PUBLICATION
Progesterone receptor membrane component-1 regulates hepcidin biosynthesis
- Authors
- Li, X., Rhee, D.K., Malhotra, R., Mayeur, C., Hurst, L.A., Ager, E., Shelton, G., Kramer, Y., McCulloh, D., Keefe, D., Bloch, K.D., Bloch, D.B., Peterson, R.T.
- ID
- ZDB-PUB-151216-16
- Date
- 2016
- Source
- The Journal of Clinical Investigation 126(1): 389-401 (Journal)
- Registered Authors
- Li, Xiang, Peterson, Randall
- Keywords
- none
- MeSH Terms
-
- Mice
- Androstanols/pharmacology
- Hepcidins/biosynthesis*
- Hepcidins/genetics
- Gene Expression Regulation
- Signal Transduction
- Female
- Progesterone/pharmacology
- Zebrafish
- STAT3 Transcription Factor/physiology
- Humans
- Mifepristone/pharmacology
- Hep G2 Cells
- Membrane Proteins/physiology*
- Receptors, Progesterone/physiology*
- Animals
- Bone Morphogenetic Proteins/physiology
- Cation Transport Proteins/analysis
- Cation Transport Proteins/genetics
- PubMed
- 26657863 Full text @ Journal of Clin. Invest.
Citation
Li, X., Rhee, D.K., Malhotra, R., Mayeur, C., Hurst, L.A., Ager, E., Shelton, G., Kramer, Y., McCulloh, D., Keefe, D., Bloch, K.D., Bloch, D.B., Peterson, R.T. (2016) Progesterone receptor membrane component-1 regulates hepcidin biosynthesis. The Journal of Clinical Investigation. 126(1):389-401.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping