Iron transport and liver injury in mouse models of hereditary haemochromatosis

[Truncated abstract] Fundamental biochemical activities, such as, oxygen transport, energy production and cellular proliferation are all dependent on iron-containing proteins. Although iron is essential, excess is toxic due to its ability to catalyse the production of reactive oxygen species and damage cellular macromolecules (Chua et al. 2007). Hereditary haemochromatosis (HH) is an autosomal recessive disorder in which excessive absorption of dietary iron leads to iron accumulation in the parenchymal tissues. Excessive iron accumulation is most prominent in the liver as well as in the pancreas, pituitary, heart, joints and skin and may lead to liver fibrosis, cirrhosis and hepatocellular carcinoma, diabetes mellitus, impotence, cardiac failure, arthritis and skin hyperpigmentation. There are five types of HH caused by mutations in genes that encode proteins involved in the synthesis of hepatic regulatory peptide hepcidin, and its receptor, ferroportin that regulate iron metabolism. The general aim of this study was to characterise the roles of the proteins; haemochromatosis protein (HFE) and transferrin receptor 2 (TFR2) which are mutated in HH type 1 and 3, respectively, in iron transport and the regulation of iron metabolism. The general aim of this study was to characterise the roles of the proteins; haemochromatosis protein (HFE) and transferrin receptor 2 (TFR2) which are mutated in HH type 1 and 3, respectively, in iron transport and the regulation of iron metabolism. Disruption of both HFE and TFR2 in mice (Hfe-/-xTfr2mut) resulted in a more severe iron loaded phenotype with increased plasma iron, non-transferrin bound iron (NTBI) concentration, transferrin saturation, and liver iron content compared with mice with disruption in either HFE (Hfe-/-) or TFR2 (Tfr2mut) alone. Hfe-/-xTfr2mut mice had elevated liver Bmp6 mRNA expression consistent with increased liver iron content. However, disruption of Hfe and Tfr2 expression resulted in ineffective liver p-Smad 1,5,8 signalling leading to reduced liver Hamp1 expression. The more severe iron-loaded phenotype in Hfe-/-xTfr2mut mice compared with single mutant mice suggests a model of iron-dependent regulation of hepcidin where both HFE and TFR2 act as plasma iron sensors via parallel and possibly converging signalling pathways...