Similar Datasets
Project description:Liver injury causes “transdifferentiation” of quiescent hepatic stellate cells (Q-HSCs) into wound repairing myofibroblasts (MF-HSCs), whose uncontrolled activation leads ultimately to liver fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, using a compendium of in vitro, ex vivo and in vivo models of fibrogenic liver injuries in addition to human liver samples, we report that O-linked β D N acetylglucosaminylation (O GlcNAcylation), a post-translational modification (PTM) considered as nutritional sensor, is increased during myofibroblastic activation of HSCs and is required for their pro-fibrotic activities. Mechanistically, a multi omics approach combining proteomic, epigenomic and transcriptomic data mining revealed that O GlcNAcylation controls the transcriptional program of MF-HSCs by targeting the key fibrogenic transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of fibrogenic transcriptional regulatory elements. Altogether, this study unravels the fibrogenic role of protein O-GlcNAcylation identifying a vulnerable regulatory process in activated HSCs.
2024-05-21 | PXD045860 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-22 | GSE243107 | GEO
Project description:O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in hepatic stellate cells (HSCs)
| PRJNA1016371 | ENA
Project description:O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in hepatic stellate cells
| PRJNA1016361 | ENA
Project description:Our data describe autophagic flux in primary rat hepatic stellate cells (rHSCs) treated with pro-fibrotic growth factor, transforming growth factor beta (TGF-β). An autophagy flux experiment determines the rate of synthesis and degradation of the autophagosome marker, LC3-II in the presence and absence of the lysosomal inhibitor bafilomcyin, which blocks LC3-II degradation in lysosomes. The effects of a test agent on LC3-II flux through the autophagic pathway is determined immunochemically by its relative amounts detected in lysates of cells treated with and without bafilomycin. This measurement helps to validate whether exposure to an agent affects the biogenesis or the degradation of autophagosomes during autophagy, a major macromolecular degrading mechanism in eukaryotic cells. ("Rev-erb Agonist and TGF-β Similarly Affect Autophagy but Differentially Regulate Hepatic Stellate Cell Fibrogenic Phenotype" (Thomes et al., in press) [1].
| S-EPMC5156597 | biostudies-literature
Project description:Liver fibrosis occurs in response to chronic liver injury and is characterized by an excessive deposition of extracellular matrix. Activated hepatic stellate cells are primarily responsible for this process. A possible strategy to counteract the development of hepatic fibrosis could be the reversion of the activated phenotype of hepatic stellate cells. Extracellular vesicles (EVs) are nanosized membrane vesicles involved in intercellular communication. Our previous studies have demonstrated that EVs derived from human liver stem cells (HLSCs), a multipotent population of adult stem cells of the liver with mesenchymal-like phenotype, exert in vivo anti-fibrotic activity in the liver. However, the mechanism of action of these EVs remains to be determined. We set up an in vitro model of hepatic fibrosis using a human hepatic stellate cell line (LX-2) activated by transforming growth factor-beta 1 (TGF-β1). Then, we investigated the effect of EVs obtained from HLSCs and from human bone marrow-derived mesenchymal stromal cells (MSCs) on activated LX-2. The incubation of activated LX-2 with HLSC-EVs reduced the expression level of alpha-smooth muscle actin (α-SMA). Conversely, MSC-derived EVs induced an increase in the expression of pro-fibrotic markers in activated LX-2. The analysis of the RNA cargo of HLSC-EVs revealed the presence of several miRNAs involved in the regulation of fibrosis and inflammation. Predictive target analysis indicated that several microRNAs (miRNAs) contained into HLSC-EVs could possibly target pro-fibrotic transcripts. In particular, we demonstrated that HLSC-EVs shuttled miR-146a-5p and that treatment with HLSC-EVs increased miR-146a-5p expression in LX-2. In conclusion, this study demonstrates that HLSC-EVs can attenuate the activated phenotype of hepatic stellate cells and that their biological effect may be mediated by the delivery of anti-fibrotic miRNAs, such as miR-146a-5p.
| S-EPMC8593217 | biostudies-literature
Project description:Activated HSCs are liver stromal cells that play an important rôle in tissue repair and fibrosis. We performed gene expression profiling analysis using data obtained from RNA-seq of LX-2 cells treated for 48h with control siRNAs (siCTL) or siRNAs specific for ADAMTS12 (siADAMTS12)
2023-01-29 | GSE223753 | GEO
Project description:Liver fibrosis, characterized by excessive extracellular matrix deposition, is driven by activated hepatic stellate cells (HSCs). Due to the limited availability of anti-fibrotic drugs, research con-tinues to explore potential therapeutic agents. Moringa oleifera Lam. (MO), known for its various bioactive properties, is being investigated for its anti-fibrotic potential. This study focused on 1-phenyl-2-pentanol (1-PHE), a compound derived from MO leaves, and its impact on LX-2 hu-man hepatic stellate cell activation. TGF-β1-stimulated LX-2 cells were treated with MO extract or 1-PHE, and liver fibrosis markers were assessed at both gene and protein levels. Proteomic analysis and molecular docking were employed to identify potential protein targets and signaling pathways affected by 1-PHE. 1-PHE treatment downregulated fibrosis markers, including colla-gen type I alpha 1 chain (COL1A1), collagen type IV alpha 1 chain (COL4A1), mothers against decapentaplegic homolog 2 and 3 (SMAD2/3), and matrix metalloproteinase-2 (MMP2), and re-duced the secretion of matrix metalloproteinase-9 (MMP9). Proteomic analysis revealed the pos-sible mechanism of 1-PHE in modulating the Wnt/β-catenin pathway. These findings suggest that 1-PHE may suppress HSCs activation by inhibiting the TGF-β1 and Wnt/β-catenin signaling pathways, indicating its potential as an anti-liver fibrosis agent. Further research is warranted to validate these findings.
2024-10-17 | PXD052809 | Pride
Project description:We found that the number of tumor-infiltrating myofibroblasts was positively correlated to tumor acidification status in hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs), the predominant precursors of liver myofibroblasts, were activated and transdifferentiated into myofibroblasts under acidic culture condition. To identify the molecular phenotype of LX-2 cells in acidic culture conditions, we further conducted a gene expression profile analysis. LX-2 cells cultured in pH 7.2 or pH 6.2 medium separately for six days was used in gene expression microarray analysis.
2013-07-29 | E-GEOD-49301 | biostudies-arrayexpress
Project description:Purpose: We recently identified 39 human microRNAs, which effectively suppress hepatitis B virus (HBV) replication in hepatocytes. Because chronic HBV infection often results in active, hepatitis-related liver fibrosis, we assessed whether any of these microRNAs have anti-fibrotic potential and predicted that miR-6133-5p may target several fibrosis-related genes. Methods: The hepatic stellate cell line LX-2 was transfected with miR-6133-5p mimic and subsequently treated with TGF-β. mRNA and protein products of COL1A1, encoding collagen, and ACTA2, an activation marker of hepatic stellate cells, were quantified. Results: Expression of COL1A1 and ACTA2 was markedly reduced in LX-2 cells treated with miR-6133-5p. Interestingly, phosphorylation of JNK also was significantly decreased by miR-6133-5p treatment. The expression of several predicted target genes of miR-6133-5p, including TGFBR2 and FGFR1, was also reduced in miR-6133-5p-treated cells. The knockdown of TGFBR2 by the corresponding small interfering RNA greatly suppressed the expression of COL1A1 and ACTA2. Treatment with the JNK inhibitor, SP600125, also suppressed COL1A1 and ACTA2 expression, indicating that TGFBR2 and JNK would mediate the anti-fibrotic effect of miR-6133-5p. Downregulation of FGFR1 may result in a decrease of phosphorylated AKT, ERK, and JNK. Conclusions: miR-6133-5p has a strong anti-fibrotic effect, mediated by inactivation of TGFBR2, AKT and JNK.
2020-09-25 | GSE158478 | GEO