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Exome sequencing of Alcohol-associated Hepatitis

ABSTRACT: Exome sequencing of Alcohol-associated Hepatitis

PROVIDER: PRJNA1117969 | ENA |

REPOSITORIES: ENA

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Exome sequencing of Alcohol-associated Hepatitis

Project description:Exome sequencing of Alcohol-associated Hepatitis

| PRJNA1117968 | ENA

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

Project description: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.

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

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

Project description: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.

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IL-8+ neutrophils drive inexorable inflammation in severe alcohol-associated hepatitis [scRNA-seq]

Project description:Patients with alcohol-associated liver cirrhosis (AC) may develop severe alcohol-associated hepatitis (sAH), but the mechanisms underlying the transition from AC to sAH still remain unclear. We performed single cell RNA (scRNA) sequencing analysis of livers and peripheral white blood cells (WBC) from sAH and AC patients. We found that the significant difference between sAH and AC was that sAH livers had a markedly higher number of neutrophil subsets than AC livers. Thus, we further focused on the neutrophil cluster and found two distinct sAH-specific liver neutrophils are notably characterized by heightened expression of CXCL8 (IL-8) defined as IL-8+ neutrophils blood. Our current study has demonstrated that sAH had self-sustaining IL-8+ neutrophil accumulation that likely drives inexorable liver inflammation and failure in sAH. Based on our study, we believe targeting IL-8+ neutrophils is a promising therapeutic strategy for sAH.

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Bulk RNA sequencing of liver biopsy-derived organoids from patients with alcohol-associated liver disease and paired tissues

Project description:RNA sequencing was performed on liver organoids obtained from biopsies (b-Orgs) and paired tissues collected at different stages of alcohol-associated liver disease (ALD) using biliary (BEC) and hepatocyte (HEP) culture conditions. Different "generations" and passages of b-Orgs cultured with HEP medium were also sequenced. Besides, sequencing was also performed on vehicle and b-Orgs treated with Alcohol-associated hepatitis (AH)-medium. Finally, standard cholangiocyte organoids (Chol-Orgs) generated by dissociation of end-stage liver resections from ALD patients were sequenced.

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

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

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Profiling of exome mutations associated with progression of HBV-related hepatocellular carcinoma

Project description:We profiled the mutations and gene expressions of early and advanced hepatocellular carcinoma (HCC) related with Hepatitis B-viral infection. Integrative analysis was performed with whole-exome sequencing and gene expression profiles of the 12 cases of early and advanced HCCs and paired non-tumoral adjacent liver tissues. 12 HCC Samples

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IL-8+ neutrophils drive inexorable inflammation in severe alcohol-associated hepatitis [scRNA-seq]

Project description:IL-8+ neutrophils drive inexorable inflammation in severe alcohol-associated hepatitis [scRNA-seq]

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

Project description:Alcohol-associated hepatitis induces hepatocyte senescence which is reduced following disease resolution I

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