CXCR4 DRIVES HEPATOCYTE REPROGRAMMING IN ALCOHOL-RELATED LIVER DISEASE
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA818680 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18432523.fastq.gz | Fastqsanger.gz | |||
| SRR18432524.fastq.gz | Fastqsanger.gz | |||
| SRR18432525.fastq.gz | Fastqsanger.gz | |||
| SRR18432526.fastq.gz | Fastqsanger.gz | |||
| SRR18432527.fastq.gz | Fastqsanger.gz |
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Project description:Backgruound and aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). However, the mechanisms and the impact of hepatocyte reprogramming in liver disease are poorly understood. Here we show that both hepatocytes expressing KRT7 (hepatobiliary (HB) cells) and ductular reaction cells were increased in decompensated cirrhotic patients and AH, but only HB cells correlated with poor liver function, reduced liver synthetic capacity and poor outcome. Transcriptomic analysis of microdissected HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming together with inflammatory, stemness and cancer gene programs. In this context, CXCR4 pathway was highly enriched in HB cells, and CXCR4 correlated with disease severity and reduced expression of hepatocyte transcription factors and albumin. Mechanistically, TGFβ induced the expression of CXCR4 in primary hepatocytes, and its ligand CXCL12 promoted hepatocyte reprogramming. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte gene expression and promoted liver injury. Pharmacological inhibition of CXCR4 reverted hepatocyte loss of identity and reduced ductular reaction and fibrosis progression. Conclusions: This study shows the association of hepatocyte reprogramming with disease progression and poor outcome in AH. Moreover, we identify CXCR4 as a driver of hepatocyte reprogramming as well as a potential therapeutic target in chronic liver injury.
2023-04-06 | GSE199168 | GEO
Project description:Background & aimsLoss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood.MethodsHB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity.ResultsHere, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression.ConclusionsThis study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH.Impact and implicationsHere, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair.
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Project description:Alcohol-associated liver disease (ALD) affects millions of people worldwide, while pharmacological therapies are limited. CCAAT/enhancer binding protein α (CEBPA) in hepatocytes is known to regulate the progression of liver fibrosis; however, the role of hepatocyte-specific CEBPA in modulating the ALD progression is still unknown. Here, hepatic CEBPA expression was found to be decreased during ALD progression in humans. CebpaΔHep mice had enhanced ALD induced both in short-term and long-term alcohol feeding. Temporal and spatial hepatocyte-specific CEBPA loss at the later stage of ALD in CebpaΔHep,ERT2 mice functionally promoted ALD. Mechanistically, hepatocyte CEBPA loss directly deactivated Orm1 expression in hepatocytes that resulted in reduced secretion of ORM1 and enhancement of ALD progression. Both hepatocyte ORM1 expression and serum ORM1 levels were found to be negatively correlated with the ALD progression in humans, while loss of hepatocyte ORM1 in mice sharply enhanced ALD. Both forced hepatocyte-specific CEBPA overexpression and hepatocyte-specific ORM1 overexpression by adeno-associated viruses rescued the progression of ALD in CebpaΔHep mice. Notably, treatment of recombinant ORM1 protein improved the progression of ALD in CebpaΔHep mice. These results reveal a key role for hepatocyte-specific CEBPA-ORM1 axis in ALD progression, which supports hepatocyte CEBPA to be a novel therapeutic target for the treatment of ALD.
2026-03-03 | GSE291057 | GEO
Project description:Why alcohol-induced liver disease (ALD) resolves after abstinence in most people but progresses to liver failure in others remains poorly understood. Experimental models show that increased exposure to pro-inflammatory cytokines exacerbates ALD, yet clinical trials targeting these cytokines have failed. The TNFα-inducible zinc finger protein 36 (ZFP 36) family of RNA binding proteins controls the outcomes of TNFα exposure by destabilizing suites of mRNAs that execute the pleiotropic downstream actions of TNFα. To investigate the role of RNA binding protein ZFP36L1 in regulating hepatocyte fate and its contribution in the progression of ALD.We selectively deleted ZFP36L1 in mouse hepatocytes (ZFP36L1HEPKO) to assess its impact on ALD progression, transcriptional reprogramming, senescence and direct mRNA targets. In parallel, we analyzed human liver explants to evaluate ZFP36L1 in relation to hepatocyte senescence, disease severity, and zinc-dependent regulation.Deletion of ZFP36L1 exacerbated ALD and activated transcriptional programs driving ductal trans-differentiation, inflammation and senescence. Mechanistically, ZFP36L1 directly destabilized Cdkn1a (p21) and Jag1 mRNAs, thereby suppressing hepatocyte senescence and JAG1-NOTCH signaling. In human liver explants, ZFP36L1 activity declined in parallel with increasing hepatocyte senescence and ALD severity, and was closely associated with impaired zinc-dependent signaling. Manipulation of zinc availability altered ZFP36L1 activity and expression of its direct targets. These findings uncover a zinc-dependent ZFP36L1-regulon that governs hepatocyte fate by repressing p21- and JAG1-driven senescence and NOTCH activation, and highlight ZFP36L1as a promising therapeutic target in ALD.
2026-04-02 | GSE326874 | GEO
Project description:Objective: YAP impairs hepatocyte regeneration in alcohol-related hepatitis (AH) but its impact on fibrogenesis remains unknown. Our aim was to describe fibrogenesis during AH and the relationship between impaired hepatocyte regeneration and fibrogenesis. Design: Fibrosis distribution and colocalization of YAP and αSMA were assessed by immunostaining. Extracellular matrix (ECM) composition in patients with severe AH (n=22) or alcohol-related cirrhosis (Cirrh, n=24) and healthy livers (Ctrl, n=15) was assessed by bulk and spatial proteomics and PCR. We generated organoids from AH and Cirrh livers and evaluated their impact on myofibroblasts in a 3D coculture model. Cirrh organoids were transduced with an active YAP and cocultured with myofibroblasts. Myofibroblasts were also cultured with medium from transduced (YAP medium) or not-transduced hepatocytes (CTRL medium).
2025-09-09 | PXD044031 | Pride
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.
2025-08-25 | PXD053109 | Pride
Project description:NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma
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Project description:Hepatocyte-specific CEBPA-ORM1 axis restricts alcohol-associated liver disease
| PRJNA1231473 | ENA
Project description:The goal of this study was to identify signalling molecules downstream of CXCR4 in breast cancer cells. For this purpose, we sorted CXCR4-positive and CXCR4-negative cells from MDA-MB-231 breast cancer cell line by flow cytometry and performed microarrays analysis. Three sets of samples, each in quadruplicate, were analyzed. These include CXCR4-positive subpopulation, CXCR4-positive subpopulation treated with SDF-1 (ligand for CXCR4, also called CXCL12) for one hour and CXCR4-negative subpopulation.
2010-04-28 | E-GEOD-15893 | biostudies-arrayexpress
Project description:NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma [ChIP-Seq]
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