Molecular responses of iron regulatory proteins to iron overload in human liver

Neonaki, Maria (2006) Molecular responses of iron regulatory proteins to iron overload in human liver. Doctoral thesis, London Metropolitan University.

856480.pdf - Published Version

Download (117MB) | Preview

Abstract / Description

Iron is one of the most abundant metals in nature and a necessary element for life. It is not iron per se but rather its implication in the generation of reactive oxygen species that makes the metal harmful when present in excess as seen in iron overload disorders, such as in hereditary haemochromatosis (HH). And although the intricate mechanisms that maintain iron homeostasis are beginning to transpire, the aetiology of this disorder remains elusive despite knowledge of the causative mutations in HFE. In an attempt to gain an insight into the complexity of HH, transcript and protein levels of key iron-related molecules were investigated in liver specimens from patients with HFE-related HH. Protein levels of iron regulatory protein 1 (IRP1), a known regulator of iron uptake and storage in cells, were found to be consistently down-regulated in the liver of patients with HFE-related HH and also in a human hepatoma cell line exposed to ferric ammonium citrate. The intracellular localisation of the protein was also studied and in addition to the cytoplasmic and perinuclear presence of IRP1, a nuclear existence was also evident in transiently transfected cells. Protein levels of transferrin receptor 2 (TfR2) were found to be upregulated in the liver of both untreated as well as treated HH patients, and correlated directly, irrespective of mutations in HFE, with the degree of transferrin saturation, reaching saturable levels at high hepatic iron concentrations. The underlying mechanism of the observed decrease in IRP1 and increase in TfR2 protein levels in these patients was further investigated at the mRNA level and pointed to a posttranscriptional level of control for both molecules. Hepcidin has recently been dubbed as the main regulator of dietary iron absorption and levels of the transcript in the liver of HH patients failed to respond to the extent of the iron burden, pointing to a central role of this molecule in the aetiology of this disorder.

Item Type: Thesis (Doctoral)
Additional Information:
Uncontrolled Keywords: iron intake; iron overload; liver disorders; hereditary haemochromatosis (HH)
Subjects: 500 Natural Sciences and Mathematics > 570 Life sciences; biology
600 Technology > 610 Medicine & health
Department: School of Human Sciences
Library Services and Special Collections
Depositing User: Mary Burslem
Date Deposited: 09 Feb 2023 14:27
Last Modified: 09 Feb 2023 14:27


Downloads per month over past year

Downloads each year

Actions (login required)

View Item View Item