Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis

Abstract

Hereditary hemochromatosis (HH) is a common inherited iron overload disorder. 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 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 5 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 upregulated in HFE-HH compared to controls (P 5 0.001 and P 5 0.018, respectively). Conclusion: New data arising 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;52:1266-1273

Hepcidin expression in the liver of rats fed a magnesium-deficient diet

“…Similar results were also recently obtained in patients with hereditary haemochromatosis with mutation of the HFE gene (31) . In the liver of Fe-overloaded mice, both Hfe and Hemojuvelin expressions were increased (20) .…”

Transforming Growth Factor β1 (TGF-β1) Activates Hepcidin mRNA Expression in Hepatocytes

“…The (5,20,21). HJV was identified as a coreceptor for BMP signaling, and HFE and TfR2 act together with HJV to maintain high hepcidin levels.…”

“…It binds to the cellular iron exporter Ferroportin (Fpn) 5 to trigger its internalization and degradation (1). Hepcidin expression is regulated by several signals, including plasma iron levels, hepatic iron stores, inflammation, erythropoietic activity, and hypoxia (2).…”

“…Hepcidin expression is regulated by several signals, including plasma iron levels, hepatic iron stores, inflammation, erythropoietic activity, and hypoxia (2). Plasma iron levels and hepatic iron stores activate BMP6-ALK2/3-Smad1/5/8 signaling through a yet poorly defined mechanism to transcriptionally modulate hepcidin synthesis (3)(4)(5). Notably, hepcidin can be mildly increased upon chronic iron loading of BMP6 knock-out mice, suggesting that the BMP6 pathway does not completely account for the iron response of hepcidin (4).…”

“…Interestingly, Smad1/5/8 phosphorylation is attenuated not only in mice with HJV deficiency but also in mice and patients that lack HFE or TfR2. Therefore, it was proposed that HFE and TfR2 may form a functional complex with HJV to stimulate hepcidin expression (5,20,21). Indeed, expression of recombinant HFE, TfR2, and HJV in cultured cells reveals formation of a protein complex (22).…”