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Nuclear factor ?B up-regulation of CCAAT/enhancer-binding protein ? mediates hepatocyte resistance to tumor necrosis factor ? toxicity.

ABSTRACT: The sensitization of hepatocytes to cell death from tumor necrosis factor ? (TNF?) underlies many forms of hepatic injury, including that from toxins. Critical for hepatocyte resistance to TNF? toxicity is activation of nuclear factor ?B (NF-?B) signaling, which prevents TNF?-induced death by the up-regulation of protective proteins. To further define the mechanisms of hepatocyte sensitization to TNF? killing, immunoblot analysis comparing livers from mice treated with lipopolysaccharide (LPS) alone or LPS together with the hepatotoxin galactosamine (GalN) was performed to identify TNF?-induced protective proteins blocked by GalN. Levels of CCAAT/enhancer-binding protein ? (C/EBP?) were increased after LPS treatment but not GalN/LPS treatment. In a nontransformed rat hepatocyte cell line, TNF?-induced increases in C/EBP? protein levels were dependent on NF-?B-mediated inhibition of proteasomal degradation. Pharmacological inhibition of c-Jun N-terminal kinase (JNK) did not affect C/EBP? degradation, indicating that the process was JNK-independent. C/EBP? functioned to prevent cell death as adenoviral C/EBP? overexpression blocked TNF?-induced apoptosis in cells sensitized to TNF? toxicity by NF-?B inhibition. C/EBP? inhibited TNF?-induced caspase 8 activation and downstream mitochondrial cytochrome c release and caspase 3 and caspase 7 activation. Studies in primary hepatocytes from c/ebp?(-/-) mice confirmed that loss of C/EBP? increased death from TNF?. c/ebp?(-/-) mice were also sensitized to liver injury from a nontoxic dose of LPS or TNF?. The absence of jnk2 failed to reverse the GalN-induced block in C/EBP? induction by LPS, again demonstrating that C/EBP? degradation was JNK-independent.C/EBP? is up-regulated by TNF? and mediates hepatocyte resistance to TNF? toxicity by inhibiting caspase-dependent apoptosis. In the absence of NF-?B signaling, proteasomal degradation of C/EBP? is increased by a JNK-independent mechanism and promotes death from TNF?.

SUBMITTER: Wang Y

PROVIDER: S-EPMC2991433 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Nuclear factor κB up-regulation of CCAAT/enhancer-binding protein β mediates hepatocyte resistance to tumor necrosis factor α toxicity.

Wang Yongjun Y Singh Rajat R Xiang Youqing Y Greenbaum Linda E LE Czaja Mark J MJ

Hepatology (Baltimore, Md.) 20101026 6

<h4>Unlabelled</h4>The sensitization of hepatocytes to cell death from tumor necrosis factor α (TNFα) underlies many forms of hepatic injury, including that from toxins. Critical for hepatocyte resistance to TNFα toxicity is activation of nuclear factor κB (NF-κB) signaling, which prevents TNFα-induced death by the up-regulation of protective proteins. To further define the mechanisms of hepatocyte sensitization to TNFα killing, immunoblot analysis comparing livers from mice treated with lipopol ...[more]

PMID: 20979051

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Project description:AIM:To uncover the role of hepatocyte nuclear factor 4 alpha (HNF4?) in regulating hepatic expression of microRNAs. METHODS:Microarray and real-time PCR were used to determine hepatic expression of microRNAs in young-adult mice lacking Hnf4? expression in liver (Hnf4?-LivKO). Integrative genomics viewer software was used to analyze the public chromatin immunoprecipitation-sequencing datasets for DNA-binding of HNF4?, RNA polymerase-II, and histone modifications to loci of microRNAs in mouse liver and human hepatoma cells. Dual-luciferase reporter assay was conducted to determine effects of HNF4? on the promoters of mouse and human microRNAs as well as effects of microRNAs on the untranslated regions (3'UTR) of two genes in human hepatoma cells. RESULTS:Microarray data indicated that most microRNAs remained unaltered by Hnf4? deficiency in Hnf4?-LivKO mice. However, certain liver-predominant microRNAs were down-regulated similarly in young-adult male and female Hnf4?-LivKO mice. The down-regulation of miR-101, miR-192, miR-193a, miR-194, miR-215, miR-802, and miR-122 as well as induction of miR-34 and miR-29 in male Hnf4?-LivKO mice were confirmed by real-time PCR. Analysis of public chromatin immunoprecipitation-sequencing data indicates that HNF4? directly binds to the promoters of miR-101, miR-122, miR-194-2/miR-192 and miR-193, which is associated with histone marks of active transcription. Luciferase reporter assay showed that HNF4? markedly activated the promoters of mouse and human miR-101b/miR-101-2 and the miR-194/miR-192 cluster. Additionally, miR-192 and miR-194 significantly decreased activities of luciferase reporters for the 3'UTR of histone H3F3 and chromodomain helicase DNA binding protein 1 (CHD1), respectively, suggesting that miR-192 and miR-194 might be important in chromosome remodeling through directly targeting H3F3 and CHD1. CONCLUSION:HNF4? is essential for hepatic basal expression of a group of liver-enriched microRNAs, including miR-101, miR-192, miR-193a, miR-194 and miR-802, through which HNF4? may play a major role in the post-transcriptional regulation of gene expression and maintenance of the epigenome in liver.

Dataset Information

Nuclear factor ?B up-regulation of CCAAT/enhancer-binding protein ? mediates hepatocyte resistance to tumor necrosis factor ? toxicity.

Publications

Nuclear factor κB up-regulation of CCAAT/enhancer-binding protein β mediates hepatocyte resistance to tumor necrosis factor α toxicity.

Similar Datasets

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