[Synergistic action of 4-hydroxynonenal and tumor necrosis factor involving the NF-kB/IkBa signaling pathway in alcohol-induced liver injury].
Zhonghua Gan Zang Bing Za Zhi
; 21(10): 747-52, 2013 Oct.
Article
em Zh
| MEDLINE
| ID: mdl-24331632
ABSTRACT
OBJECTIVE:
To investigate the effects and mechanism of intracellular 4-hydroxynonenal (4-HNE) accumulation on tumor necrosis factor (TNF)-induced hepatotoxicity in alcoholic liver disease (ALD).METHODS:
An ALD model was established in male C57BL/6 mice (6-8 weeks old) by feeding an ethanol-containing diet for 5 weeks; mice given regular (non-ethanol) diet served as controls. ALD-related changes in 4-HNE and TNF levels were detected by western blotting. The underlying mechanisms of this molecular effect were examined by pre-treating HepG2 cells with 4-HNE followed by exposure to various concentrations of TNF. Effects on cell death were evaluated by MTT assay. Effects on TNF-mediated upstream factors' expression were detected by ELISA, western blotting, and real-time PCR. Effects on the TNF-induced inhibitor of NF-kB (IkBa) activity (phosphorylation status) and its formation of adducts were detected by western blotting and immunoprecipitation.RESULTS:
ALD mice showed increased hepatic 4-HNE and TNF levels, and the increases were associated with extent of liver injury. Cell culture studies revealed that 4-HNE, at non-toxic concentrations, sensitized hepatocytes to TNF killing, which was associated with suppressed NF-kB trans activity. Furthermore, 4-HNE prevented phosphorylation of IkBa without affecting upstream IkB kinase activity. The ALD-enhanced 4-HNE content was found to associated with increased formation of 4-HNE-IkBa adduction for both the 4-HNE - treated hepatocytes in culture and in the livers of ALD mice.CONCLUSION:
Alcohol-induced increase in 4-HNE accumulation represents a potent and clinically relevant mechanism of sensitizing hepatocytes to TNF-induced toxicity. These data support the notion that decreasing or eliminating accumulated intracellular 4-HNE can serve as a potential therapeutic option for ALD.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Fator de Necrose Tumoral alfa
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Aldeídos
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Hepatopatias Alcoólicas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
Zh
Revista:
Zhonghua Gan Zang Bing Za Zhi
Ano de publicação:
2013
Tipo de documento:
Article