Iron overload by transferrin receptor protein 1 regulation plays an important role in palmitate-induced insulin resistance in human skeletal muscle cells

Abstract

Free fatty acid is considered to be one of the major pathogenic factors of inducing insulin resistance. The association between iron disturbances and insulin resistance has recently begun to receive a lot of attention. Although skeletal muscles are a major tissue for iron utilization and storage, the role of iron in palmitate (PA)-induced insulin resistance is unknown. We investigated the molecular mechanism underlying iron dysregulation in PA-induced insulin resistance. Interestingly, we found that PA simultaneously increased intracellular iron and induced insulin resistance. The iron chelator deferoxamine dramatically inhibited PA-induced insulin resistance, and iron donors impaired insulin sensitivity by activating JNK. PA up-regulated transferrin receptor 1 (tfR1), an iron uptake protein, which was modulated by iron-responsive element-binding proteins 2. Knockdown of tfR1 and iron-responsive element-binding proteins 2 prevented PA-induced iron uptake and insulin resistance. PA also translocated the tfR1 by stimulating calcium influx, but the calcium chelator, BAPTA-AM, dramatically reduced iron overload by inhibiting tfR1 translocation and ultimately increased insulin sensitivity. Iron overload may play a critical role in PA-induced insulin resistance. Blocking iron overload may thus be a useful strategy for preventing insulin resistance and diabetes.-Cui, R., Choi, S.-E., Kim, T. H., Lee, H. J., Lee, S. J., Kang, Y., Jeon, J. Y., Kim, H. J., Lee, K.-W. Iron overload by transferrin receptor protein 1 regulation plays an important role in palmitate-induced insulin resistance in human skeletal muscle cells.