The role of the liver in the pathogenesis of hereditary haemochromatosis

遗传性血色病（HH）1型是一种非常常见的铁代谢遗传性疾病，影响1：200澳大利亚人。HH通常由HFE基因突变引起，导致膳食铁的过度吸收和器官（特别是肝脏）的渐进性铁负荷。未检测到的进行性铁积累可能具有严重的临床后果，包括肝硬化、关节炎、糖尿病和心脏病。HFE在正常铁代谢中的作用以及HFE突变如何导致铁过载的发展尚不清楚。已鉴定出其他类型的HH，其具有与HH 1型相似的临床特征，这是由于铁调素或血幼素（2型）和转铁蛋白受体2基因（3型）的突变。据认为，HFE与这些分子一起在相同或密切相关的途径中起作用，以调节铁代谢。假设HFE和转铁蛋白受体2作为身体铁水平的传感器，其向铁储存调节剂铁调素发出信号以控制膳食铁的吸收和铁在肝脏中的沉积。在这项研究中，我们将使用HFE和转铁蛋白受体2突变的小鼠，这些小鼠具有人类HH 1型和3型的许多特征，以鉴定1）HFE和转铁蛋白受体2如何感知身体铁水平，2）它们如何向铁调素发出信号以调节铁代谢，以及3）HFE和转铁蛋白受体2的突变如何导致铁水平的功能失调和铁调素信号传导受损，从而导致HH中铁吸收增加和肝脏铁过载。这项研究将提供有关HFE和其他密切相关的分子在调节正常铁代谢和HH中铁过载发展中的作用的新知识，并确定诸如铁调素的分子用于预防和治疗铁过载的治疗用途的潜力。

Hereditary Haemochromatosis (HH) type 1 is a very common inherited disorder of iron metabolism that affects 1:200 Australians. HH is usually caused by mutations in the HFE gene and leads to excessive absorption of dietary iron and progressive iron loading of organs, particularly the liver. Undetected, progressive iron accumulation may have serious clinical consequences including cirrhosis, arthritis, diabetes mellitus and heart disease. The role of HFE in normal iron metabolism and how mutations in HFE lead to the development of Fe overload are unknown. Other types of HH have been identified that have similar clinical characteristics to HH type 1 which are due to mutations in hepcidin or haemojuvelin (type 2) and transferrin receptor 2 genes (type 3). It is thought that HFE acts together with these molecules in the same or closely related pathways to regulate iron metabolism. It is hypothesised that HFE and transferrin receptor 2 act as sensors of body iron levels which signal to the iron stores regulator, hepcidin to control the absorption of dietary iron and the deposition of iron in the liver. In this study, we will use mice with mutations in HFE and transferrin receptor 2 which have many of the characteristics of human HH type 1 and type 3 to identify 1) how HFE and transferrin receptor 2 sense body iron levels, 2) how they signal to hepcidin to regulate iron metabolism and 3) how mutations in HFE and transferrin receptor 2 lead to dysfunctional sensing of iron levels and impaired signalling to hepcidin causing increased iron absorption and liver iron overload in HH. This study will provide new knowledge about the role of HFE and other closely related molecules in the regulation of normal iron metabolism and the development of iron overload in HH and identify the potential of molecules such as hepcidin for therapeutical use for the prevention and treatment of iron overload.