4.7 Article

CD36 initiated signaling mediates ceramide-induced TXNIP expression in pancreatic beta-cells

Journal

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1852, Issue 11, Pages 2414-2422

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2015.08.009

Keywords

Diabetes; Beta-cell dysfunction; Ceramide; CD36; TXNIP; NF-kappa B

Funding

  1. Yeungnam University Medical Center

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Diverse mechanisms are involved in the pathogenesis of beta-cell failure in type 2 diabetes. Of them, the accumulation of ceramide, a bioactive lipid metabolite, is suggested to play a major role in inflammatory and stress responses that induce diabetes. However, the downstream inflammatory target of ceramide has not been defined. Using rat islets and the INS-ID-cell line, we hypothesized that activation of the redox sensitive protein TXNIP is involved in ceramide-induced beta-cell dysfunction. Incubation of INS-1 cells and primary islets with C2-ceramide (N-acetyl-sphingosine) downregulated insulin and PDX-1 expression and increased beta-cell apoptosis. Ceramide treatment induced a time dependent increase in TXNIP gene expression accompanied by activation of nuclear factor (NF)-kappa B and reduced mitochondrial thioredoxin (TRX) activity. Pretreatment with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked ceramide-induced up-regulation of TXNIP expression and activity of NF-kappa B. Blockade of NF-kappa B nuclear translocation by the peptide SN50 prevented ceramide-mediated TXNIP induction. Furthermore, SSO also attenuated ceramide-induced early loss of insulin signaling and apoptosis. Collectively, our results unveil a novel role of CD36 in early molecular events leading to NF-kappa B activation and TXNIP expression. These data suggest that CD36 dependent NF-kappa B-TXNIP signaling contributes to the ceramide-induced pathogenesis of pancreatic beta-cell dysfunction and failure. (C) 2015 Elsevier B.V. All rights reserved.

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