Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis.
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.


METHODS
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.


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.


CONCLUSIONS
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.
Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz, CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
Silvia
S
Affò
Marlene
M
Dominguez
Juan José
JJ
Lozano
Pau
P
Sancho-Bru
Daniel
D
Rodrigo-Torres
Oriol
O
Morales-Ibanez
Montserrat
M
Moreno
Cristina
C
Millán
Aurora
A
Loaeza-del-Castillo
José
J
Altamirano
Juan Carlos
JC
García-Pagán
Vicente
V
Arroyo
Pere
P
Ginès
Juan
J
Caballería
Robert F
RF
Schwabe
Ramon
R
Bataller
D000818:Animals; D015153:Blotting, Western; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D006519:Hepatitis, Alcoholic / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011379:Prognosis; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000074050:TWEAK Receptor; D015854:Up-Regulation
D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse