Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury
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ABSTRACT:
PROVIDER: PRJNA1095826 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28538426_1.fastq.gz | Fastqsanger.gz | |||
| SRR28538426_2.fastq.gz | Fastqsanger.gz | |||
| SRR28538427_1.fastq.gz | Fastqsanger.gz | |||
| SRR28538427_2.fastq.gz | Fastqsanger.gz | |||
| SRR28538428_1.fastq.gz | Fastqsanger.gz |
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Project description:Nrf2 antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/HO-1 in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerts a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondria-targeted SOD2 overexpression attenuate the toxicity of bilirubin. Additionally, the expression of Nrf2 and HO-1 is significantly elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.
2024-04-08 | GSE263093 | GEO
Project description:We used microarrays to provide a transcriptomic signature of different types of cholestasis evoked by 3 different drugs and obstructive surgery Adverse outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an adverse outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum stress in intrahepatic cholestasis, and autophagy and necroptosis in both intrahepatic as extrahepatic cholestasis. This study demonstrates that AOPs constitute dynamic tools that should be frequently updated with new input information.
2020-06-16 | GSE152494 | GEO
Project description:Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequentlyleads to liver injury, inflammation, fibrosis, and ultimately liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury in α-naphthylisothiocyanate (ANIT)-treated and Mdr2 deficiency mice. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.
2023-08-19 | GSE240733 | GEO
Project description:Heme oxygenase(HO-1) has been shown to protect against I/R injury, but its effects on testicular I/R is very limited. Therefore, this study aims to investigate the effects of HO-1 on testicular I/R and the underlying mechanism.Knockout of HO-1 rats by TALEN technique.Immunofluorescence and immunohistochemistry was used to detect HO-1 nuclear translocation. Flow cytometry was used to detect cell apoptosis and cell cycle.High-resolution miRNA,mRNA sequencing, real-time PCR and western blot were performed to select testicular I/R injury related genes with strong conservation in HO-1 knockout rats.Double luciferase reporter assay was used to verify the relationship between c-Jun and miR-221/222.We found that HO-1 improved the pathological damage caused by testicular I/R in vivo. We verified the nuclear translocation of HO-1 and its protective effect on hypoxia/reoxygenation(H/R) damage in GC-1 cells.And our results indicated that HO-1 protein itself rather than heme breakdown metabolites might play a key role in testicular I/R.Gene sequencing was performed to screen out MiR221/222 and its downstream gene-thymocyte selection associated high mobility group box(TOX). In addition, we found that HO-1 increased phosphorylation of c-Jun in H/R group.We knocked down c-Jun in GC-1 cells and observed a decrease in the expression of miR-221/222.And we found by inhibiting HO-1,we observed a decrease in the expression of c-jun and miR-221/222,which could be rescued by adding c-jun. The dual luciferase reporter assay confirmed the interaction between c-Jun and miR-221/222. Collectively, HO-1 possesses a protective effect on testicular I/R via phosphorylated c-Jun-miR-221/222-TOX pathway.
2024-02-14 | GSE236536 | GEO
Project description:In this study, we examined C57BL/6J and AJ mice who received either sham surgery or cholestatic intestinal injury. Mice were anesthetized by inhaled isoflurane anesthesia. The abdomen was clipped and then prepared in sterile fashion with 70% ethyl-ethanol followed by betadine. A transverse upper abdominal incision was performed. The CBD was dissected away from the portal vein and was ligated near its junction with the duodenum using aneurysm clips engineered with a precisely standardized opening/closing mechanism. The abdominal wall was then closed in a two-layer fashion using absorbable sutures. Sham-operated mice were treated identically but without dissection or ligation of the CBD. Male AJ and C57BL6J mice, 8 weeks of age, were randomly assigned to surgery or sham (n=3 microarrays per strain/condition).
2013-12-31 | E-GEOD-47099 | biostudies-arrayexpress
Project description:Cholestatic injuries, featured with regional damage around the periportal, cause considerable mortality without curative therapies. It is technically challenging to dissect regional cell-cell interactions and molecular changes to fully understand cholangiopathies. Here, we generated a high-definition atlas of spatiotemporal transcriptome during cholestatic injury and repair. Remarkably, cholangiocytes functioned as a periportal hub by integrating signals from neighboring cells. We also dissected periportal damage, spatial heterogenous reprogramming and zonal regeneration, which appeared to be strongly associated with cholangiocyte. Moreover, spatiotemporal analyses revealed a key inhibitory rheostat for hepatocyte proliferation. Together, our study provides a comprehensive resource that is instrumental to demarcate regional cholestatic injury.
2022-12-02 | GSE219169 | GEO
Project description:Heme oxygenase(HO-1) has been shown to protect against I/R injury, but its effects on testicular I/R is very limited. Therefore, this study aims to investigate the effects of HO-1 on testicular I/R and the underlying mechanism.Knockout of HO-1 rats by TALEN technique.Immunofluorescence and immunohistochemistry was used to detect HO-1 nuclear translocation. Flow cytometry was used to detect cell apoptosis and cell cycle.High-resolution miRNA,mRNA sequencing, real-time PCR and western blot were performed to select testicular I/R injury related genes with strong conservation in HO-1 knockout rats.Double luciferase reporter assay was used to verify the relationship between c-Jun and miR-221/222.We found that HO-1 improved the pathological damage caused by testicular I/R in vivo. We verified the nuclear translocation of HO-1 and its protective effect on hypoxia/reoxygenation(H/R) damage in GC-1 cells.And our results indicated that HO-1 protein itself rather than heme breakdown metabolites might play a key role in testicular I/R.Gene sequencing was performed to screen out MiR221/222 and its downstream gene-thymocyte selection associated high mobility group box(TOX). In addition, we found that HO-1 increased phosphorylation of c-Jun in H/R group.We knocked down c-Jun in GC-1 cells and observed a decrease in the expression of miR-221/222.And we found by inhibiting HO-1,we observed a decrease in the expression of c-jun and miR-221/222,which could be rescued by adding c-jun. The dual luciferase reporter assay confirmed the interaction between c-Jun and miR-221/222. Collectively, HO-1 possesses a protective effect on testicular I/R via phosphorylated c-Jun-miR-221/222-TOX pathway.
2024-02-14 | GSE237563 | GEO
Project description:Cholestatic liver diseases are highly prevalent and lack effective treatment, ultimately progressing to end-stage liver diseases. Our recent study indicates that the interplay between c-MYC and lncRNA H19 exacerbates the ductular reaction during cholestasis. However, the underlying mechanisms and their potential as therapeutic targets remain unclear. In this study, we demonstrate that senkyunolide A (SenA) effectively mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting the downstream H19/Let-7a/Lin28a axis. Through comprehensive characterization using CHIP analysis, protein truncation, amino acid mutation or deletion, and the development of SenA derivatives, we identified a potential interaction between the carbonyl group in SenA and Arg483 in TRAF6, disrupting the TRAF6-HDAC3 complex. This dissociation facilitates the binding of HDAC3 to the MYC promoter region, resulting in enhanced histone deacetylation and transcriptional suppression. Here, we highlight the therapeutic potential of SenA in cholestatic liver diseases by elucidating its role in epigenetic regulation.
2025-02-07 | GSE255293 | GEO
Project description:Sulforaphane alleviates hepatocyte pyroptosis via activating Nrf2-HO-1 signaling during septic acute liver injury
| PRJNA1308495 | ENA
Project description:BackgroundCharacterized by the presence of inflammation, fibrosis, and bile duct proliferation, cholestatic liver disease (CLD) affects people of all age groups. Takeda G-protein-coupled receptor (TGR5) has been implicated in the suppression of inflammation via toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB). Kupffer cells and their M1 polarization play important roles in inflammation and cholestatic liver injury via production of pro-inflammatory cytokines. Nevertheless, the function of TGR5 signaling in CLD is largely unknown.MethodsWe conducted liver tissue experiments, animal experiments, serum marker testing, liver histology analysis, Kupffer cell experiments, RNA extraction and Real-time PCR, western blotting, evaluation of ROS production by flow cytometry and statistical differences were analyzed by student t-test using GraphPad Prism.ResultsWe found that serum bile acid (BA) and TGR5 levels were elevated in patients with cholestasis cirrhosis. Knockout of TGR5 in animals significantly increased bile duct ligation (BDL)-caused liver injury through increasing oxidative stress, promoting M1-predominant polarization of Kupffer cells, and elevating the serum levels of inflammatory cytokines. In contrast, TGR5 activation inhibited ROS production, secretion of pro-inflammatory cytokines, and M1-predominant polarization of Kupffer cells. Moreover, results showed that TGR5 exerted its effects via suppressing NF-κB signaling and activating nuclear factor 2 (Nrf2)/HO-1 signaling. Finally, the effect of TGR5 on cholestatic liver damage was also confirmed in vivo.ConclusionsTGR5 activation protected against BDL-induced CLD by both suppressing inflammation via inhibiting the NF-κB pathway and reducing ROS production via activation of Nrf2/HO-1 signaling. These findings show the importance of TGR5 in CLD and provide new insight into therapeutic strategies for CLD.
| S-EPMC8350648 | biostudies-literature