Iron Regulation of Hepcidin Despite Attenuated Smad1,5,8 Signaling in Mice Without Transferrin Receptor 2 or Hfe

Elena Corradini,Molly Rozier,Delphine Meynard,Adam Odhiambo,Herbert Y Lin,Qi Feng,Mary C Migas,Robert S Britton,Jodie L Babitt,Robert E Fleming

doi:10.1053/j.gastro.2011.06.077

Elena Corradini, Molly Rozier + Show 8 more

Open Access

https://doi.org/10.1053/j.gastro.2011.06.077

Copy DOI

Abstract

HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes. Hepatic iron concentrations and messenger RNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad)1,5,8 and Id1 messenger RNA levels were measured as markers of Bmp/Smad signaling. Whereas Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also showed attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. These observations show that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via the Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver Bmp6 messenger RNA or steady-state P-Smad1,5,8 levels.

Highlights

BACKGROUND & AIMSHFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression
In Tfr[2] mice and Hfe/Tfr[2] mice, hepcidin up-regulation occurred without an increase in liver P-Smad[1,5,8] levels. These results indicate that Hfe and Tfr[2] are each necessary for normal signaling from Bmp[6] to hepcidin, that each can influence hepcidin expression independent of the other, and that mechanisms regulating hepcidin expression in response to dietary iron exist that do not require Hfe or Tfr[2]
Hepatic nonheme iron concenFigure 1. trations were measured in wild-type mice and murine models of hemochromatosis (Hfe, Tfr[2], and Hfe/Tfr2) on a standard iron diet (270 ppm iron)

Summary

Introduction

BACKGROUND & AIMSHFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/ Smad[1,5,8] pathway using mice with targeted disruption of Tfr[2], Hfe, or both genes. METHODS: Hepatic iron concentrations and messenger RNA expression of Bmp[6] and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in PSmad[1,5,8] levels in response to dietary iron loading. Mice with combined loss of Hfe and Tfr[2] up-regulate hepcidin in response to dietary iron loading without increases in liver Bmp[6] messenger RNA or steadystate P-Smad[1,5,8] levels

Objectives

Methods

Results

Conclusion