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Expert Opin Ther Targets. 2011 Sep;15(9):1061-71. doi: 10.1517/14728222.2011.588209. Epub 2011 Jun 2.

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

Author information

1
University of Tübingen, Institute of Physiology, Germany. florian.lang@uni-tuebingen.de

Abstract

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 β-cell apoptosis, lipotoxicity and amyloid-induced β-cell death.

EXPERT OPINION:

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.

PMID:
21635197
DOI:
10.1517/14728222.2011.588209
[Indexed for MEDLINE]

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