Iron regulation of hepcidin through Hfe and Hjv: Common or distinct pathways?
Authors: Kostas Pantopoulos
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: Mutations in the high iron HFE or hemojuvelin (HJV) gene are associated with the adult or juvenile form 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 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 loading2 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.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 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–/–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 coelimination of Hfe did not exacerbate the phenotype of Hjv deficiency.1 Hemochromatosis is not acute but develops over time due to unrestricted dietary iron absorption. The experimental iron‐loading approaches undertaken by Wu et al.1 and Kent et al.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