Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidinJournal of Molecular Medicine

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Authors
Patricia Kent, Nicole Wilkinson, Marco Constante, Carine Fillebeen, Konstantinos Gkouvatsos, John Wagner, Marzell Buffler, Christiane Becker, Klaus Schümann, Manuela M. Santos, Kostas Pantopoulos
Year
2015
DOI
10.1007/s00109-015-1253-7
Subject
Molecular Medicine / Medicine (all) / Drug Discovery / Genetics (clinical)

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ORIGINAL ARTICLE

Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin

Patricia Kent & Nicole Wilkinson & Marco Constante & Carine Fillebeen &

Konstantinos Gkouvatsos & John Wagner & Marzell Buffler & Christiane Becker &

Klaus Schümann & Manuela M. Santos & Kostas Pantopoulos

Received: 29 October 2014 /Revised: 10 December 2014 /Accepted: 29 December 2014 # Springer-Verlag Berlin Heidelberg 2015

Abstract

Functional inactivation ofHFE or hemojuvelin (HJV) is causatively linked to adult or juvenile hereditary hemochromatosis, respectively. Systemic iron overload results from inadequate expression of hepcidin, the iron regulatory hormone.

While HJV regulates hepcidin by amplifying bone morphogenetic protein (BMP) signaling, the role of HFE in the hepcidin pathway remains incompletely understood. We investigated the pathophysiological implications of combined Hfe and

Hjv ablation in mice. Isogenic Hfe−/− and Hjv−/− mice were crossed to generate double Hfe−/−Hjv−/− progeny. Wild-type control and mutant mice of all genotypes were analyzed for serum, hepatic, and splenic iron content, expression of iron metabolism proteins, and expression of hepcidin and Smad signaling in the liver, in response to a standard or an ironenriched diet. As expected, Hfe−/− and Hjv−/−mice developed relatively mild or severe iron overload, respectively, which corresponded to the degree of hepcidin inhibition. The double

Hfe−/−Hjv−/− mice exhibited an indistinguishable phenotype to single Hjv−/− counterparts with regard to suppression of hepcidin, serum and hepatic iron overload, splenic iron deficiency, tissue iron metabolism, and Smad signaling, under both dietary regimens. We conclude that the hemochromatotic phenotype caused by disruption ofHjv is not further aggravated by combined Hfe/Hjv deficiency. Our results provide genetic evidence that Hfe and Hjv operate in the same pathway for the regulation of hepcidin expression and iron metabolism.

Key messages & Combined disruption of Hfe and Hjv phenocopies single

Hjv deficiency. & Single Hjv−/− and double Hfe−/−Hjv−/− mice exhibit comparable iron overload. & Hfe and Hjv regulate hepcidin via the same pathway.

Keywords Hemochromatosis . Iron overload . BMP/SMAD

Introduction

Hereditary hemochromatosis (HH) is a genetically heterogenous disease of systemic iron overload [1]. It is characterized by increased fluxes of iron from intestinal enterocytes and tissue macrophages to the bloodstream, which eventually leads to excessive iron accumulation within parenchymal cells. HH is caused by inadequate expression of hepcidin, a liver-derived peptide hormone. Physiologically, hepcidin is induced in response to iron or other stimuli and serves to restrict further iron fluxes from cells by binding to the iron exporter ferroportin, promoting its lysosomal degradation [2].

Patricia Kent, Nicole Wilkinson and Marco Constante contributed equally to this work.

Electronic supplementary material The online version of this article (doi:10.1007/s00109-015-1253-7) contains supplementary material, which is available to authorized users.

P. Kent :N. Wilkinson :M. Constante :C. Fillebeen :

K. Gkouvatsos : J. Wagner :K. Pantopoulos (*)

Lady Davis Institute for Medical Research, Jewish General Hospital, and Department of Medicine, McGill University, Montreal, QC,

Canada e-mail: kostas.pantopoulos@mcgill.ca

M. Constante :M. M. Santos

Centre de Recherche, Centre Hospitalier de l’Université de Montréal (CHUM), and Département de Médecine, Université de Montréal,

Montreal, QC, Canada

M. Buffler :C. Becker

Animal Nutrition Unit, Technische Universität München,

Freising-Weihenstephan, Germany

K. Schümann

Molecular Nutrition Unit, Research Center for Nutrition and Food

Science, Technische Universität München,

Freising-Weihenstephan, Germany

J Mol Med

DOI 10.1007/s00109-015-1253-7

In HH, hepcidin levels are low and cannot be appropriately adjusted to iron load, disrupting iron homeostasis.

The most prevalent type of HH is related to mutations in

HFE, which was discovered as the “hemochromatosis gene” by linkage disequilibrium studies and haplotype analysis [3].

The HFE protein is an atypical major histocompatibility complex (MHC) class I molecule and is expressed in many cell types, including hepatocytes, macrophages, and enterocytes.

Many HH patients carry a common C282Y mutation that abrogates the binding of HFE to β2-microglobulin and thus the trafficking of the complex to the cell surface [1]. Nevertheless, the clinical penetrance of this mutation depends on additional factors such as gender, race, genetic modifiers, and alcohol intake. Hfe−/− mice misregulate hepcidin expression and develop iron overload, the degree of which varies among different strains [4]. Thus, these animals recapitulate key pathophysiological and genetic aspects of HFE-related HH.

Juvenile hemochromatosis (JH) is a rare, early onset form of HH that is caused by profound hepcidin insufficiency. JH is mostly linked to pathogenic mutations in the HJV gene (also known as HFE2 or RGMC) that encodes HJV, a member of the repulsive guidance molecule (RGM) family of proteins [5]. HJV is predominantly expressed in hepatocytes and striated muscles. Hjv−/− mice constitute a model for JH as they express minuscule levels of hepcidin and develop severe iron overload [6].

HFE and HJV function as upstream regulators of iron signaling to hepcidin [6, 7]. This requires their expression in hepatocytes, as only liver-specific ablation of either Hfe [8] or Hjv [9, 10] in mice leads to iron overload. Hepcidin is transcriptionally induced in response to elevated serum or hepatic iron by apparently distinct mechanisms.

HFE has been considered as a mediator of hepcidin induction by serum iron. Early biochemical studies showed that it interacts with transferrin receptor 1 (TfR1) at the transferrin (Tf) binding site and thereby inhibits cellular iron uptake [11].