HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression

Wu, Xing; Wang, Yan; Wu, Qian; Cheng, Wai Hang; Liu, Wenjing; Zhao, Yueshui; Mayeur, Claire; Schmidt, Paul; Yu, Paul B.; Wang, Fudi; Xia, Yin

doi:10.1182/blood-2014-01-552281

Cited by 112 publications

(77 citation statements)

References 35 publications

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“…Although work in vitro has demonstrated that HFE, TFR2, and HJV may form a stable complex that functions to regulate hepcidin expression through HJV (38), other data suggest that this interaction is dispensable or works through a different mechanism (39,40). To this end, recent work has demonstrated that HFE directly interacts with ALK3, stabilizing the receptor on the cell surface and helping transduce a signal for hepcidin transcriptional regulation (41). Further research will be required to fully comprehend how these proteins, as well as other effectors of BMP/SMAD signaling, work together to regulate hepcidin expression.…”

Section: Regulation Of Hepcidin Through the Bone Morphogenetic Proteimentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

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139

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Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

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Section: Regulation Of Hepcidin Through the Bone Morphogenetic Proteimentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

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139

105

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“…1 This finding is potentially of great importance in light of recent genome-wide association and adipose tissue transcriptomic studies that implicated F13A1 in human obesity.…”

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confidence: 99%

“…Myneni et al now describe a function for the A subunit synthesized during adipocyte differentiation. 1 They demonstrate that the A subunit forms an active transglutaminase that translocates to the cell surface and promotes assembly of fibronectin into extracellular matrix, which in turn causes the differentiating cells to proliferate more in response to insulin, a key differentiation agent, while slowing down differentiation and accumulation of lipid. Two experimental paradigms implicate the A subunit in these events: inhibition by a small molecule called NC9 that incorporates irreversibly into transglutaminases and a comparative study of fibroblasts cultured from mice in which the A subunit had been knocked out.…”

mentioning

confidence: 99%

How mutant HFE causes hereditary hemochromatosis

Muckenthaler¹

2014

Blood

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In this issue of Blood, Wu et al describe the molecular function of HFE, the gene most commonly mutated in hereditary hemochromatosis (HH).1 HH is the most frequent genetic disorder of the Western world. The authors show that HFE prevents ubiquitination and proteasomal degradation of bone-morphogenetic protein (BMP) receptor type I (Alk3), thereby increasing expression of this receptor on the cell surface of hepatocytes. As a consequence, transcription of the iron-hormone hepcidin is activated.

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“…This is also supported by the indistinguishable responses of single Hjv -/-and double Hfe -/-Hjv -/-mice to dietary iron loading 2 and is in line with recent biochemical data suggesting that HFE stimulates hepcidin expression by stabilizing ALK3, a type I bone morphogenetic protein receptor. 3 It is known that HJV functions as a bone morphogenetic protein coreceptor that enhances the bone morphogenetic protein signaling pathway. Residual induction of hepatic hepcidin mRNA was evident in both Hjv -/-and Hfe -/-Hjv -/-genotypes after 4-week feeding with a high-iron diet.…”

Section: Iron Regulation Of Hepcidin Through Hfe and Hjv: Common Or Dmentioning

confidence: 99%

Iron regulation of hepcidin through Hfe and Hjv: Common or distinct pathways?

Pantopoulos

2015

Hepatology

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venesection was observed in this subgroup in any endpoint, including hepatic steatosis, alanine aminotransaminase (ALT), and insulin resistance. Additionally, in our cohort, 25 (34%) and 26 (36%) subjects had NASH defined by cytokeratin (CK)18 value >275 IU/L and significant insulin resistance defined as a homeostasis model of assessment for insulin resistance >4.0 (see Table 1). Although interpretation of post-hoc analyses needs to be performed with caution, we could detect no impact of venesection on study endpoints, apart from serum ferritin, in patients with presumed NASH or insulin resistance.Biopsies were not performed at study entry or finish, limiting the ability to examine the treatment effect on histological endpoints. However, given the lack of change in any validated serum marker of liver injury (ALT, CK18, and Hepascore) or level of steatosis, as determined by magnetic resonance imaging, we feel it would be unlikely that phlebotomy would have produced a significant histological effect.The phlebotomy intervention resulted in a significantly greater reduction in serum ferritin levels in the treatment group, compared to the control population, with the intervention group undergoing a median number of seven venesections up to a maximum of 19 sessions. Despite this, only 10 of 33 subjects in the treatment group reached a target ferritin level of <45 ng/mL, with the median ferritin level at end of treatment being 111 ng/mL. This reflects the invasiveness and inconvenience of phlebotomy treatment. No dose-response relationship was observed between size of ferritin reduction or number of venesection sessions and change in endpoints over the duration of the study.In summary, our study has demonstrated phlebotomy has no significant impact on liver steatosis, liver injury, or insulin resistance across a spectrum of patients with NAFLD. As mentioned in our discussion, we agree with Ryan et al. that we have not excluded a therapeutic effect of phlebotomy on the small subgroup of NAFLD patients with histological evidence of NASH, significant hepatic iron overload, and insulin resistance. Overall, this subgroup represents a minority of subjects with NAFLD, and dedicated adequately powered randomized, controlled intervention trials examining venesection in this population remain to be performed.

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HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression

Cited by 112 publications

References 35 publications

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

How mutant HFE causes hereditary hemochromatosis

Iron regulation of hepcidin through Hfe and Hjv: Common or distinct pathways?

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