title: Caspase-2 and JNK activated by saturated fatty acids are not involved in apoptosis induction but modulate ER stress in human pancreatic β-cells.
abstract: BACKGROUND
  Fatty acid-induced apoptosis and ER stress of pancreatic β-cells contribute to the development of type 2 diabetes, however, the molecular mechanisms involved are unclear.
  
  
  OBJECTIVE
  In this study we have tested the role of caspase-2 and suggested ER stress mediator JNK in saturated fatty acid-induced apoptosis of the human pancreatic β-cells NES2Y.
  
  
  RESULTS
  We found that stearic acid at apoptosis-inducing concentration activated ER stress signaling pathways, i.e. IRE1α, PERK and ATF6 pathways, in NES2Y cells. During stearic acid-induced apoptosis, JNK inhibition did not decrease the rate of apoptosis nor the activation of caspase-8, -9, -7 and -2 and PARP cleavage. In addition, inhibition of JNK activity did not affect CHOP expression although it did decrease the induction of BiP expression after stearic acid treatment. Caspase-2 silencing had no effect on PARP as well as caspase-8, -9 and -7 cleavage and the induction of CHOP expression, however, it also decreased the induction of BiP expression. Surprisingly, caspase-2 silencing was accompanied by increased phosphorylation of c-Jun.
  
  
  CONCLUSIONS
  We have demonstrated that caspase-2 as well as JNK are not key players in apoptosis induction by saturated fatty acids in human pancreatic β-cells NES2Y. However, they appear to be involved in the modulation of saturated fatty acid-induced ER stress signaling, probably by a mechanism independent of c-Jun phosphorylation.
authors: Division of Cell and Molecular Biology & Center for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors: Vlasta
authors: V
authors: Němcová-Fürstová
authors: Kamila
authors: K
authors: Balušíková
authors: Jan
authors: J
authors: Srámek
authors: Roger F
authors: RF
authors: James
authors: Jan
authors: J
authors: Kovář
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D053143:Caspase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D013229:Stearic Acids / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D013229:Stearic Acids; D014157:Transcription Factors; D051742:Transcription Factor CHOP; C031183:stearic acid; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D053143:Caspase 2; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9