title: Down-regulation of peroxisome proliferator-activated receptor γ coactivator-1α expression in fatty acid-induced pancreatic beta-cell apoptosis involves nuclear factor-κB pathway.
abstract: 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 γ coactivator-1α (PGC-1α) expression in βTC3 cells as well as the possible role of nuclear factor-κB (NF-κB) in this process.
  
  
  METHODS
  Hoechst 33258 was used to detect βTC3 cell apoptosis, which was induced by PA stimulation for 12 hours. PGC-1α expression was analyzed by reverse transcription polymerase chain reaction, IκB kinase β (IKKβ), IκBα, NF-κB-inducing kinase (NIK) and Rel-B expressions were analyzed by Western blotting. MG132 was employed to block the endogenous IκBα degradation before PA administration, and then its effect on PA-inducing cell apoptosis and PGC-1α 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-1α mRNA. After exposing βTC3 cells to 0.5 mmol/L PA for different time periods (0, 4, 6, 8, 10 and 12 hours), IKKβ protein expression increased while IκBα, NIK and Rel-B protein expression declined in a time-dependent manner. Pretreatment with MG132 to inhibit the degradation of IκBα, partially prevented the down-regulation of PGC-1α mRNA expression after 12-hour PA treatment in accordance with the decrease of PA induced apoptosis.
  
  
  CONCLUSIONS
  NF-κB canonical pathway was activated in PA-mediated βTC3 cell apoptosis, whereas non-canonical pathway was inhibited. Reduced PGC-1α expression by PA in βTC3 cells could involve the activation of canonical NF-κB pathway, so as to deteriorate the PA induced apoptosis.
authors.affiliation: Department of Endocrinology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: He
authors.forename: Xiao-Pei
authors.initials: XP
authors.lastname: Cao
authors.forename: Ru-Zhu
authors.initials: RZ
authors.lastname: Chen
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Zhu
authors.forename: Xue-Lan
authors.initials: XL
authors.lastname: Wang
authors.forename: Yan-Bing
authors.initials: YB
authors.lastname: Li
authors.forename: Hai-Peng
authors.initials: HP
authors.lastname: Xiao
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D006360:Heat-Shock Proteins; D007976:Leupeptins; D016328:NF-kappa B; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D019308:Palmitic Acid; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde