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Progesterone receptor membrane component-1 regulates hepcidin biosynthesis
Xiang Li, … , Donald B. Bloch, Randall T. Peterson
Xiang Li, … , Donald B. Bloch, Randall T. Peterson
Published December 14, 2015
Citation Information: J Clin Invest. 2016;126(1):389-401. https://doi.org/10.1172/JCI83831.
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Research Article Hematology Article has an altmetric score of 46

Progesterone receptor membrane component-1 regulates hepcidin biosynthesis

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Abstract

Iron homeostasis is tightly regulated by the membrane iron exporter ferroportin and its regulatory peptide hormone hepcidin. The hepcidin/ferroportin axis is considered a promising therapeutic target for the treatment of diseases of iron overload or deficiency. Here, we conducted a chemical screen in zebrafish to identify small molecules that decrease ferroportin protein levels. The chemical screen led to the identification of 3 steroid molecules, epitiostanol, progesterone, and mifepristone, which decrease ferroportin levels by increasing the biosynthesis of hepcidin. These hepcidin-inducing steroids (HISs) did not activate known hepcidin-inducing pathways, including the BMP and JAK/STAT3 pathways. Progesterone receptor membrane component-1 (PGRMC1) was required for HIS-dependent increases in hepcidin biosynthesis, as PGRMC1 depletion in cultured hepatoma cells and zebrafish blocked the ability of HISs to increase hepcidin mRNA levels. Neutralizing antibodies directed against PGRMC1 attenuated the ability of HISs to induce hepcidin gene expression. Inhibiting the kinases of the SRC family, which are downstream of PGRMC1, blocked the ability of HISs to increase hepcidin mRNA levels. Furthermore, HIS treatment increased hepcidin biosynthesis in mice and humans. Together, these data indicate that PGRMC1 regulates hepcidin gene expression through an evolutionarily conserved mechanism. These studies have identified drug candidates and potential therapeutic targets for the treatment of diseases of abnormal iron metabolism.

Authors

Xiang Li, David K. Rhee, Rajeev Malhotra, Claire Mayeur, Liam A. Hurst, Emily Ager, Georgia Shelton, Yael Kramer, David McCulloh, David Keefe, Kenneth D. Bloch, Donald B. Bloch, Randall T. Peterson

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Figure 3

HISs do not activate the BMP or STAT3 signaling pathway.

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HISs do not activate the BMP or STAT3 signaling pathway.
(A and B) SMAD1...
(A and B) SMAD1/5 phosphorylation (P-SMAD 1/5) and total SMAD1 (T-SMAD 1) levels in HepG2 cells exposed to vehicle (V) or BMP6 (20 ng/ml) for 2 hours and to progesterone (30 μM) or mifepristone (30 μM) for up to 24 hours. (C and D) STAT3 phosphorylation and total STAT3 levels in HepG2 cells exposed to vehicle or IL-6 (100 ng/ml) for 2 hours and to progesterone (30 μM) or mifepristone (30 μM) for up to 24 hours. Representative Western blots from 3 independent experiments are shown in A–D. (E) Treatment of HepG2 cells with BMP6 (20 ng/ml) for 24 hours increased Id1 promoter activity (BRE-luc), while treatment with progesterone (30 μM) or mifepristone (30 μM) had no effect on Id1 promoter activity. (F and G) Treatment of HepG2 cells for 24 hours with (F) BMP6 (20 ng/ml) or (G) IL-6 (100 ng/ml) increased hepcidin promoter activity nearly 15-fold and 5-fold, respectively, as measured by the hepcidin luciferase promoter assay (Hep-luc), while treatment of HepG2 cells with progesterone (30 μM) or mifepristone (30 μM) did not affect hepcidin promoter activity. Results in E–G are expressed as mean ± SEM, #P < 0.001 compared with vehicle treated, ANOVA (n = 6 per group). (H and I) qPCR for id1 and liv1 gene expression in zebrafish. Three-day-old wild-type zebrafish larvae were treated with progesterone (5 μM) or mifepristone (5 μM) for 12 hours and then lysed prior to qPCR analysis. Results are expressed as mean ± SEM (n = 4 per group).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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