Vice versa, hepatocellular transgenic over-expression of Hfe in mice lacking endogenous Hfe resulted in significant upregulation of hepcidin and normalization of transferrin saturation and liver iron levels Schmidt et al. Collectively, these data establish hepatocytic- Hfe as the regulator of hepatic hepcidin expression and imply that regulatory cues involved in maintaining iron homeostasis are centered in the liver. The above investigations argue for the role of Hfe in hepatocytes to regulate hepcidin expression and thus iron homeostasis.
In the last couple of years first insights into to molecular mechanism coupling Hfe to hepcidin expression have begun to emerge. It is proposed that Hfe is sequestered by TfR1 protein in an iron-sensing complex located in the hepatocyte cell membrane Figure 1 Goswami and Andrews, The close interaction between Hfe and TfR1 is disrupted upon binding of circulating transferrin bound iron which binds with higher affinity to TfR1 Figure 1 Goswami and Andrews, However a direct interaction between Hfe and TfR2 could not be confirmed in vivo suggesting that TfR2 may regulate hepcidin expression in an Hfe-independent manner Schmidt and Fleming, Importantly, Hfe-mediated hepcidin expression is abolished by the loss of endogenous Hjv protein implicating for co-dependency between Hfe and the Hjv Schmidt et al.
Sensing of transferrin-bound iron and regulation of hepcidin expression in hepatocytes. In contrast to phlebotomy therapies that manipulate the excess of iron, few pilot approaches were conducted with the aim to target the defective molecular mechanisms underlying the HFE-HH. Short- and long-term hepcidin injections, or hepatic over-expression of hepcidin transgene in Hfe -deficient mice resulted in successful reconstitution of hepcidin expression to the levels present in wild type mice.
Due to severe side-effect peritoneal calcification that accompanied prolonged exogenous Bmp6 treatment in mice Corradini et al. Noteworthy, both Hfe and hepcidin are expressed in several extra-hepatic tissues e. During erythropoietic stress conditions hepcidin expression is severely hampered which in turn signals for enhanced iron absorption, iron mobilization from the stores and iron utilization by the erythron.
However a direct role of Hfe in erythroid cells and its contribution to cellular and overall iron homeostasis remains still to be confirmed. Beyond the hepatocytes. The regulatory cues controlling iron metabolism are centered in the liver where hepatocytic- Hfe directs the production of the liver iron hormone hepcidin.
The lack of hepatocytic- Hfe leads to inadequate production of hepcidin which results in increased iron uptake by the duodenum, iron release from macrophages into the circulation and deposition of the excess of iron in numerous tissues causing systemic iron overload indicated by black arrows.
The actions of the Hfe in extra-hepatocytic cells, such as erythroid and macrophages indicated by grey circle , have recently been proposed suggesting for previously neglected functions of the Hfe in these cells. These selective extra-hepatocytic functions of Hfe are involved in the control of local, tissue-specific iron homeostasis however their impact on systemic iron regulation and the relevance for the Hfe-HH associated pathologies remains still to be discovered.
Furthermore, Hfe may be involved in controlling iron homeostasis in a non-hepcidin dependent manner. It was proposed that Hfe may act to control iron release or iron uptake in cells since expression of HFE protein in HT29 human colon carcinoma cells, THP-1 cells, or in monocytes derived from HFE-HH patients inhibited iron release from the cells and resulted in increased iron accumulation without affecting iron uptake Montosi et al.
In line with this, recent in vivo studies demonstrated that Hfe actions in macrophages are not required for the control of hepatic hepcidin expression Makui et al. Surprisingly, liver macrophages Kupffer cells were not rescued by the action of the donor, wild type hepatocytic- Hfe Garuti et al. These observations bring up a tantalizing thought whether Hfe is only required for the up regulation of hepcidin in response to elevated iron levels and thus for the maintenance of cellular and systemic iron pool, or the functions of this MHC-class I like molecule may be uncoupled from the control of iron homeostasis.
Understanding distinct pathways that Hfe employs beyond the hepatocytes and beyond hepcidin regulation may leap translational medicine research in that some symptoms assigned to HH as a consequence of iron overload may be recognized appropriately and may better be treated by organ-specific therapies rather than systemic iron-depletion. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Trends Mol. Hereditary hemochromatosis is a genetic disease that alters the body's ability to regulate iron absorption. Hereditary hemochromatosis HH is a genetic disease that alters the body's ability to regulate iron absorption. If correctly diagnosed, HH is easily and effectively treated, but if untreated, it can lead to severe organ damage. Caucasians of northern European descent are at highest risk. An estimated one million people in the United States have hereditary hemochromatosis.
HH causes the body to absorb too much iron. Normally humans extract needed iron from food via the intestines. When there is an adequate amount of iron, the body reduces its absorption to avoid excessive accumulations. In a person with HH, the mechanism for regulating iron absorption is faulty and the body absorbs too much iron.
Over time - several years - this excess iron is deposited in the cells of the liver, heart, pancreas, joints and pituitary gland, leading to diseases such as cirrhosis of the liver, liver cancer, diabetes, heart disease and joint disease.
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