title: Progesterone receptor membrane component-1 regulates hepcidin biosynthesis.
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.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: David K
authors.initials: DK
authors.lastname: Rhee
authors.forename: Rajeev
authors.initials: R
authors.lastname: Malhotra
authors.forename: Claire
authors.initials: C
authors.lastname: Mayeur
authors.forename: Liam A
authors.initials: LA
authors.lastname: Hurst
authors.forename: Emily
authors.initials: E
authors.lastname: Ager
authors.forename: Georgia
authors.initials: G
authors.lastname: Shelton
authors.forename: Yael
authors.initials: Y
authors.lastname: Kramer
authors.forename: David
authors.initials: D
authors.lastname: McCulloh
authors.forename: David
authors.initials: D
authors.lastname: Keefe
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Donald B
authors.initials: DB
authors.lastname: Bloch
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
mesh_terms: D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D027682:Cation Transport Proteins / Q000032:analysis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D064451:Hepcidins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D015027:Zebrafish; D000098742:Ferroportin
chemical_list: D000732:Androstanols; D019485:Bone Morphogenetic Proteins; D027682:Cation Transport Proteins; D064451:Hepcidins; D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor; D000098742:Ferroportin; D015735:Mifepristone; D011374:Progesterone; C002976:epitiostanol