The role of the liver in the pathogenesis of hereditary haemochromatosis

遗传性血色素沉着病（HH） 1型是一种非常常见的遗传性铁代谢疾病，影响1:20 00澳大利亚人。HH通常由HFE基因突变引起，并导致膳食铁的过度吸收和器官（尤其是肝脏）铁的进行性负荷。未被发现的进行性铁积累可能导致严重的临床后果，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。其他类型的HH已被确定具有与HH 1型相似的临床特征，这是由于hepcidin或hememojuvelin（2型）和转铁蛋白受体2基因（3型）的突变。人们认为HFE与这些分子在相同或密切相关的途径中共同调节铁代谢。据推测，HFE和转铁蛋白受体2作为体内铁水平的传感器，向铁储存调节剂hepcidin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,我们将使用老鼠在HFE基因突变和转铁蛋白受体2的许多人类HH 1型和3型的特点来确定1)HFE和转铁蛋白受体2感觉身体铁水平,2)如何信号hepcidin调节铁代谢和3)如何在HFE基因突变和转铁蛋白受体2导致铁水平失调的传感和信号受损hepcidin导致增加铁的吸收在HH和肝铁过载。本研究将为HFE及其他密切相关分子在HH正常铁代谢调控和铁超载发展中的作用提供新的认识，并确定hepcidin等分子在预防和治疗铁超载方面的治疗潜力。

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.