Ceramide formation as a target in beta-cell survival and function

• Published in: Expert opinion on therapeutic targets Vol. 15; no. 9; p. 1061
• Main Authors: Lang, Florian, Ullrich, Susanne, Gulbins, Erich
• Format: Journal Article
• Language: English
• Published: England 01.09.2011
• Subjects: Amyloid - metabolism; Animals; Apoptosis; Cell Survival; Ceramides - biosynthesis; Ceramides - metabolism; Diabetes Mellitus - drug therapy; Diabetes Mellitus - physiopathology; Drug Delivery Systems; Humans; Insulin-Secreting Cells - metabolism; Ion Channels - metabolism; Signal Transduction; Sphingomyelin Phosphodiesterase - metabolism; Sphingosine N-Acyltransferase - metabolism
• ISSN: 1744-7631
• DOI: 10.1517/14728222.2011.588209

Ceramide may be synthesized de novo or generated by sphingomyelinase-dependent hydrolysis of sphingomyelin. The role of ceramide, ceramide-sensitive signaling and ion channels in β-cell apoptosis, lipotoxicity and amyloid-induced β-cell death. Ceramide participates in β-cell dysfunction and apoptosis after exposure to TNFα, IL-1β and IFN-γ, 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 β-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), downregulation 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 β-cell survival and function may be therapeutically relevant, because ceramide formation can be suppressed by pharmacological inhibition of ceramide synthetase and/or sphingomyelinase.