The vast majority of patients carry the missense Cys282Tyr mutation of the HFE gene. Hepcidin, the central regulator of iron homeostasis, is deficient

in HH, leading to unchecked iron absorption and subsequent iron overload. The bone morphogenic protein (BMP)/small mothers against decapentaplegic (Smad) signaling cascade is central to the regulation of hepcidin. Recent data from HH mice models indicate that this pathway may be defective in the absence of the HFE protein. Hepatic selleck chemicals BMP/Smad signaling has not been characterized in a human HFE-HH cohort to date. Hepatic expression of BMP/Smad-related genes was examined in 20 HFE-HH males with significant iron overload, and compared to seven male HFE wild-type controls using quantitative real-time reverse transcription polymerase chain reaction. Hepatic expression of BMP6 was appropriately elevated in HFE-HH compared to controls (P = 0.02), likely related to iron overload. Despite this, no increased expression of the BMP target genes hepcidin

and Id1 was observed, and diminished phosphorylation of Smad1/Smad5/Smad8 protein relative to iron burden was found upon immunohistochemical analysis, suggesting that impaired BMP signaling occurs in HFE-HH. Furthermore, Smad6 and Smad7, inhibitors of BMP signaling, were up-regulated in HFE-HH compared to controls (P = 0.001 and P = 0.018, respectively). Conclusion: New data arising Selleckchem PF-01367338 from this study suggest that impaired BMP signaling underlies the hepcidin deficiency of HFE-HH. Moreover, the inhibitory Smads, Smad6, and Smad7 are identified as potential disruptors of this signal and, hence, contributors to the pathogenesis of this disease. (HEPATOLOGY 2010;) Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by iron overload. Unregulated iron absorption from the intestine and release from macrophages primarily affects the liver, the main storage site of this essential mineral. Left untreated, iron excess may

progress to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma.1, 2 The most common form of HH (type 1) results from the missense Cys282Tyr (C282Y) mutation of the HFE (hemochromatosis) gene. Although it is a disease of variable penetrance and considerable heterogeneity, the vast majority of patients with HH are homozygous for Resminostat the C282Y mutation.3, 4 The mutant C282Y HFE protein is unable to bind beta-2-microglobulin and fails to reach the cell membrane, resulting in a misfolded, nonfunctional protein.5 HFE represents a nonclassical major histocompatability complex type 1 molecule expressed in several different tissues. Liver-specific HFE knockout in animal models resulted in a phenotype similar to HFE-HH, suggesting the liver is where HFE exerts its main effect on iron metabolism.6, 7 Upon interacting with diferric transferrin and transferrin receptor 1 (TfR1) at the hepatocyte cell surface, HFE is thought to shift to form part of an iron-sensing complex through its interaction with TfR2.