Dataset Information

Alcohol-associated hepatitis induces hepatocyte senescence which is reduced following disease resolution

ABSTRACT: Background & Aims: Alcohol-associated hepatitis (AH) is an acute form of alcohol-related liver disease (ArLD) with high mortality rate. AH is histologically characterised by cellular processes including steatosis, inflammation and cell death. Apoptosis is the most studied form of cell death in AH; however, the role of cellular senescence, another response to cellular injury, in AH is unknown. Here we aim to explore the mechanisms of ArLD pathophysiology and define the role of senescence in AH. Methods: We performed RNA sequencing and bioinformatics analysis of transjugular liver biopsies (n=65) from AH patients participating in the ISAIAH clinical trial. We also carried out multiomic analysis of an in vitro hepatocyte model of AH. We also performed additional bioinformatics reanalysis of existing AH transcriptomic datasets. Results: Senescence markers and pathways are increasingly expressed in hepatocytes as ArLD progresses towards AH. We find dysregulation of senescence, inflammation and hepatocyte function is reversed at transcriptomic level following AH resolution. We identify dysregulation of two senescence-associated protein complexes, cytochrome c oxidase and the proteasome, which may act as senescence-induction mechanisms. Our in vitro model reveals senescence induction is a direct effect of ethanol on hepatocytes. Conclusions: Our results show a central role for senescence in AH and suggest senolytics as potential therapeutics in early ALD to limit AH severity.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Liver

SUBMITTER: Alex von Kriegsheim

LAB HEAD: Stuart Forbes

PROVIDER: PXD053109 | Pride | 2025-08-25

REPOSITORIES: Pride

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Publications

Longitudinal paired liver biopsies and transcriptome profiling in alcohol-associated hepatitis reveal dynamic changes in cellular senescence.

Rodrigo-Torres Daniel D Kilpatrick Alastair M AM Ferreira-Gonzalez Sofia S Aird Rhona E RE Atkinson Stephen Rahul SR Gadd Victoria L VL Man Tak Yung TY Tyson Luke D LD Dhondalay Gopal Krishna R GKR Vergis Nikhil N Arteel Gavin E GE Thursz Mark R MR Martinez-Gili Laura L Forbes Stuart J SJ

Gut 20250807 9

<h4>Background and aims</h4>Alcohol-associated hepatitis (AH) is an acute form of alcohol-related liver disease (ALD) with high mortality rate. AH is histologically characterised by cellular processes, including steatosis, inflammation and cell death. Apoptosis is the most studied form of cell death in AH; however, the role of cellular senescence, another response to cellular injury, in AH is unknown. Here, we explore the mechanisms of ALD pathophysiology and describe the role of senescence in A ...[more]

PMID: 40122595

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Project description:BACKGROUND: Alcohol-related liver disease ranges from silent alcoholic steatohepatitis (sASH), an asymptomatic and compensated phenotype, to life- threatening alcoholic hepatitis (AH). A systematic comparative study of the clinical, histological and molecular features of these subtypes is lacking. METHODS : Two large cohorts of patients were recruited in an international, observational multi-center study: a retrospective cohort of patients with sASH (n=110) and a prospective cohort of patients with AH (two subgroups with n=121 and 104). sASH and AH were compared by doing clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis. FINDINGS: Age and mean alcohol intake were similar in patients with sASH vs AH. AH showed lower mean arterial pressure than sASH. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma- glutamyl transferase levels than AH. Individuals with AH demonstrated profound liver failure, lower blood pressure and increased mortality. Histologically, the grade of steatosis, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and progenitor cell expansion were more frequent among AH patients. One-year mortality was 10% in sASH and 50% in AH. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. Globally, AH patients exhibited changes in 4,921 genes, while the number of dysregulated genes in sASH patients was less pronounced -1,327-. While sASH was characterized by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. INTERPRETATION: Despite comparable daily alcohol intake, AH patients presented with worse liver function and hemodynamic status compared to sASH. Bilirubinostasis, severe fibrosis and progenitor cell expansion were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared to sASH.

Project description:Background & aims: The role of microRNAs (miRNAs) in Alcoholic Hepatitis (AH) and their potential as therapeutic targets in liver disease has not been explored yet. This study aims at profiling miRNA in AH and identifying dysregulated miRNAs involved in AH pathophysiology. Methods: miRNA expression arrays were performed in 13 AH, 5 alcohol liver disease-induced cirrhosis (ALD-CH), 5 nonalcoholic steatohepatitis induced cirrhosis (NASH-CH), 4 HCV-induced cirrhosis (HCV-CH) and 6 non-injured liver control samples. Genome wide expression profile was retrieved for 12 paired AH and control samples. MiRNA and mRNA expression data was integrated and identified miRNAs were validated in AH samples and in animal models of liver injury. Results:Â The miRNA array showed 111 upregulated and 66 downregulated miRNAs in AH versus healthy subjects. The comparison of miRNA profile in liver samples from AH among ALD-CH, HCV-CH and NASH-CH identified 18 miRNAs specifically dysregulated in AH. Integrative miRNA and mRNA analysis in AH identified dysregulated miRNAs for which their target genes were also dysregulated. A functional analysis of identified miRNAs and their targets revealed their involvement in the regulation of canonical pathways related to apoptosis, fatty acid metabolism and cell cycle among others. miRNAs expression (miR-182, miR-21, miR-155, miR-214, miR-432, miR-422a) was validated in an independent cohort of AH. MiR-182 expression correlated with cholestasis, disease severity and short-term mortality. Moreover, miR-182 expression is associated to cholestasis with ductular reaction but not to fibrosis and inflammation in animal models of liver injury. Conclusions:Â AH is characterized by an important dysregulation of miRNA expression with a unique miRNA profile. MiRNAs specifically expressed in AH are associated to cholestasisâ¦ Uncovered miRNAs are involved in important pathophysiological features in AH suggesting ta regulation of he role of miRNAs in the regulation of AH, and highlight miR-182 as a potential regulator of its pathophysiology. miRNA expression arrays were performed in 13 AH(Alcoholic hepatitis), 5 alcohol liver disease-induced cirrhosis (ALD-CH), 5 nonalcoholic steatohepatitis induced cirrhosis (NASH-CH), 4 HCV-induced cirrhosis (HCV-CH) and 6 non-injured liver control samples(CTRL).

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