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

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.

Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis

“…High SPINK1 expression was observed after partial hepatectomy in mice, concurrent with hepatocyte proliferation and Kupffer cell activation. Consistent with the up-regulation of Fn14 reported in AH [50], we observed a significantly higher gene expression in improvers compared to nonimprovers. The interaction between Fn14 and TWEAK is important to promote LPC expansion and liver regeneration, as reported in animal studies [24,51].…”

PREP1 deficiency downregulates hepatic lipogenesis and attenuates steatohepatitis in mice

“…Whether PREP1 itself or nearby loci affect lipid metabolism or are implicated in NAFLD in humans remains to be clarified. Current evidence indicates that PREP1 expression is increased in patients with alcoholic steatohepatitis, supporting the hypothesis that PREP1 may also have a role in humans [44].…”

Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

“…In this regard, a recent study demonstrated that CREB3, another transmembrane bZIP transcription factor closely related to CREBH, activates apoA-IV transcription upon overexpression ( 46 ). It would GSE48452, GSE37031, and GSE28619) (31)(32)(33)(34). ApoA-IV is a 46 kDa glycoprotein (43 kDa for mouse) that has been implicated in multiple metabolic functions ( 14,35 ).…”