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Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis.
- Source :
-
Gut [Gut] 2013 Mar; Vol. 62 (3), pp. 452-60. Date of Electronic Publication: 2012 May 25. - Publication Year :
- 2013
-
Abstract
- Objective: Alcoholic hepatitis (AH) is a severe clinical condition that needs novel therapies. The identification of targets for therapy is hampered by the lack of animal models of advanced AH. The authors performed a translational study through a transcriptome analysis in patients with AH to identify new molecular targets.<br />Design: Hepatic gene expression profiling was assessed by DNA microarray in patients with AH (n=15) and normal livers (n=7). Functional analysis was assessed by gene set enrichment analysis. Quantitative PCR was performed in patients with AH (n=40), hepatitis C (n=18), non-alcoholic steatohepatitis (n=20) and in mouse models of acute and chronic liver injury. Protein expression was assessed by immunohistochemistry and western blotting.<br />Results: Gene expression analysis showed 207 genes >5-fold differentially expressed in patients with AH and revealed seven pathways differentially regulated including 'cytokine-cytokine receptor interaction'. Several tumour necrosis factor (TNF) superfamily receptors, but not ligands, were overexpressed in AH. Importantly, Fn14 was the only TNF superfamily receptor exclusively upregulated in AH compared with other liver diseases and correlated with both 90-day mortality and severity of portal hypertension. Fn14 protein expression was detected in areas of fibrogenesis and in a population of hepatocytes. Fn14 expression was increased in experimental models of liver injury and was detected in progenitor cells.<br />Conclusion: Translational research revealed that TNF superfamily receptors are overexpressed in AH. Fn14, the receptor for TNF-like weak inducer of apoptosis, is selectively upregulated in patients with AH. TNF superfamily receptors could represent a potential target for therapy.
- Subjects :
- Animals
Blotting, Western
Cluster Analysis
Cytokines genetics
Cytokines metabolism
Female
Gene Expression Profiling
Hepatitis, Alcoholic drug therapy
Humans
Immunohistochemistry
Male
Mice
Mice, Inbred C57BL
Microarray Analysis
Middle Aged
Molecular Targeted Therapy
Prognosis
Prospective Studies
Real-Time Polymerase Chain Reaction
Receptors, Tumor Necrosis Factor metabolism
Signal Transduction
TWEAK Receptor
Up-Regulation
Gene Expression Regulation physiology
Hepatitis, Alcoholic genetics
Receptors, Tumor Necrosis Factor genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 62
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 22637703
- Full Text :
- https://doi.org/10.1136/gutjnl-2011-301146