Protective effect of UDCA against IL-11- induced cardiac fibrosis is mediated by TGR5 signalling
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ABSTRACT:
PROVIDER: PRJEB82464 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13947869_1.fastq.gz | Fastqsanger.gz | |||
| ERR13947869_2.fastq.gz | Fastqsanger.gz | |||
| ERR13947870_1.fastq.gz | Fastqsanger.gz | |||
| ERR13947870_2.fastq.gz | Fastqsanger.gz | |||
| ERR13947871_1.fastq.gz | Fastqsanger.gz |
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Project description:1.1 Introduction Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts into myofibroblasts these cells produce large quantities of extracellular matrix, resulting in myocardial scar. The profibrotic process is multi-factorial, meaning identification of effective treatments has been limited. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis however its mechanism and role in cardiac fibrosis is less well understood. 1.2 Methods In this study, we used cellular models of cardiac fibrosis and living myocardial slices to characterise the macroscopic and cellular responses of the myocardium to UDCA treatment. We complemented this approach by conducting RNA-seq on cardiac fibroblasts isolated from dilated cardiomyopathy patients. This allowed us to gain insights into the mechanism of action and explore whether the IL-11 and TGFβ/ WWP2 profibrotic networks are influenced by UDCA. Finally, we used fibroblasts from a TGR5 KO mouse to confirm the mechanism of action. 1.3 Results and Discussion We found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGFβ/ WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the treatment of multiple cardiac diseases. UDCA is well tolerated in the treatment of other diseases, indicating it is an excellent candidate for further in-human trials.
2024-11-30 | E-MTAB-14602 | biostudies-arrayexpress
Project description:TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs) and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype littermates were fed a diet supplemented with 1%LCA for 84 hours. Liver injury and gene expression changes induced by the LCA-diet revealed an enrichment of pathways associated with inflammation, proliferation and matrix remodelling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signalling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signalling and modulates portal pressure.
2019-11-19 | GSE139075 | GEO
Project description:Glioblastoma multiforme (GBM) is the deadliest form of brain tumor with a median survival time of 15 months due to drug resistance. Ursodeoxycholic acid (UDCA) is approved of cancer suppressive potential in several tumors. Here we researched on the antitumor potential of UDCA on GBM. The CCK-8 and colony formation was used for detecting cell viability. RNA sequencing hinted transcriptional profile and pathways. PCR and western blot tested the change of related markers. Phenotype changes as cell cycle, apoptosis, MMP and ROS were measured. UDCA inhibited GBM cell viability in a dose- and time-dependent way. RNA sequencing results exhibited UDCA treatment was related to glioma progression and located on mitochondria and endoplasmic reticulum (ER). Cell cycle was arrested in G1 phase followed by caspase-independent apoptosis. UDCA led to decreased MMP, overproduction of ROS and ER stress. Three main stress sensors ATF6, IRE1αand PERK were activated in acute phase. Combining UDCA with bortezomib achieved a synergistic effect via enhancing PERK/ATF4/CHOP pathway and alleviating IRE1α activation. UDCA inhibited GBM progression and the combination with bortezomib achieved a synergistic effect via protracted ER stress. UDCA, alone or with combination of BTZ, presented a promising drug for GBM.
2020-01-17 | GSE143798 | GEO
Project description:The progression of myocardial infarction (MI) involves multiple metabolic disorders. Bile acid metabolites have been increasingly recognized as pleiotropic signalling molecules that regulate multiple cardiovascular functions. G protein-coupled bile acid receptor (TGR5) is one of the receptors sensing bile acids to mediate their biological functions. In this study, we aimed to elucidate the effects of bile acids-TGR5 signaling pathways in myocardial infarction (MI).Mice underwent either the LAD ligation model of MI or sham operation. Both MI and sham mice were gavaged with 10 mg/kg/d DCA or vehicle control since 3-day before the operation. Administration of DCA improved cardiac function at the 3th-day post-MI. The effects of DCA in the heart were determined by RNA-sequencing experiments.
2020-09-24 | GSE158415 | GEO
Project description:The objective of this study was to investigate the effects of UDCA on J774A.1 cells induced inflammation by LPS. The control group treated with LPS and the UDCA group treated with both LPS and UDCA. Compared with control group, the UDCA group could reduce the inflammation effects in J774A.1 cells.
2023-02-08 | GSE174489 | GEO
Project description:Primary biliary cholangitis (PBC) is a liver-specific autoimmune disease. Treatment of PBC with ursodeoxycholic acid (UDCA) is not sufficient to prevent disease progression, new and creative approaches to treating patients with PBC are urgently required. Double-negative T (DNT) cells, unique regulatory T cells, play crucial roles in maintaining immune system homeostasis. However, both the absolute number and proportion of liver DNT cells were reduced in PBC patients. Hence, it is worth pursuing that whether replenishment of DNT cells can improve the hepatic function and pathology of PBC. In this study, adoptive transfer of DNT cells significantly decreases plasma levels of ALT, AST, AMA-M2 and IgM in both dnTGFβ RII and 2OA-BSA-immunized PBC mouse models. In addition, DNT cells exhibit a strong suppression on liver T cells. While combination therapy with DNT cells and UDCA predominantly ameliorate liver inflammation and extensively inhibit hepatic T and B cells. In vitro study further reveals that UDCA promotes the proliferation of DNT cells, increased functional molecule perforin and reduced inhibitory molecule NKG2A and EPCR expression, resulting in augmenting the suppressive function of DNT cells via FXR/JNK signaling pathway in both mice and human DNT cells. In conclusion, UDCA augments the suppressive function of DNT cells via FXR/JNK. A single transfer of DNT cells in combination with UDCA strongly ameliorates PBC in mice. This study provides a potential application of DNT cell-based therapy for PBC. Methods: The DNT cells incubation with anti-CD3/CD28 antibodies were stimulated with UDCA (60uM) for 48 hours, then transcriptome sequencing studies were performed on DNT cells RNA.Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced by the University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=1.41 and pvalue <= 0.05 between UDCA treated and control DNT cells were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment.
2023-10-31 | GSE215278 | GEO
Project description:The G protein-coupled bile acid receptor TGR5 (Gpbar1) modulates endothelin-1 signalling in liver
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Project description:Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5 expression in BECs may contribute to PSC pathogenesis.
2021-03-12 | GSE168758 | GEO
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Project description:To identify the E3 ubiquitin ligases that bound to TGR5 and promoted subsequent ubiquitination and degradation, mass spectrometry in GMCs transfected myc-TGR5 was performed with immunoprecipitation.
2023-06-27 | PXD043329 |