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Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis
  1. Silvia Affò1,
  2. Marlene Dominguez1,
  3. Juan José Lozano1,
  4. Pau Sancho-Bru1,
  5. Daniel Rodrigo-Torres1,
  6. Oriol Morales-Ibanez1,
  7. Montserrat Moreno1,
  8. Cristina Millán1,
  9. Aurora Loaeza-del-Castillo1,
  10. José Altamirano1,
  11. Juan Carlos García-Pagán1,
  12. Vicente Arroyo1,
  13. Pere Ginès1,
  14. Juan Caballería1,
  15. Robert F Schwabe2,
  16. Ramon Bataller1
  1. 1Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centre Esther Koplowitz, CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
  2. 2Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
  1. Correspondence to Dr Ramon Bataller, Liver Unit, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain; bataller{at}clinic.ub.es

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.

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.

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.

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.

  • Alcoholic liver disease
  • liver injury
  • microarray analysis
  • cytokines
  • fibrogenesis
  • liver
  • liver cirrhosis
  • fibrosis
  • stem cells
  • acute liver failure
  • alcohol-induced injury
  • alcohol
  • chronic liver disease
  • hepatic haemodynamics
  • portal hypertension
  • ascites
  • fluid retention in liver disease
  • hepato-renal syndrome
  • liver regeneration
  • hepatic fibrosis
  • hepatic stellate cell

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Footnotes

  • Transcript profiling: Microarray data have been deposited in NCBI's Gene Expression Omnibus (GEO; accession number GSE28619).

  • Funding This study was supported by grants from the Instituto de Salud Carlos III (FIS PI080237, FIS PS09/01164 and FIS PI080126 to RB, JC and PG, respectively). SA received a grant from IDIBAPS. PS-B was funded by the Ministerio de Ciencia e Innovación, Juan de la Cierva (JCI-2009-03849) and by the Instituto de Salud Carlos III, Miguel Servet (CP11/00071). DR-T received a grant from the Ministerio de Educación, FPU programme. MD and JA received a grant from Fundación Banco Bilbao Vizcaya Argentaria. This work was performed in Centre Esther Koplowitz (CEK).

  • Competing interests None.

  • Ethics approval Approval provided by the Ethics Committee of the Hospital Clinic of Barcelona, Spain.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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