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The small molecule, genistein, increases hepcidin expression in human hepatocytes

Zhen, Aileen W, Nguyen, Nancy H, Gibert, Yann, Motola, Shmulik, Buckett, Peter, Wessling-Resnick, Marinne, Fraenkel, Ernest and Fraenkel, Paula G 2013, The small molecule, genistein, increases hepcidin expression in human hepatocytes, Hepatology, vol. 58, no. 4, pp. 1315-1325.

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Title The small molecule, genistein, increases hepcidin expression in human hepatocytes
Author(s) Zhen, Aileen W
Nguyen, Nancy H
Gibert, Yann
Motola, Shmulik
Buckett, Peter
Wessling-Resnick, Marinne
Fraenkel, Ernest
Fraenkel, Paula G
Journal name Hepatology
Volume number 58
Issue number 4
Start page 1315
End page 1325
Total pages 11
Publisher John Wiley & Sons
Place of publication Hoboken, N. J.
Publication date 2013
ISSN 0270-9139
1527-3350
Keyword(s) Small molecule
Genistien
Hepcidin expression
Summary Hepcidin, a peptide hormone that decreases intestinal iron absorption and macrophage iron release, is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. Endogenous stimulants of Hepcidin transcription include bone morphogenic protein 6 (BMP6) and interleukin-6 (IL-6) by effects on mothers against decapentaplegic homolog (Smad)4 or signal transducer and activator of transcription (Stat)3, respectively. We conducted a small-scale chemical screen in zebrafish embryos to identify small molecules that modulate hepcidin expression. We found that treatment with the isoflavone, genistein, from 28-52 hours postfertilization in zebrafish embryos enhanced Hepcidin transcript levels, as assessed by whole-mount in situ hybridization and quantitative real-time reverse-transcriptase polymerase chain reaction. Genistein's stimulatory effect was conserved in human hepatocytes: Genistein treatment of HepG2 cells increased both Hepcidin transcript levels and promoter activity. We found that genistein's effect on Hepcidin expression did not depend on estrogen receptor signaling or increased cellular iron uptake, but was impaired by mutation of either BMP response elements or the Stat3-binding site in the Hepcidin promoter. RNA sequencing of transcripts from genistein-treated hepatocytes indicated that genistein up-regulated 68% of the transcripts that were up-regulated by BMP6; however, genistein raised levels of several transcripts involved in Stat3 signaling that were not up-regulated by BMP6. Chromatin immunoprecipitation and ELISA experiments revealed that genistein enhanced Stat3 binding to the Hepcidin promoter and increased phosphorylation of Stat3 in HepG2 cells. Conclusion: Genistein is the first small-molecule experimental drug that stimulates Hepcidin expression in vivo and in vitro. These experiments demonstrate the feasibility of identifying and characterizing small molecules that increase Hepcidin expression. Genistein and other candidate molecules may subsequently be developed into new therapies for iron overload syndromes.
Language eng
Field of Research 060601 Animal Physiology - Biophysics
Socio Economic Objective 920105 Digestive System Disorders
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2013, John Wiley & Sons
Persistent URL http://hdl.handle.net/10536/DRO/DU:30058922

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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Created: Tue, 10 Dec 2013, 11:13:12 EST by Jane Moschetti

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