| First Author | Dou X | Year | 2012 |
| Journal | Am J Pathol | Volume | 181 |
| Issue | 5 | Pages | 1702-10 |
| PubMed ID | 22982442 | Mgi Jnum | J:190120 |
| Mgi Id | MGI:5448098 | Doi | 10.1016/j.ajpath.2012.08.004 |
| Citation | Dou X, et al. (2012) Inhibition of NF-kappaB activation by 4-hydroxynonenal contributes to liver injury in a mouse model of alcoholic liver disease. Am J Pathol 181(5):1702-10 |
| abstractText | Long-term alcohol exposure sensitizes hepatocytes to tumor necrosis factor-alpha (TNF) cytotoxicity. 4-Hydroxynonenal (4-HNE) is one of the most abundant and reactive lipid peroxides. Increased hepatic 4-HNE contents present in both human alcoholics and alcohol-fed animals. In the present study, we investigated the effects of intracellular 4-HNE accumulation on TNF-induced hepatotoxicity and its potential implication in the pathogenesis of alcoholic liver disease. Male C57BL/6 mice were fed an ethanol-containing or a control diet for 5 weeks. Long-term alcohol exposure increased hepatic 4-HNE and TNF levels. Cell culture studies revealed that 4-HNE, at nontoxic concentrations, sensitized hepatocytes to TNF killing, which was associated with suppressed NF-kappaB transactivity. Further investigation demonstrated that 4-HNE prevented TNF-induced inhibitor of kappaBalpha phosphorylation without affecting upstream IkappaB kinase activity. An immunoprecipitation assay revealed that increased 4-HNE content was associated with increased formation of 4-HNE-inhibitor of kappaBalpha adduction in both 4-HNE-treated hepatocytes and in the livers of alcohol-fed mice. Prevention of intracellular 4-HNE accumulation by bezafibrate, a peroxisome proliferator-activated receptor-alpha agonist, protected hepatocytes from TNF killing via NF-kappaB activation. Supplementation of N-acetylcysteine, a glutathione precursor, conferred a protective effect on alcohol-induced liver injury in mice, was associated with decreased hepatic 4-HNE formation, and improved hepatic NF-kappaB activity. In conclusion, increased 4-HNE accumulation represents a potent and clinically relevant sensitizer to TNF-induced hepatotoxicity. These data support the notion that removal of intracellular 4-HNE can serve as a potential therapeutic option for alcoholic liver disease. |
