Down-regulation of liver iron-regulatory protein 1 in haemochromatosis.

Cellular iron homoeostasis is maintained by iron sensor proteins known as iron-regulatory proteins (IRPs), which act post-transcriptionally by binding RNA stem-loop structures, termed iron-responsive elements (IREs), present on the mRNAs of proteins involved in iron storage, utilization and transport. IRP1 is a bifunctional protein that can act either as a cytoplasmic aconitase or as an IRE-binding protein. The RNA-binding activity of IRP1 is regulated post-translationally by the insertion or extrusion of a 4Fe-4S cluster, without changes in the levels of protein. In hereditary haemochromatosis (HH) accumulation of iron in parenchymal tissues, including the liver, occurs, possibly through dysfunctional IRP1. Investigation of IRP1 expression in liver biopsies from HH patients showed that the protein is completely absent or markedly reduced in heavily iron-loaded HH patients. Real-time PCR was then conducted in an attempt to investigate the mRNA levels and establish the underlying mechanism behind the disappearing act of IRP1. The two possibilities are: transcriptional regulation (through the inhibition of transcription) or post-transcriptional regulation (either through increased turnover of protein or inhibition of translation) of IRP1. Preliminary data suggest that transcription of IRP1 is not affected by chronic iron overload, and down-regulation may be attributable instead to degradation of the protein.