Hepcidin is the principal
iron regulatory
hormone, controlling the systemic absorption and remobilization of
iron from intracellular stores. The expression of the
hepcidin gene, HAMP, is increased in patients with
anemia of
chronic disease. Previously, the synthetic compound K7174 was identified through chemical screening as a novel inhibitor of the adhesion of monocytes to
cytokine-stimulated endothelial cells. K7174 also ameliorated
anemia induced by inflammatory
cytokines in mice, which suggests a possible involvement of
hepcidin regulation. The present study was performed to assess the impact of K7174 on
hepcidin expression in a human
hematoma cell line and in mice in vivo. We first demonstrated that K7174 treatment in HepG2 cells significantly decreased HAMP expression. Then, we conducted microarray analysis to determine the molecular mechanism by which K7174 inhibits HAMP expression. Transcriptional profiling confirmed the downregulation of HAMP. Surprisingly, we found that K7174 strongly induced GDF15, known as a negative regulator of HAMP expression. Western blotting analysis as well as ELISA confirmed the induction of GDF15 by K7174 treatment. Furthermore, K7174-mediated HAMP suppression was rescued by the silencing of GDF15 expression. Interestingly, we found that K7174 also upregulates CEBPB. Promoter analysis and
chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15. Subsequently, we also examined whether K7174 inhibits
hepcidin expression in mice. Quantitative RT-PCR analysis with liver samples from K7174-treated mice demonstrated significant upregulation of Gdf15 and downregulation of Hamp expression, as compared to control mice. Furthermore, serum
hepcidin concentration was also significantly decreased in K7174-treated mice. In conclusion, K7174 inhibits
hepcidin expression partly by inducing GDF15.
K-7174 may be a potential therapeutic option to treat
anemia of
chronic disease.