THYROID-HORMONE MODULATES THE INTERACTION BETWEEN IRON REGULATORY PROTEINS AND THE FERRITIN MESSENGER-RNA IRON-RESPONSIVE ELEMENT

The cytoplasmic iron regulatory protein (IRP) modulates iron homeostas is by binding to iron-responsive elements (IREs) in the transferrin re ceptor and ferritin mRNAs to coordinately regulate transferrin recepto r mRNA stability and ferritin mRNA translational efficiency, respectiv ely. These studies demonstrate that thyroid hormone (T-3) can modulate the binding activity of the IRP to an IRE in vitro and in vivo. T-3 a ugmented an iron-induced reduction in IRP binding activity to a ferrit in IRE in RNA electrophoretic mobility shift assays using cytoplasmic extracts from human liver hepatoma (HepG2) cells. Hepatic IRP binding to the ferritin IRE also diminished after in vivo administration of T- 3 with iron to rats. In transient transfection studies using HepG2 cel ls and a human ferritin IRE-chloramphenicol acetyltransferase (H-IRE-C AT) construct, T-3 augmented an iron-induced increase in CAT activity by similar to 45%. RNase protection analysis showed that this increase in CAT activity was not due to a change in the steady state level of CAT mRNA. Nuclear T-3-receptors may be necessary for this T-3-induced response, because the effect could not be reproduced by the addition o f T-3 directly to cytoplasmic extracts and was absent in CV-1 cells wh ich lack T-3-receptors. We conclude that T-3 can functionally regulate the IRE binding activity of the IRP. These observations provide evide nce of a novel mechanism for T-3 to up-regulate hepatic ferritin expre ssion, which may in part contribute to the elevated serum ferritin lev els seen in hyperthyroidism.