RGD Reference Report - Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis. - Rat Genome Database

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Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis.

Authors: Xiong, S  She, H  Zhang, AS  Wang, J  Mkrtchyan, H  Dynnyk, A  Gordeuk, VR  French, SW  Enns, CA  Tsukamoto, H 
Citation: Xiong S, etal., Am J Physiol Gastrointest Liver Physiol. 2008 Sep;295(3):G512-21. doi: 10.1152/ajpgi.90327.2008. Epub 2008 Jul 3.
RGD ID: 8694397
Pubmed: PMID:18599584   (View Abstract at PubMed)
PMCID: PMC2536779   (View Article at PubMed Central)
DOI: DOI:10.1152/ajpgi.90327.2008   (Journal Full-text)

One prime feature of alcoholic liver disease (ALD) is iron accumulation in hepatic macrophages/Kupffer cells (KC) associated with enhanced NF-kappaB activation. Our recent work demonstrates a peroxynitrite-mediated transient rise in intracellular labile iron (ILI) as novel signaling for endotoxin-induced IKK and NF-kappaB activation in rodent KC. The present study investigated the mechanism of KC iron accumulation and its effects on ILI response in experimental ALD. We also tested ILI response in human blood monocytes. Chronic alcohol feeding in rats results in increased expression of transferrin (Tf) receptor-1 and hemochromatosis gene (HFE), enhanced iron uptake, an increase in nonheme iron content, and accentuated ILI response for NF-kappaB activation in KC. Ex vivo treatment of these KC with an iron chelator abrogates the increment of iron content, ILI response, and NF-kappaB activation. The ILI response is evident in macrophages derived from human blood monocytes by PMA treatment but not in vehicle-treated monocytes, and this differentiation-associated phenomenon is essential for maximal TNF-alpha release. PMA-induced macrophages load iron dextran and enhance ILI response and TNF-alpha release. These effects are reproduced in KC selectively loaded in vivo with iron dextran in mice and more importantly aggravate experimental ALD. Our results suggest enhanced iron uptake as a mechanism of KC iron loading in ALD and demonstrate the ILI response as a function acquired by differentiated macrophages in humans and as a priming mechanism for ALD.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HFEHumanAlcoholic Liver Diseases  ISOHfe (Rattus norvegicus)mRNA:increased expression:liver and Kupffer cell (rat)RGD 
HfeRatAlcoholic Liver Diseases  IEP mRNA:increased expression:liver and Kupffer cell (rat)RGD 
HfeMouseAlcoholic Liver Diseases  ISOHfe (Rattus norvegicus)mRNA:increased expression:liver and Kupffer cell (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hfe  (homeostatic iron regulator)

Genes (Mus musculus)
Hfe  (homeostatic iron regulator)

Genes (Homo sapiens)
HFE  (homeostatic iron regulator)


Additional Information