LncRNA H19 exacerbates hepatic inflammation and oxidative stress in alcohol-related liver disease by sponging miR-22 to derepress SIRT1
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315288 | GEO | 2026/06/30
REPOSITORIES: GEO
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Project description:Long non-coding RNAs (lncRNAs) constitute a significant portion of the human genome. LncRNA H19 is among the first identified lncRNAs and is highly expressed during fetal development but decreases in the liver shortly after birth. H19 is reactivated during the development of various liver diseases; however, the role of H19 in the pathogenesis of alcohol-associated liver disease (ALD) remains elusive. Elevated levels of H19 were observed in human peripheral blood and livers of patients with alcohol-associated cirrhosis and alcohol-associated hepatitis. Similar observations were also seen in the livers of ethanol-fed mice. Hepatic overexpression of H19 promoted ethanol-induced liver steatosis and injury. Metabolomics analysis revealed a significant decrease in methionine levels in H19-overexpressed mouse livers. H19 was found to inhibit Betaine-homocysteine methyltransferase (BHMT), a key enzyme in methionine synthesis. H19 regulated the alternative splicing process of Bhmt through Polypyrimidine tract-binding protein 1 (PTBP1), resulting in a decrease in the Bhmt protein-coding variant. Maternally specific knockout of H19 (H19Mat+/-) or liver-specific knockout of the H19 differentially methylation domain (H19DMDHep-/-) in ethanol-fed mice led to an increase in BHMT expression and improvement in hepatic steatosis. Additionally, restoration of BHMT rescued H19 overexpression-mediated ethanol-induced fatty liver. In summary, we identified a novel mechanism of H19 regulating BHMT alternative splicing and methionine metabolism through PTBP1 in ALD. Targeting the H19-PTBP1-BHMT pathway could be a potential therapeutic intervention in patients with ALD.
2025-05-01 | GSE267404 | GEO
Project description:LncRNA H19 exacerbates hepatic inflammation and oxidative stress in alcohol-related liver disease by sponging miR-22 to derepress SIRT1
| PRJNA1395585 | ENA
Project description:Dystrophin proteomic regulation in Muscular Dystrophies (MD) remains unclear. We report that a long noncoding RNA (lncRNA) H19 associates with dystrophin. To investigate the biological roles of this interaction in vivo, we performed mass spectrometry analysis of dystrophin and its associated proteins in H19-proficient and -deficient C2C12 myotubes. Mass spectrometry data indicated that in H19-proficient myotubes, dystrophin associates with components of dystrophin-associated protein complex (DPC); however, in H19-deficient myotubes, dystrophin associated with UBA1, UB2G1, TRIM63 ubiquitin E3 ligase and ubiquitin. In H19-deficient myotubes, dystrophin was post-translationally modified with K48-linked poly-ubiquitination at Lys3577 (referred to as Ub-DMD). This mass spectrometry study demonstrated that lncRNA H19, associates with dystrophin and inhibits E3 ligase-dependent Ub-DMD formation and its subsequent proteasomal degradation. Based on this study, H19 RNA oligonucleotides conjugated with a muscle homing ligand Agrin (referred to as AGR-H19) and Nifenazone, a TRIM63-specific small molecule inhibitor, reverses the dystrophin degradation in iPSC-derived skeletal muscle cells from Becker Muscular Dystrophy patients. Furthermore,treatment of mdx mice with exon-skipping reagent, in combination with either AGR-H19 or Nifenazone, dramatically stablized dystrophin, preserved skeletal/cardiac muscle histology, and improved strength/heart function. In summary, this mass spectrometry study paves the way to meaningful targeted therapeutics for BMD and certain DMD patients.
2020-08-19 | PXD020566 | Pride
Project description:Galangin, a natural flavonoid, derived from honey and Alpinia officinarum Hance (Zingiberaceae) has excellent was anti-tumor and anti-inflammatory properties. w It has been extensively studied as a novel therapeutic agent forhich was widely used in the treatment of various cancers. However, the effect of galangin in HCC remains elusive. Using RNA sequencing, the differential expression of LncRNA in MHCC97H cells treated with galangin was investigated in the present study. Furthermore, the expression of H19 was also determined in MHCC97H cells following treatment with galangin. And the effect of knockdown and overexpression of H19 on cell apoptosis, cell cycle, migration and invasion of HCC cells was also evaluated. Moreover, the in vivo effect of galangin on tumor development was also determined in nude mice. This study identified aT total of 50 LncRNAs were to be significantly differentially expressed by RNA-seq analysis in MHCC97H cells treated with galangin. It has been demostreated that noncoding RNA H19 are abnormally expressed in different cancers. Our results showed that Besides, the expression of H19 was markedly reduced after following treatment with galangin treatment in MHCC97H cells. In addition, galangin could increase the occurrence of cell apoptosis. Moreover, compared to the Control group, the galangin-treated group inhibited cell migration and invasion in MHCC97H cells.To further investigated if H19 expression pattern affect cell apoptosis, migration and invasion, knock down and overexpression of H19 vector were constructed. The results of the knockdown of H19 expression showed knock down of H19 expression increased cell apoptosis and decreasedinhibited invasion. In addition, RNA-seq data showed also identified 161 mRNA which were was significantly differentially expressed after following treatment withof galangin. To further determine the underlying mechanism,confirmed cell apoptosis, p53 protein and its related proteins were was analyzed through micor RNA 675-3p (miR675-3p) which was in the H19 locus. Notably, Tthe results indicatedshowed that reduced knockdown of H19 and miR675 induced the protein expression of p53, eventually promoting cell apoptosis expression of H19 and miR675-3p increased p53 expression in MHCC97H cells. These results indicated that galangin promoted cell apoptosis through the regulation of H19 and miR675 expression in MHCC97H cells. Furthermorely, galangin was used to treated in nude mice. Tthe in vivo result showed that compared to the Control group, inhibited tumor growth was remarkably suppressed and reduced expression of H19 in galangin-treated group. Taken together, these results indicated that galangin regulated cell apoptosis which associate with p53 protein through H19 and miR675 expression in MHCC97H cells.Collectively, our data suggested that galangin plays a role in hepatocarcinogenesis through regulation of H19 expression pattern.
2020-08-12 | GSE142680 | GEO
Project description:Despite recent advances, Primary Sclerosing Cholangitis (PSC)-a chronic obstructive biliary disease-still lacks effective therapies to prevent disease progression or the need for liver transplantation. Long non-coding RNA H19 (H19) has been implicated in promoting PSC disease progression. However, the underlying cell-specific and molecular mechanisms by which H19 contributes to PSC pathogenesis remain incompletely understood. Here we used single nucleus RNA sequencing (snRNAseq) and spatial transcriptomics to elucidate the cell- and spatial-specific expression alterations associated with H19 in the Mdr2KO PSC mouse model.
2026-04-30 | GSE311100 | GEO
Project description:Treatment of pathological cardiac remodeling and subsequent heart failure represents an unmet clinical need. The well conserved lncRNA H19 shows as powerful therapeutic potential in the treatment of pathological cardiac hypertrophy. H19 is strongly repressed in failing hearts from mice, pigs and humans. Gene therapy using murine but also human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Using microarray , GSEA and ChIP-Seq we identified a link between H19 and NFAT signalling. H19 physically interacts with PRC2 to epigenetically induced Tescalcin repression which in turn leads to reduced NFAT expression and activity.
2020-08-01 | GSE153344 | GEO
Project description:<p>Background & Aims: Alcoholic liver disease (ALD) is a major public health concern. Gut dysbiosis plays a critical role in its pathogenesis, yet the specific microbial and functional shifts driving ALD progression require further elucidation. This study aims to characterize these alterations and their mechanisms.</p><p>Methods: We recruited 28 male patients with alcoholic fatty liver (AFL), 22 with alcoholic cirrhosis (ALC), and 25 healthy male controls. Fecal samples were analyzed via shotgun metagenomic sequencing and targeted short-chain fatty acid (SCFA) metabolomics. Serum samples underwent untargeted metabolomics. Key findings were validated in mouse models through fecal microbiota transplantation (FMT), bacterial gavage, and integrated transcriptomic and metabolomic analyses.</p><p>Results: Metagenomic analysis revealed a depletion of SCFA-producing bacteria (e.g., Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans) and an enrichment of enterotoxigenic Bacteroides fragilis (ETBF) in ALD patients. Fecal concentrations of acetate, propionate, and butyrate were significantly decreased and negatively correlated with serum ALT, AST, and GGT levels. Serum metabolomics identified a distinct profile in ALD, featuring elevated levels of metabolites such as 9,10-DHOME and reduced levels of specific lysophosphatidylcholines. Multi-omics integration suggested microbial regulation of ALD via bile acid and SCFA pathways. FMT from ALD patients exacerbated alcohol-induced liver injury in mice. Gavage with ETBF significantly worsened ALD phenotypes in mice, likely mediated by Bacteroides fragilis toxin (BFT)-induced gut barrier damage and inflammation. Mouse multi-omics further demonstrated that ETBF perturbation enhanced the tryptophan-kynurenine metabolic pathway and upregulated hepatic retinol metabolism, contributing to increased liver injury, inflammation, and fibrosis.</p><p>Conclusion: Gut dysbiosis characterized by the loss of beneficial SCFA producers and the rise of pathogenic ETBF is pivotal in ALD progression. ETBF exacerbates disease via toxin-driven barrier dysfunction and the dysregulation of tryptophan and retinol metabolic pathways, revealing novel mechanistic insights and potential therapeutic targets.</p>
2026-01-10 | MTBLS13650 | MetaboLights
Project description:<p>Background & Aims: Alcoholic liver disease (ALD) is a major public health concern. Gut dysbiosis plays a critical role in its pathogenesis, yet the specific microbial and functional shifts driving ALD progression require further elucidation. This study aims to characterize these alterations and their mechanisms.</p><p>Methods: We recruited 28 male patients with alcoholic fatty liver (AFL), 22 with alcoholic cirrhosis (ALC), and 25 healthy male controls. Fecal samples were analyzed via shotgun metagenomic sequencing and targeted short-chain fatty acid (SCFA) metabolomics. Serum samples underwent untargeted metabolomics. Key findings were validated in mouse models through fecal microbiota transplantation (FMT), bacterial gavage, and integrated transcriptomic and metabolomic analyses.</p><p>Results: Metagenomic analysis revealed a depletion of SCFA-producing bacteria (e.g., Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans) and an enrichment of enterotoxigenic Bacteroides fragilis (ETBF) in ALD patients. Fecal concentrations of acetate, propionate, and butyrate were significantly decreased and negatively correlated with serum ALT, AST, and GGT levels. Serum metabolomics identified a distinct profile in ALD, featuring elevated levels of metabolites such as 9,10-DHOME and reduced levels of specific lysophosphatidylcholines. Multi-omics integration suggested microbial regulation of ALD via bile acid and SCFA pathways. FMT from ALD patients exacerbated alcohol-induced liver injury in mice. Gavage with ETBF significantly worsened ALD phenotypes in mice, likely mediated by Bacteroides fragilis toxin (BFT)-induced gut barrier damage and inflammation. Mouse multi-omics further demonstrated that ETBF perturbation enhanced the tryptophan-kynurenine metabolic pathway and upregulated hepatic retinol metabolism, contributing to increased liver injury, inflammation, and fibrosis.</p><p>Conclusion: Gut dysbiosis characterized by the loss of beneficial SCFA producers and the rise of pathogenic ETBF is pivotal in ALD progression. ETBF exacerbates disease via toxin-driven barrier dysfunction and the dysregulation of tryptophan and retinol metabolic pathways, revealing novel mechanistic insights and potential therapeutic targets.</p>
2026-01-10 | MTBLS13649 | MetaboLights
Project description:<p>Background & Aims: Alcoholic liver disease (ALD) is a major public health concern. Gut dysbiosis plays a critical role in its pathogenesis, yet the specific microbial and functional shifts driving ALD progression require further elucidation. This study aims to characterize these alterations and their mechanisms.</p><p>Methods: We recruited 28 male patients with alcoholic fatty liver (AFL), 22 with alcoholic cirrhosis (ALC), and 25 healthy male controls. Fecal samples were analyzed via shotgun metagenomic sequencing and targeted short-chain fatty acid (SCFA) metabolomics. Serum samples underwent untargeted metabolomics. Key findings were validated in mouse models through fecal microbiota transplantation (FMT), bacterial gavage, and integrated transcriptomic and metabolomic analyses.</p><p>Results: Metagenomic analysis revealed a depletion of SCFA-producing bacteria (e.g., Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans) and an enrichment of enterotoxigenic Bacteroides fragilis (ETBF) in ALD patients. Fecal concentrations of acetate, propionate, and butyrate were significantly decreased and negatively correlated with serum ALT, AST, and GGT levels. Serum metabolomics identified a distinct profile in ALD, featuring elevated levels of metabolites such as 9,10-DHOME and reduced levels of specific lysophosphatidylcholines. Multi-omics integration suggested microbial regulation of ALD via bile acid and SCFA pathways. FMT from ALD patients exacerbated alcohol-induced liver injury in mice. Gavage with ETBF significantly worsened ALD phenotypes in mice, likely mediated by Bacteroides fragilis toxin (BFT)-induced gut barrier damage and inflammation. Mouse multi-omics further demonstrated that ETBF perturbation enhanced the tryptophan-kynurenine metabolic pathway and upregulated hepatic retinol metabolism, contributing to increased liver injury, inflammation, and fibrosis.</p><p>Conclusion: Gut dysbiosis characterized by the loss of beneficial SCFA producers and the rise of pathogenic ETBF is pivotal in ALD progression. ETBF exacerbates disease via toxin-driven barrier dysfunction and the dysregulation of tryptophan and retinol metabolic pathways, revealing novel mechanistic insights and potential therapeutic targets.</p>
2026-02-06 | MTBLS13858 | MetaboLights
Project description:Long non-coding RNAs (lncRNAs) regulate diverse cellular processes and are associated with many age-associated diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we characterize the role of lncRNA H19 in senescence. We show that H19 levels decline as cells undergo senescence, and depletion of H19 results in premature senescence. We find that repression of H19 is triggered by the loss of CTCF and prolonged activation of p53 as part of the senescence pathway. Mechanistically, the loss of H19 drives senescence via increased let7b mediated targeting of EZH2. We further demonstrate that H19 is required for senescence inhibition by the mTOR inhibitor rapamycin, where it maintains lncRNA H19 levels throughout the cellular lifespan and thus prevents the reduction of EZH2 that would otherwise lead to cellular senescence. Therefore, lncRNA H19 is crucial in maintaining the balance between sustained cell growth and the onset of senescence.
2022-11-30 | GSE211157 | GEO