Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Blockade of lL17 signaling reverses alcohol-induced liver injury, and excessive alcohol drinking in mice.

ABSTRACT: Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL17 Receptor A (IL17ra-/-), or pharmacological blockade of IL17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice, and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL17A positively correlated with the alcohol use in excessive drinkers, and was further increased in patients with ALD as compared to healthy individuals. Our data suggest that IL17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL17A may provide a novel strategy for treatment of alcohol-induced pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE137228 | GEO | 2020/04/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease

Project description:Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in mitochondria-associated ER membranes (MAMs) mediates Ca2+ accumulation-induced mitochondrial dysfunction in ALD via the formation of glucose-regulated protein 75 (GRP75)-mediated MAM Ca2+-channeling (MCC) complex. Unbiased transcriptomic analysis reveals pyruvate dehydrogenase kinase 4 (PDK4) as a prominently inducible MAM kinase in ALD. Additional mass spectrometry analysis unveils the critical role of PDK4 in promoting alcohol-induced MCC complex formation and mitochondrial dysfunction by phosphorylating GRP75. Non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced mitochondrial Ca2+ accumulation and dysfunction. Conversely, ectopic induction of MAM formation in PDK4-deficient mice abrogate the protective effect in alcohol-induced liver injury. Together, our study defines the mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.

2023-05-10 | PXD039478 | Pride

Primary alcohol-activated human and mouse Hepatic Stellate Cells (HSCs) share similarities in gene expression profiles

Project description:Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins (ECM) and formation of a fibrous scar. Hepatic Stellate Cells (HSCs) are the major source of Collagen Type I producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol-induced activation of human and mouse HSCs is not fully understood. We compared the gene expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n=3) or without underlying liver disease (n=4) using RNA-Seq analysis. Furthermore, the gene expression profile of ALD hHSCs was compared to that of alcohol-activated mHSCs (isolated from intragastric (IG) alcohol-fed mice), or carbon-tetrachloride (CCl4)-activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, and alcohol- and CCl4-activated mHSCs share the expression of common HSC activation (Col1a1, Acta1, PAI-1, TIMP1, LOXL2), indicating that a common mechanism underlies activation of human and mouse HSCs. Furthermore, alcohol-activated mHSCs most closely recapitulate the gene expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely upregulated in primary cultured alcohol-activated hHSCs and freshly isolated mHSCs, which include CSF1R, PLEK, LAPTM5, CD74, CD53, MMP9, CD14, CTSS, TYROBP, ITGB2, and other genes (compared to CCl4-activated mHSCs). We identified genes in alcohol-activated mHSCs from IG alcohol-fed mice that are largely consistent with the gene expression profile of primary cultured hHSCs from ALD patients. These genes are unique to alcohol-induced HSC activation in two species, and therefore, may become new targets or readout for anti-fibrotic therapy in experimental models of ALD.

2020-04-10 | GSE141100 | GEO

Gene expression changes in liver tissues from alcohol treated mice

2013-02-12 | GSE44237 | GEO

Gene expression changes in liver tissues from alcohol treated mice

Project description:transcriptomic changes in the early stages of ALD in mice fed the Lieber-Decarli liquid diet with or without alcohol for four months to identify biomarkers for the early stage of alcohol induced liver damage. Mice were sampled after 1, 2 and 4 months treatment. Two-condition experiment, control vs. alcohol treated at specified time point. Sample pooled from six biological replicates in each group. Reverse-fluorescence replicates.

2013-02-12 | E-GEOD-44237 | biostudies-arrayexpress

Sex specific role of KDM5B demethylase in Alcohol-associated Liver Disease development and resolution

Project description:Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. Recently we identified hepatic demethylases KDM5B and KDM5C as important sex-specific epigenetic regulators of alcohol response in the liver. In this study we aimed to study the molecular mechanisms of KDM5-dependent ALD development and resolution. We found that alcohol induces pathological changes in cell-cell communication in the liver that are in part mediated by epigenetic changes in hepatocytes mediated by histone demethylase KDM5B. Using cell type specific knockout mice, we found that KDM5B histone demethylase was a key regulator of alcohol-induced epigenetic changes in hepatocytes. Moreover, it regulated hepatocytes-non-parenchymal cell crosstalk that promoted inflammation and fibrosis development in ALD. This mechanism was specific to females. In males KDM5B deficiency was not sufficient to prevent fibrosis development. In contrast KDM5B demethylase loss promoted fibrosis resolution in both males and females. This mechanism involved changes in hepatocyte-macrophage crosstalk and LXRα activation, which we identified to be critical for the fibrosis resolution process. CONCLUSION: In summary, KDM5B demethylase is a regulator of cell-cell crosstalk involved in disease progression in females and in disease resolution in both sexes.

2023-10-07 | GSE244240 | GEO

Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease [bulk TCR-seq]

Project description:Alcohol-associated liver disease is accompanied by changes in the intestinal mycobiome. How fungal dysbiosis contributes to liver disease is not clear. T-helper (Th17) cells mediate immune responses against fungi, but the interleukin 17 (IL17) pathway has been associated with pathogenesis of alcohol-associated liver disease. Here, we demonstrate that Candida albicans (C. albicans)-specific Th17 cells are increased in the circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration to mice results in migration of C. albicans-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin reduced intestinal fungal overgrowth, decreased C. albicans-specific Th17 cells in the liver, and reduced features of ethanol-induced liver disease in mice. Transgenic mice that express a T-cell receptor (TCR) reactive to Candida antigens develop more severe ethanol-induced liver disease than transgene-negative littermates; disease severity was reduced by administration of an antibody against IL17 to the TCR transgenic mice. Adoptive transfer of C. albicans-reactive Th17 cells exacerbated ethanol-induced liver disease in wild-type mice. IL17 receptor A (IL17ra) signaling in Kupffer cells was required for the effects of C. albicans-reactive Th17 cells. Our findings indicate that ethanol increases C. albicans-reactive Th17 cells, which contribute to alcohol-associated liver disease.

2023-02-16 | GSE215929 | GEO

Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease [scRNA & scTCR-seq]

2023-02-16 | GSE215930 | GEO

Transcriptomic data from the liver of Ahr knockout mice

Project description:Alcoholic liver disease, which varies in severity from mild steatosis to cirrhosis and hepatitis, is one of the most prevalent chronic liver diseases worldwide. Excessive alcohol consumption remains the leading cause of ALD and alcohol-related complications and deaths. However, no medications have been developed to treat this disease and its pathogenesis remains elusive. Here, to understand alcohol-induced AhR activation in more detail, transcriptomic data was conducted using livers from mice subjected to either control or Lieber-DeCarli alcohol diets.

2022-09-06 | GSE179398 | GEO

Sex specific role of KDM5 demethylases in Alcohol-associated Liver Disease

Project description:Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. The specific mechanisms responsible for ALD development and progression are not fully understood, and there is limited therapy for any stage of ALD. Sex differences are often disregarded in in genetic and mechanistic studies. We aimed to take an unbiased approach to define sex specific pathways in livers exposed to alcohol. METHODS: Mice were fed LieberDeCarli alcohol liquid diet for 3 weeks. To identify the role of Kdm5b and Kdm5c we injected mice with AAV-shControl at 2x10^11 gc per mouse or AAV-shKdm5b and AAV-Kdm5c vectors at 10^11 gc per mouse. To assess the role of AhR we injected mice with AAV-shControl or AAV-shAhR vectors at 10^11 gc per mouse. RESULTS: We found several pathways affected by alcohol in sex specific way and identified KDM5 demethylases as contributors to that specificity.

2022-02-08 | GSE195889 | GEO

The Gut Microbe-Derived Metabolite Trimethylamine is a Biomarker of and Therapeutic Target in Alcohol-Associated Liver Disease

Project description:BACKGROUND & AIMS: There is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcoholic hepatitis (AH). However, mechanisms by which gut microbiota synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. METHODS: We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, and identified the metabolite trimethylamine (TMA) as a gut microbe-derived biomarker of AH. In subsequent studies, we treated mice with non-lethal mechanism-based bacterial choline TMA lyase inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. RESULTS: We show the gut microbial choline metabolite trimethylamine (TMA) is elevated in AH patients, which is correlated with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial choline TMA lyase activity protects mice from ethanol-induced liver injury. TMA lyase inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome community and host liver transcriptome. CONCLUSIONS: The microbial metabolite TMA is a biomarker of AH, and blocking TMA production from gut microbes can blunt ALD in mice.

2021-03-31 | GSE157681 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data