Down-regulation of peroxisome proliferator-activated receptor γ coactivator-1α expression in fatty acid-induced pancreatic beta-cell apoptosis involves nuclear factor-κB pathway

Background Pancreatic beta-cell apoptosis induced by lipotoxicity, to a large extent, contributes to the progression of type 2 diabetes. To investigate the mechanism of free fatty acid induced apoptosis, we aimed to study the effects of palmitic acid (PA) on the apoptosis and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) expression in beta TC3 cells as well as the possible role of nuclear factor-kappa B (NF-kappa B) in this process. Methods Hoechst 33258 was used to detect beta TC3 cell apoptosis, which was induced by PA stimulation for 12 hours. PGC-1 alpha expression was analyzed by reverse transcription polymerase chain reaction, I kappa B kinase beta (IKK beta), I kappa B alpha, NF-kappa B-inducing kinase (NIK) and Rel-B expressions were analyzed by Western blotting. MG132 was employed to block the endogenous I kappa B alpha degradation before PA administration, and then its effect on PA-inducing cell apoptosis and PGC-1 alpha mRNA expression was analyzed. Results Significant increased cell apoptosis was found at the concentration of 0.5 mmol/L and 1.0 mmol/L PA administration. PA (0.5 mmol/L) could extensively reduced the expression of PGC-1 alpha mRNA. After exposing beta TC3 cells to 0.5 mmol/L PA for different time periods (0, 4, 6, 8, 10 and 12 hours), IKK beta protein expression increased while I kappa B alpha, NIK and Rel-B protein expression declined in a time-dependent manner. Pretreatment with MG132 to inhibit the degradation of I kappa B alpha, partially prevented the down-regulation of PGC-1 alpha mRNA expression after 12-hour PA treatment in accordance with the decrease of PA induced apoptosis. Conclusions NF-kappa B canonical pathway was activated in PA-mediated beta TC3 cell apoptosis, whereas non-canonical pathway was inhibited. Reduced PGC-1 alpha expression by PA in beta TC3 cells could involve the activation of canonical NF-kappa B pathway, so as to deteriorate the PA induced apoptosis. Chin Med J 2011;124(22):3657-3663