Abstract
BackgroundThe dysregulated cytokine metabolism and activity are crucial to the development of fulminant hepatic failure (FHF), and many different cytokines have been identified. However, the precise gene expression profile and their interactions association with FHF are yet to be further elucidated.MethodsIn this study, we detected the digital gene expression profile (DGEP) by high-throughput sequencing in normal and FHF mouse liver, and the candidate genes and potential targets for FHF therapy were verified. And the FHF mouse model was induced by D-Galactosamine (GalN)/lipopolysaccharide (LPS).ResultsTotally 12727 genes were detected, and 3551 differentially expressed genes (DEGs) were obtained from RNA-seq data in FHF mouse liver. In FHF mouse liver, many of those DEGs were identified as differentially expressed in metabolic process, biosynthetic process, response to stimulus and response to stress, etc. Similarly, pathway enrichment analysis in FHF mouse liver showed that many significantly DEGs were also enriched in metabolic pathways, apoptosis, chemokine signaling pathways, etc. Considering the important role of nuclear factor-kappa B (NF-κB) in metabolic regulation and delicate balance between cell survival and death, several DEGs involved in NF-κB pathway were selected for experimental validation. As compared to normal control, NF-κBp65 and its inhibitory protein IκBα were both significantly increased, and NF-κB targeted genes including tumor necrosis factor α(TNFα), inducible nitric oxide synthase (iNOS), interleukin-1β, chemokines CCL3 and CCL4 were also increased in hepatic tissues of FHF. In addition, after NF-κB was successfully pre-blocked, there were significant alteration of hepatic pathological damage and mortality of FHF mouse model.ConclusionsThis study provides the globe gene expression profile of FHF mouse liver, and demonstrates the possibility of NF-κB gene as a potential therapeutic target for FHF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0380-9) contains supplementary material, which is available to authorized users.
Highlights
Fulminant hepatic failure (FHF) is a severe, life-threatening disorder, which is characterized by a dramatic clinical syndrome resulting from massive hepatocyte death [1,2]
There is a large number of evidence showing that the dysregulated cytokine metabolism and activity are crucial to the progression of liver damage and the
Animal experiments involved in screening of differentially expressed genes (DEGs) in fulminant hepatic failure (FHF) mouse liver (Part. 1), and verification of some potential candidate genes related to the progression of FHF
Summary
Fulminant hepatic failure (FHF) is a severe, life-threatening disorder, which is characterized by a dramatic clinical syndrome resulting from massive hepatocyte death [1,2]. Expression microarrays have been applied for genome-wide expression analysis for identification of differentially expressed genes (DEGs) associated with liver injury [6]. These studies provided new information regarding gene expression patterns in FHF, interactions between genes and affected pathways may have been missed because of technical limitations. DGEP experiments often involve measuring the relative amount of mRNA expressed in two or more experimental conditions. The dysregulated cytokine metabolism and activity are crucial to the development of fulminant hepatic failure (FHF), and many different cytokines have been identified. The precise gene expression profile and their interactions association with FHF are yet to be further elucidated
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