Document Detail


The hypoxia-inducible factor-C/EBPα axis controls ethanol-mediated hepcidin repression.
MedLine Citation:
PMID:  22869521     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Erik R Anderson; Matthew Taylor; Xiang Xue; Angelical Martin; David S Moons; M Bishr Omary; Yatrik M Shah
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-06
Journal Detail:
Title:  Molecular and cellular biology     Volume:  32     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-11     Completed Date:  2012-11-26     Revised Date:  2013-12-18    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4068-77     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / metabolism
Antimicrobial Cationic Peptides / genetics,  metabolism*
Basic Helix-Loop-Helix Transcription Factors / metabolism*
CCAAT-Enhancer-Binding Protein-alpha / genetics,  metabolism*
Cell Line
Down-Regulation
Erythropoiesis
Ethanol / metabolism*
Hepcidins
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Liver / metabolism*
Mice
Smad Proteins / metabolism
Grant Support
ID/Acronym/Agency:
CA148828/CA/NCI NIH HHS; DK095201/DK/NIDDK NIH HHS; DK34933/DK/NIDDK NIH HHS; DK47918/DK/NIDDK NIH HHS; P30 DK034933/DK/NIDDK NIH HHS; R01 CA148828/CA/NCI NIH HHS; R01 DK047918/DK/NIDDK NIH HHS; R01 DK095201/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antimicrobial Cationic Peptides; 0/Basic Helix-Loop-Helix Transcription Factors; 0/CCAAT-Enhancer-Binding Protein-alpha; 0/HAMP protein, human; 0/Hamp1 protein, mouse; 0/Hepcidins; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Smad Proteins; 0/endothelial PAS domain-containing protein 1; 3K9958V90M/Ethanol
Comments/Corrections

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