Molecular basis of HFE-hemochromatosis

Abstract

Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies.

Keywords: Bmp/Smad signaling; HH; Hfe; extra-hepatic Hfe; hepcidin.

FIGURE 1

Sensing of transferrin-bound iron and regulation of hepcidin expression in hepatocytes. The iron-sensing process involves binding of transferrin-bound iron to TfR1 causing a dissociation of Hfe from the Hfe/TfR1 partnership, relocation of Hfe to TfR2 and presumably the formation of a large membrane-bound complex composed of Hfe/TfR2/Hjv and BMPRII and I. This hepatocyte-membrane complex activates transduction cascade involving the phosphorylation of the Smad1/5/8 and subsequent binding of common Smad4 protein to form a transcriptional complex which directly activates hepcidin transcription. The Bmp/Smad signaling is the central pathway for the regulation of hepcidin transcription. Lack of Hfe and other components of the membrane-bound complex severely impair the phosphorylation of Smad1/5/8 and consequently the transcription of hepcidin. Combined deficiency of Hfe and TfR2 results in decreased Erk/Mapk signaling activity in the liver, implicating that additional or parallel signaling pathway to Bmp/Smad may be involved in the control of hepatic hepcidin transcription.

FIGURE 2

Beyond the hepatocytes. The regulatory cues controlling iron metabolism are centered in the liver where hepatocytic-Hfe directs the production of the liver iron hormone hepcidin. The lack of hepatocytic-Hfe leads to inadequate production of hepcidin which results in increased iron uptake by the duodenum, iron release from macrophages into the circulation and deposition of the excess of iron in numerous tissues causing systemic iron overload (indicated by black arrows). The actions of the Hfe in extra-hepatocytic cells, such as erythroid and macrophages (indicated by grey circle), have recently been proposed suggesting for previously neglected functions of the Hfe in these cells. These selective extra-hepatocytic functions of Hfe are involved in the control of local, tissue-specific iron homeostasis however their impact on systemic iron regulation and the relevance for the Hfe-HH associated pathologies remains still to be discovered.