title: The hypoxia-inducible factor-C/EBPα axis controls ethanol-mediated hepcidin repression.
abstract: Hepcidin is a liver-derived peptide hormone and the master regulator of systemic iron homeostasis. Decreased hepcidin expression is a common feature in alcoholic liver disease (ALD) and in mouse models of ethanol loading. Dysregulation of hepcidin signaling in ALD leads to liver iron deposition, which is a major contributing factor to liver injury. The mechanism by which hepcidin is regulated following ethanol treatment is unclear. An increase in liver hypoxia was observed in an acute ethanol-induced liver injury model. The hypoxic response is controlled by a family of hypoxia-inducible transcription factors (HIFs), which are composed of an oxygen-regulated alpha subunit (HIFα) and a constitutively present beta subunit, aryl hydrocarbon receptor nuclear translocator (HIFβ/Arnt). Disruption of liver HIF function reversed the repression of hepcidin following ethanol loading. Mouse models of liver HIF overexpression demonstrated that both HIF-1α and HIF-2α contribute to hepcidin repression in vivo. Ethanol treatment led to a decrease in CCAAT-enhancer-binding protein alpha (C/EBPα) protein expression in a HIF-dependent manner. Importantly, adenoviral rescue of C/EBPα in vivo ablated the hepcidin repression in response to ethanol treatment or HIF overexpression. These data provide novel insight into the regulation of hepcidin by hypoxia and indicate that targeting HIFs in the liver could be therapeutic in ALD.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Anderson
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.forename: Angelical
authors.initials: A
authors.lastname: Martin
authors.forename: David S
authors.initials: DS
authors.lastname: Moons
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D004920:Erythropoiesis; D000431:Ethanol / Q000378:metabolism*; D064451:Hepcidins; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D051785:Smad Proteins / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D023181:Antimicrobial Cationic Peptides; D051792:Basic Helix-Loop-Helix Proteins; D022763:CCAAT-Enhancer-Binding Protein-alpha; D000431:Ethanol; D064451:Hepcidins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051785:Smad Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C578702:HAMP protein, human; C579599:Hamp protein, mouse