The functional link between HFE and hepcidin- its contribution to iron metabolism regulation

Tese de doutoramento, Biologia (Biologia Molecular), Universidade de Lisboa, Faculdade de Ciências, 2013

Iron is essential for several vital biological processes. Its deficiency and overload drive to the development of several pathologies. To maintain iron homeostasis, the organism controls the dietary iron absorption by enterocytes, recycling by macrophages and storage in hepatocytes. These processes are mainly controlled by hepcidin, a liver-derived hormone which synthesis is prompted by increased iron levels. It targets the iron exporter ferroportin-1, blocking iron release from cells. Hepcidin expression is regulated by HFE, on an iron-dependent manner. Besides controlling hepcidin expression in the liver, HFE seems to directly inhibit dietary iron absorption by the enterocytes. When mutated, it is responsible for the development of hereditary hemochromatosis, the most frequent iron-loading pathology. The main purpose of this work was to unveil the mechanisms responsible for HFE regulation and how they affect hepcidin expression and dietary iron absorption in normal and pathologic conditions. Here we show that HFE is target of a tissue-specific post-transcriptional regulation by alternative splicing. We identified eight alternatively spliced transcripts. Amongst them we found that the transcripts resulting from the total or partial inclusion of HFE intron 4 code for a soluble form of HFE protein (sHFE). Its expression increases with intracellular iron and it is secreted to the extracellular environment in association with its chaperone β2-microglobulin. We also found that sHFE down-regulates the expression of hephaestin in the enterocytes, an oxidase that partners ferroportin-1 in iron export from these cells.

Fundação para a Ciência e a Tecnologia (FCT, PTDC/BD/60718/2009)