Iron Stores Modulate Hepatic Hepcidin Expression by an <i>HFE</i>-Independent Pathway

<i>Background/Aims:</i> In <i>HFE</i>-related hereditary hemochromatosis an inappropriately low hepatic expression of the iron-regulatory peptide hepcidin (encoded by <i>HAMP</i>) has been suggested to cause iron overload. The aim of the present study was to evaluate whether the hepatic expression of <i>HAMP</i> in relation to iron stores requires <i>HFE</i> or might involve other important iron-related genes including <i>HJV</i> (encoding hemojuvelin) and <i>TFR2 </i>(encoding transferrin receptor-2). <i>Methods:</i> Using quantitative RT-PCR, the iron-dependent hepatic expression patterns of <i>HAMP</i>, <i>HJV</i>, and <i>TFR2</i> were evaluated in human and murine <i>HFE</i>-related hemochromatosis. <i>Results:</i> The overall level of hepatic <i>HAMP</i> expression in human and murine <i>HFE</i>-related hemochromatosis is impaired but can still be modulated by iron stores. Moreover, we demonstrate an <i>HFE</i>-independent correlation between the expression of <i>HAMP</i> and <i>TFR2</i> in mouse and human livers. On the other hand, a strong correlation between the hepatic expression of <i>HAMP</i> and <i>HJV</i> was only found in hemochromatosis patients and <i>Hfe</i>-deficient mice. <i>Conclusion:</i> The central pathogenetic step in <i>HFE</i>-related hemochromatosis is an impaired basal expression of <i>HAMP</i> rather than a lack of <i>HAMP</i> upregulation in response to iron stores. An <i>HFE</i>-independent pathway that seems to involve <i>TFR2</i> and <i>HJV</i> can regulate <i>HAMP</i> expression under conditions of iron overload.