Almost all organisms need iron for vital functions, such as oxygen transport, energy production and DNA synthesis. However, in the event of iron excess, free iron appears that induces the formation of free radicals, which in turn cause oxidative stress to the cell. Hereditary hemochromatosis (HH) is a common disorder in which absorption of iron in the small intestine is disproportionally high, leading to the accumulation of the metal in different organs, mainly in the liver, pancreas and heart. In the absence of treatment, iron overload leads to organ damage which may become irreversible and reduce life expectancy. Common complications include liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis and cardiomyopathy. Several genes may be mutated in HH patients, the most common being mutations in the HFE gene, but also in HJV, HAMP, TFR2 and SLC40A1. In the first part of this thesis the expression profiles of recently identified genes related with iron metabolism were elucidated. HJV mRNA and protein were present in the skeletal muscle, heart and liver of mice. In humans, HJV mRNA was expressed in the same locations. Neogenin, a protein which interacts with HJV, had a very wide expression profile in mice, with the highest levels in reproductive organs. In the second part of this thesis we induced iron overload in mice by feeding them an iron-supplemented diet. We studied the expression of genes in the heart and skeletal muscle of these mice. Iron excess affected the expression of myosin and actin genes, pivotal for the physiology of muscle tissue. Interestingly, some transcription factors and enzymes regulated in these mice could have a connection with the development of insulin resistance and cardiac complications. In the third part, the tissues studied were liver and duodenum and, in addition to the mouse model of dietary iron overload, we used mice with disrupted HFE gene, a model of HH. The iron diet affected the expression of genes in response to oxidative stress in both tissues. In the liver, additionally, some affected genes may be connected with liver hyperplasia and the development of hepatocellular carcinoma. The lack of HFE gene, on the other hand, induced the expression of many genes associated with response to injury or inflammation in the liver. In the duodenum, many genes of digestive enzymes were induced. This study revealed genes whose regulation under iron overload in mice may explain the connection between iron excess in the organism and the pathogenesis associated with it. Based on our results, future studies on the function of these genes in humans in relation with iron metabolism will help understand better the pathogenesis of iron overload.
