title: CD36 initiated signaling mediates ceramide-induced TXNIP expression in pancreatic beta-cells.
abstract: Diverse mechanisms are involved in the pathogenesis of β-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-1 β-cell line, we hypothesized that activation of the redox sensitive protein TXNIP is involved in ceramide-induced β-cell dysfunction. Incubation of INS-1 cells and primary islets with C2-ceramide (N-acetyl-sphingosine) downregulated insulin and PDX-1 expression and increased β-cell apoptosis. Ceramide treatment induced a time dependent increase in TXNIP gene expression accompanied by activation of nuclear factor (NF)-κB 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-κB. Blockade of NF-κB 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-κB activation and TXNIP expression. These data suggest that CD36 dependent NF-κB-TXNIP signaling contributes to the ceramide-induced pathogenesis of pancreatic β-cell dysfunction and failure.
authors: Institute of Medical Science, Yeungnam University College of Medicine, Daegu, South Korea.
authors: Udayakumar
authors: U
authors: Karunakaran
authors: Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, South Korea.
authors: Jun Sung
authors: JS
authors: Moon
authors: Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, South Korea.
authors: Hyoung Woo
authors: HW
authors: Lee
authors: Institute of Medical Science, Yeungnam University College of Medicine, Daegu, South Korea; Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, South Korea. Electronic address: kcwon@med.yu.ac.kr.
authors: Kyu Chang
authors: KC
authors: Won
keywords: Beta-cell dysfunction; CD36; Ceramide; Diabetes; NF-κB; TXNIP