title: Inhibition of hepcidin transcription by growth factors.
abstract: The hepatic peptide hormone hepcidin controls the duodenal absorption of iron, its storage, and its systemic distribution. Hepcidin production is often insufficient in chronic hepatitis C and alcoholic liver disease, leading to hyperabsorption of iron and its accumulation in the liver. Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) mediate hepatic regeneration after liver injury. We examined the effect of these growth factors on hepcidin synthesis by hepatocytes. HGF and EGF treatment of primary mouse hepatocytes, as well as EGF administration in mice, suppressed hepcidin messenger RNA (mRNA) synthesis. The suppression of hepcidin by these growth factors was transcriptional, and was mediated by a direct effect of HGF and EGF on the bone morphogenetic protein (BMP) pathway regulating hepcidin synthesis. We further show that growth factors interfered with nuclear localization of activated sons of mothers against decapentaplegic (Smad) and increased the nuclear pool of the BMP transcriptional corepressor TG-interacting factor (TGIF). In a kinase screen with small-molecule kinase inhibitors, inhibitors in the PI3 kinase pathway and in the mitogen-activated ERK kinase/extracellular signal-regulated kinase (MEK/ERK) pathway prevented HGF suppression of hepcidin in primary mouse hepatocytes.
  
  
  CONCLUSIONS
  HGF and EGF suppress hepatic hepcidin synthesis, in part through PI3 kinase MEK/ERK kinase pathways which may be modulating the nuclear localization of BMP pathway transcriptional regulators including activated Smads1/5/8 and the corepressor TGIF. EGF, HGF, and possibly other growth factors that activate similar pathways may contribute to hepcidin suppression in chronic liver diseases, promote iron accumulation in the liver, and exacerbate the destructive disease processes.
authors.affiliation: Department of Pathology, University of California, Los Angeles, CA 90095-1690, USA.
authors.forename: Julia B
authors.initials: JB
authors.lastname: Goodnough
authors.forename: Emilio
authors.initials: E
authors.lastname: Ramos
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics*; D014162:Transfection
chemical_list: D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D020928:Mitogen-Activated Protein Kinases