Growth factors EGF and HGF suppress hepcidin by direct interference with bone morphogenetic protein signaling

Abstract

The iron‐regulatory hormone hepcidin is a 25‐amino‐acid peptide synthesized in the liver. Hepcidin inhibits iron export into plasma and is in turn regulated by iron through a BMP6‐activated pathway. Erythropoietic activity and certain liver diseases decrease hepcidin synthesis through unknown mechanisms.We found that hepatocyte growth factor (HGF) was a potent suppressor of hepcidin in hepatocytes and in hepatic cell lines. At physiologic concentrations, HGF dose‐dependently suppressed hepcidin mRNA and hepcidin promoter‐luciferase. HGF also opposed hepcidin induction by BMP6 in both systems. HGF was likely acting directly on BMP signaling because HGF prevented the induction of an unrelated BMP‐sensitive reporter by BMP6, as well as ‐2, ‐4, and ‐9. In primary mouse hepatocytes, BMP‐driven Smad1/5/8 nuclear translocation was suppressed by HGF. The hepatocytes displayed increased activation of the MAP kinase Erk and related phosphorylation of a regulatory motif in R‐Smads known to result in nuclear exclusion. Thus, decreased nuclear concentration of activated Smad1/5/8 is a likely mechanism of the HGF suppression of hepcidin response to BMP. EGF also suppressed the induction of hepcidin mRNA and the hepcidin‐luciferase reporter by BMPs, likely by a similar mechanism. EGF, HGF or other growth factors using MAPKs could mediate the suppression of hepcidin in chronic liver diseases.This research is supported by National Institutes of Health grant #1F30DK082151.