Liver and serum iron: discrete regulators of hepatic hepcidin expression.

T o prevent pathological excesses or deficiencies, body iron balance must be tightly controlled due to the lack of a highly evolved mechanism for iron excretion. This is achieved through the liver peptide hepcidin, which efficiently regulates the processes of duodenal iron absorption, macrophage iron release and tissue iron storage, primarily in the liver. Hepcidin is released into the circulation and targets ferroportin, the iron exporter expressed on the surface of duodenal enterocytes, macrophages, and hepatocytes. The binding of hepcidin to ferroportin induces its internalization and degradation, thereby restricting iron entry from the absorptive enterocytes as well as iron release from macrophages and liver iron stores. Hence, appropriate hepcidin expression is paramount for accurate regulation of iron distribution. Indeed, impaired regulation of hepcidin synthesis caused by mutations in key upstream genes in hepcidin regulation—the classical hemochromatosis gene (HFE), transferrin receptor 2 (TFR2), hemojuvelin (HJV), or the hepcidin gene itself (HAMP)—underlies the pathogenesis of the iron overload disorder hereditary hemochromatosis (HH). HJV is a member of the repulsive guidance molecule family and a coreceptor for bone morphogenetic proteins (BMPs), implicating a role for BMP signal transduction in the transcriptional regulation of hepcidin in the liver. The signaling pathway is initiated when BMP binds to its receptors, a complex of BMP receptor (BMPR) types I and II, inducing the phosphorylation of BMPR-I by BMPR-II. This, in turn, activates phosphorylation of the intracellular small mothers against decapentaplegic homologue (SMAD) proteins SMAD1, SMAD5, and SMAD8, which then bind SMAD4, and the complex is translocated to the nucleus, promoting transcription of hepcidin. HJV has been shown to interact directly with BMP6, and their interaction facilitates activation of the BMPR complex and enhances BMP-SMAD signaling to modulate hepcidin expression. Although several BMPs including BMP2, 4, 5, 6, 7, and 9 can stimulate hepcidin expression, BMP6 is physiologically the most relevant. BMP6 is regulated by liver iron levels, increasing with iron loading and decreasing with iron depletion, inducing an up-regulation and down-regulation of Smad1/5/8 phosphorylation and HAMP expression. Studies in Bmp6 null mice have demonstrated that the absence of Bmp6 induces severe iron overload and hepcidin deficiency, highlighting the noncompensatory roles of other functional Bmps. The lack of Bmp6 resulted in inhibition of Smad1/5/8 phosphorylation and their translocation to the nucleus. In contrast, administration of exogenous Bmp6 to mice increased hepatic Hamp expression and reduced both serum iron and transferrin saturation (TS). Liverspecific Smad4 null mice also developed iron overload and impaired Bmp signaling, suppressing hepcidin production. Taken together, these observations strongly support BMP6 as the key endogenous regulator of hepcidin synthesis and iron metabolism in vivo. Recently, it was shown that inhibitory SMAD7 tempers HAMP expression by blocking the interaction of SMAD1/5/8 with SMAD4. TFR2 and HFE are thought to act as iron-sensing molecules to receive signals from circulating holotransferrin to modulate hepatic HAMP expression. TFR2 is a strong candidate as a sensor of serum TS, because it binds holotransferrin and undergoes posttranslational stabilization. As TS increases, HFE dissociates from TFR1 and binds to TFR2 to possibly convey the necessary signal downstream to stimulate hepcidin synthesis. Some studies support the premise that TFR2 and HFE interact with the BMP6–SMAD pathway, because this signaling pathway is impaired in Tfr2 and/or Hfe null mice as well as in subjects with HFE-associated HH, whereas others report no interaction. TFR2 and HFE may also signal independently of each other, because disruption of both Tfr2 and Hfe in mice causes a more severe iron overload phenotype. TFR2 and HFE, however, are likely Abbreviations:: BMP, bone morphogenetic protein; BMPR, BMP receptor; ERK1/2, extracellular signal-regulated kinases 1 and 2; HAMP, hepcidin gene; HFE, hemochromatosis gene; HH, hereditary hemochromatosis; HJV, hemojuvelin; LIC, liver iron concentration; MAPK, mitogen-activated protein kinase; SMAD, small mothers against decapentaplegic homologue; TFR2, transferrin receptor 2; TS, transferrin saturation. Address reprint requests to: John K. Olynyk, BMEDSC, MBBS, FRACP, MD, Director of Gastroenterology, Fremantle Hospital, Alma Street, Fremantle 6160, Western Australia, Australia. E-mail: [email protected]. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24449 Potential conflict of interest: Nothing to report.