Protein Kinase C Activation and Translocation to the Nucleus Are Required for Fatty Acid-Induced Apoptosis of Insulin-Secreting Cells

K. Eitel, H. Staiger, J. Rieger, H. Mischak, H. Brandhorst, M. D. Brendel, R. G. Bretzel, H.-U. Haring, M. Kellerer
2003 Diabetes  
Insulin resistance as well as pancreatic ␤-cell failure can be induced by elevated free fatty acid (FFA) levels. We studied the mechanisms of FFA-induced apoptosis in rat and human ␤-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 ϳ20% of cultured RIN1046-38 cells. Apoptosis restricted to saturated FFAs was also
more » ... ed in primary cultured human ␤-cells, suggesting that this mechanism is potentially relevant in vivo in humans. To further analyze FFAinduced 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)-␦ 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-␦. These data suggest that nuclear translocation and kinase activity of PKC-␦ are both necessary for saturated fatty acidinduced apoptosis. Diabetes 52:991-997, 2003
doi:10.2337/diabetes.52.4.991 pmid:12663471 fatcat:tzfg5fcabzgf7key4rq3bw2mlq