Insulin promotes iron uptake in human hepatic cell by regulating transferrin receptor-1 transcription mediated by hypoxia inducible factor-1

Hepatic iron is known to regulate insulin signaling pathways and to influence insulin sensitivity in insulin resistance (IR) patients. However, the role of insulin on hepatic iron homeostasis remains unexplored. Here, we report that insulin promotes transferrin-bound iron uptake but shows no influence on non transferrin-bound iron uptake in human hepatic HepG2 cells. As a mechanism we detected increased transferrin receptor-1 (TfR1) expression both at protein and mRNA levels. Unaltered stability of protein and transcript of TfR1 suggested the regulation at transcriptional level that was confirmed by promoter activity. Involvement of transcription factor hypoxia inducible factor-1 (HIF-1) was shown by mutational analyses of the TfR1 promoter region and by electrophoretic mobility shift assay. When HepG2 cells were transfected with specific siRNA targeted to 3'UTR of HIF-1α, the regulatory subunit of HIF-1; insulin-induced TfR1 expression and iron uptake were inhibited. Transfection of cDNA expressing stable form of HIF-1α reversed the increased TfR1 expression and iron uptake. These results suggest a novel role of insulin in hepatic iron uptake by a HIF-1 dependent transcriptional regulation of TfR1.