Protein kinase C delta activation and translocation to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells.
Insulin resistance as well as pancreatic beta-cell failure can be induced by elevated free fatty acid (FFA) levels. We studied the mechanisms of FFA-induced apoptosis in rat and human beta-cells. Chronic treatment with high physiological levels of saturated fatty acids (palmitate and stearate), but not with monounsaturated (palmitoleate and oleate) or polyunsaturated fatty acids (linoleate), triggers apoptosis in approximately 20% of cultured RIN1046-38 cells. Apoptosis restricted to saturated FFAs was also observed in primary cultured human beta-cells, suggesting that this mechanism is potentially relevant in vivo in humans. To further analyze FFA-induced signaling pathways leading to apoptosis, we used RIN1046-38 cells. Apoptosis was accompanied by a rapid (within 15 min) nuclear translocation of protein kinase C (PKC)-delta and subsequent lamin B1 disassembly. This translocation was impaired by the phospholipase C inhibitor U-73122, which also substantially reduced apoptosis. Furthermore, lamin B1 disassembly and apoptosis were decreased by cell transfection with a dominant-negative mutant form of PKC-delta. These data suggest that nuclear translocation and kinase activity of PKC-delta are both necessary for saturated fatty acid-induced apoptosis.
Eitel
Katrin
K
Internal Medicine IV, University of Tübingen, Tübingen, Germany.
Staiger
Harald
H
Rieger
Johannes
J
Mischak
Harald
H
Brandhorst
Heide
H
Brendel
Mathias D
MD
Bretzel
Reinhard G
RG
Häring
Hans-Ulrich
HU
Kellerer
Monika
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D007515:Islets of Langerhans / Q000166:cytology* / Q000201:enzymology; D034921:Lamin Type B / Q000378:metabolism; D019787:Linoleic Acid / Q000494:pharmacology; D009154:Mutation; D019308:Palmitic Acid / Q000494:pharmacology; D010190:Pancreatic Neoplasms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta; D051381:Rats; D015398:Signal Transduction; D013229:Stearic Acids / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D034921:Lamin Type B; D013229:Stearic Acids; D019308:Palmitic Acid; C031183:stearic acid; D019787:Linoleic Acid; C497260:Prkcd protein, rat; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D010738:Type C Phospholipases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases