Divalent metal‐dependent regulation of hepcidin expression by MTF‐1

Abstract

Edited by Stuart FergusonKeywords: Zinc Iron Hepcidin MRE-binding transcription factor-1 Metal response element a b s t r a c t Hepcidin is a small acute phase peptide that regulates iron absorption. It is induced by inflammation and infection, but is repressed by anaemia and hypoxia. Here we further reveal that hepcidin transcription also involves interactions between functional metal response elements (MREs) in its promoter, and the MRE-binding transcription factor-1. Analysis of hepcidin mRNA and protein levels in hepatoma cells suggests that its expression may be regulated by divalent metal ions, with zinc inducing maximal effects on hepcidin levels. These data suggest that this peptide may be a pleiotropic sensor of divalent metals, some of which are xenobiotic environmental toxins.

Exposure to bis(maltolato)oxovanadium(IV) increases levels of hepcidin mRNA and impairs the homeostasis of iron but not that of manganese

“…In support of our results here, in vitro studies have revealed that hepcidin transcription also involves interactions between functional metal response elements (MREs) in its promoter and the MRE-binding transcription factor-1. Analysis of hepcidin mRNA and protein levels in hepatoma cells suggests that its expression may be regulated by divalent metal ions, with zinc inducing maximal effects on hepcidin levels (Balesaria et al, 2010). Similar actions could be involved in the increased hepcidin expression in hepatic tissue after the prolonged intake of V by rats.…”

Kinetics of Tissue Iron in Experimental Autoimmune Encephalomyelitis in Rats

“…It then acts as pivotal iron regulatory hormone and a pleiotropic sensor of divalent metals that shifts the iron from circulation into cellular stores in hepatocytes and macrophages, attenuating intestinal iron absorption and a macrophage iron release [47,48]. This might be favorable in inflammation and in cancer, since this makes iron less available for invading microorganisms and growth of tumor cells [38] but is also harmful, owing to the resultant hypoferremia which concomitantly might damage several functions in the host [49].…”

Proteínas relacionadas con el metabolismo del hierro corporal

“…La regulación transcripcional, aún es motivo de investigación; hasta el momento se conoce la ausencia de IREs que puedan ser los responsables del control en la transcripción de la Hpc, pero se propone que el péptido puede ser regulado por metales divalentes, porque en la región promotora del gen se encuentra un MREs que al conjugarse con metales como el zinc o el hierro y con el MTF, genera un efecto en la expresión de la Hpc; por ejemplo, se estimula la expresión del ARNm de la Hpc cuando el metal que se une es el zinc y se bloquea cuando el metal es el hierro, sin embargo, son necesarios más estudios para aclarar este sistema de regulación (74). Además, para que sea exitosa la transcripción del péptido, se requiere de la proteína C/EBP, la cual se conjuga con el elemento promotor CCAAT y promueve la transcripción de la Hpc (33).…”

“…Las proteínas SMAD por su parte, se activan ante una concentración suficiente de hierro, forman un complejo con un morfógeno y se transfieren al núcleo para activar la expresión de la Hpc (71,74,75).…”