive amyloid and islet amyloid polypeptide or non-esterified fatty acids (lipotoxicity). Knockout of sphingomyelin synthase 1, which converts ceramide to sphingomyelin, leads to impairment of insulin secretion. Increased ceramidase activity or pharmacological inhibition of ceramide synthetase, inhibits beta-cell apoptosis. Ceramide contributes to endoplasmatic reticulum(ER) stress, decreased mitochondrial membrane potential in insulin-secreting cells and mitochondrial release of cytochrome c into the cytosol, which are all triggers of apoptotic cell death. Ceramide-dependent signaling involves activation of extracellularly regulated kinases 1 and 2 (ERK1/2), down-regulation of Period (Per)-aryl hydrocarbon receptor nuclear translocator (Arnt)-single-minded (Sim) kinase (PASK), activation of okadaic-acid-sensitive protein phosphatase 2A (PP2A) and stimulation of NADPH-oxidase with generation of superoxides and lipid peroxides. Ceramide reduces the activity of voltage gated potassium (Kv)-channels in insulin-secreting cells. The role of ceramide in beta-cell survival and function may be therapeutically relevant, because ceramide formation can be suppressed by pharmacological inhibition of ceramide synthetase and/or sphingomyelinase.
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