Iron regulation of hepcidin via HFE and HJV: common or distinct pathways?
Kostas Pantopoulos
Department of Medicine, McGill University, and Lady Davis Institute for Medical Research, Jewish General Hospital 3755 Côte Ste-Catherine Road, Montreal, H3T 1E2 Quebec, Canada tel.: (514) 340-8260 ext. 5293 fax: (514) 340-7502 email: [email protected]
Keywords: hemochromatosis, hepcidin, HFE, hemojuvelin, BMP/SMAD signaling Abbreviations: HJV, hemojuvelin; BMP, bone morphogenetic protein
Supported by a grant from the Canadian Institutes for Health Research (CIHR; MOP-86514)
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27777
This article is protected by copyright. All rights reserved.
Hepatology
Mutations in the HFE or HJV genes are associated with adult or juvenile forms of hereditary hemochromatosis, respectively, a disease of systemic iron overload that is triggered by defective expression of the iron regulatory hormone hepcidin. Two recent publications examined the roles of murine Hfe and Hjv on iron signaling to hepcidin (1, 2). They address whether these genes exhibit overlapping or distinct functions on the hepcidin pathway by generating and characterizing double Hfe-/-Hjv-/- mice. The conclusions reached are seemingly contradictory, even though the experimental data are largely consistent. Both studies report that compound inactivation of Hfe and Hjv does not further aggravate iron overload and hepcidin insufficiency caused by single Hjv ablation. A plausible interpretation is that Hfe and Hjv operate in the same pathway for iron signaling to hepcidin. 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 BMP receptor (3). HJV is known to function as BMP co-receptor that enhances the BMP 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 (2). Importantly, this was driven exclusively by the profound increase in hepatic iron, as serum iron was already maximal at the basal state and was not significantly affected by the high-iron diet. Wu et al likewise investigated the responses of the mutant mice to iron (1). The mice were previously placed on an iron-deficient diet (immediately after weaning) to prevent excessive iron accumulation, and were subsequently subjected to acute iron challenge by oral gavage. This manipulation increases serum iron without affecting hepatic iron stores; thus, hepcidin induction is driven exclusively by serum iron. Under these conditions, Hjv-/- and Hfe-/-
2 Hepatology
This article is protected by copyright. All rights reserved.
Page 2 of 3
Page 3 of 3
Hepatology
Hjv-/- mice failed to mount any hepcidin response, contrary to wild type and Hfe-/- controls. The authors concluded that Hjv and Hfe play distinct roles in regulating hepcidin (1). However, this interpretation does not take into account the key finding that co-elimination of Hfe did not exacerbate the phenotype of Hjv deficiency (1, 2). Hemochromatosis is not acute, but develops over time due to unrestricted dietary iron absorption. The experimental iron loading approaches undertaken in (1, 2) are diverse but complementary, and all results are consistent with earlier work showing that hepcidin responds to hepatic and serum iron by distinct mechanisms (4). Moreover, they validate previous data with single Hfe-/- and Hjv-/- mice, showing that Hfe and Hjv are both dispensable for hepatic iron sensing, while only Hjv, but not Hfe is required for sensing of serum iron (4).
References 1. 2.
3.
4.
Wu Q, Wang H, An P, Tao Y, Deng J, Zhang Z, Shen Y, et al. HJV and HFE Play Distinct Roles in Regulating Hepcidin. Antioxid Redox Signal 2015:in press. Kent P, Wilkinson N, Constante M, Fillebeen C, Gkouvatsos K, Wagner J, Buffler M, et al. Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin. J Mol Med (Berl) 2015:in press. Wu XG, Wang Y, Wu Q, Cheng WH, Liu W, Zhao Y, Mayeur C, et al. HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression. Blood 2014;124:1335-1343. Ramos E, Kautz L, Rodriguez R, Hansen M, Gabayan V, Ginzburg Y, Roth MP, et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology 2011;53:1333-1341.
3 Hepatology
This article is protected by copyright. All rights reserved.
Kostas Pantopoulos
Department of Medicine, McGill University, and Lady Davis Institute for Medical Research, Jewish General Hospital 3755 Côte Ste-Catherine Road, Montreal, H3T 1E2 Quebec, Canada tel.: (514) 340-8260 ext. 5293 fax: (514) 340-7502 email: [email protected]
Keywords: hemochromatosis, hepcidin, HFE, hemojuvelin, BMP/SMAD signaling Abbreviations: HJV, hemojuvelin; BMP, bone morphogenetic protein
Supported by a grant from the Canadian Institutes for Health Research (CIHR; MOP-86514)
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27777
This article is protected by copyright. All rights reserved.
Hepatology
Mutations in the HFE or HJV genes are associated with adult or juvenile forms of hereditary hemochromatosis, respectively, a disease of systemic iron overload that is triggered by defective expression of the iron regulatory hormone hepcidin. Two recent publications examined the roles of murine Hfe and Hjv on iron signaling to hepcidin (1, 2). They address whether these genes exhibit overlapping or distinct functions on the hepcidin pathway by generating and characterizing double Hfe-/-Hjv-/- mice. The conclusions reached are seemingly contradictory, even though the experimental data are largely consistent. Both studies report that compound inactivation of Hfe and Hjv does not further aggravate iron overload and hepcidin insufficiency caused by single Hjv ablation. A plausible interpretation is that Hfe and Hjv operate in the same pathway for iron signaling to hepcidin. 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 BMP receptor (3). HJV is known to function as BMP co-receptor that enhances the BMP 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 (2). Importantly, this was driven exclusively by the profound increase in hepatic iron, as serum iron was already maximal at the basal state and was not significantly affected by the high-iron diet. Wu et al likewise investigated the responses of the mutant mice to iron (1). The mice were previously placed on an iron-deficient diet (immediately after weaning) to prevent excessive iron accumulation, and were subsequently subjected to acute iron challenge by oral gavage. This manipulation increases serum iron without affecting hepatic iron stores; thus, hepcidin induction is driven exclusively by serum iron. Under these conditions, Hjv-/- and Hfe-/-
2 Hepatology
This article is protected by copyright. All rights reserved.
Page 2 of 3
Page 3 of 3
Hepatology
Hjv-/- mice failed to mount any hepcidin response, contrary to wild type and Hfe-/- controls. The authors concluded that Hjv and Hfe play distinct roles in regulating hepcidin (1). However, this interpretation does not take into account the key finding that co-elimination of Hfe did not exacerbate the phenotype of Hjv deficiency (1, 2). Hemochromatosis is not acute, but develops over time due to unrestricted dietary iron absorption. The experimental iron loading approaches undertaken in (1, 2) are diverse but complementary, and all results are consistent with earlier work showing that hepcidin responds to hepatic and serum iron by distinct mechanisms (4). Moreover, they validate previous data with single Hfe-/- and Hjv-/- mice, showing that Hfe and Hjv are both dispensable for hepatic iron sensing, while only Hjv, but not Hfe is required for sensing of serum iron (4).
References 1. 2.
3.
4.
Wu Q, Wang H, An P, Tao Y, Deng J, Zhang Z, Shen Y, et al. HJV and HFE Play Distinct Roles in Regulating Hepcidin. Antioxid Redox Signal 2015:in press. Kent P, Wilkinson N, Constante M, Fillebeen C, Gkouvatsos K, Wagner J, Buffler M, et al. Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin. J Mol Med (Berl) 2015:in press. Wu XG, Wang Y, Wu Q, Cheng WH, Liu W, Zhao Y, Mayeur C, et al. HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression. Blood 2014;124:1335-1343. Ramos E, Kautz L, Rodriguez R, Hansen M, Gabayan V, Ginzburg Y, Roth MP, et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology 2011;53:1333-1341.
3 Hepatology
This article is protected by copyright. All rights reserved.
