A hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis
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ABSTRACT:
PROVIDER: PRJNA1017780 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26069542_1.fastq.gz | Fastqsanger.gz | |||
| SRR26069542_2.fastq.gz | Fastqsanger.gz | |||
| SRR26069543_1.fastq.gz | Fastqsanger.gz | |||
| SRR26069543_2.fastq.gz | Fastqsanger.gz | |||
| SRR26069544_1.fastq.gz | Fastqsanger.gz |
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Project description:RelA and Stat3, often collaboratively, induce the synthesis of an array of factors,which orchestrate multiorgan crosstalk in health and diseases. RelA and Stat3 functions in theintestinal epithelial cells are known to tune colon inflammation. If their hepatic activity also impacts inflammation in the gut remains unclear. Here, we reveal that the combined deficiency of RelA and Stat3 specifically in hepatocytes ameliorates DSS-induced experimental colitis. Our transcriptomics analyses identified that they activated a hepatic gene program, which directed the expression of alternate bile synthesis pathway genes. Our metabolomics studies substantiated that an absence of RelA and Stat3 in hepatocytes led to a reduced accumulation of inflammatory bile acids, particularly chenodeoxycholic acid, not only in the liver but also in the gut. Indeed, knockout mice displayed a lessened expression of only in the liver but also in the gut. Indeed, knockout mice displayed a lessened expression of inflammatory cytokines and a diminished recruitment of inflammatory cells in the gut upon colitogenic insults; on the other hand, supplementing chenodeoxycholic acid was sufficient to restore the colitogenic sensitivity in these mice. In sum, we suggest that the engagement of inflammatory transcription factors in distant tissues promotes intestinal pathologies via metabolic wiring.
2024-06-23 | GSE243307 | GEO
Project description:Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specific Rela-Stat3 network as a promising therapeutic target.
| S-EPMC11321761 | biostudies-literature
Project description:A common response to physiological duress is the hepatic acute phase response, a process during which the expression of many genes is altered in the liver. Amongst these transcripts are those encoding acute phase proteins, defined as circulating proteins with significantly changed concentrations during an acute phase response. The goal of this study was to determine the influence of two transcription factors, STAT3 and NF-kappaB p65 (RelA), on hepatic gene changes including but not limited to acute phase proteins during bacterial pneumonia. Using the Cre-LoxP system, mice were generated with combined functional deletions of both STAT3 and RelA in hepatocytes. In mutant mice, Cre-recombinase was expressed under transcriptional control of an albumin promoter in the presence of homozygous floxed alleles for both STAT3 and RelA. Wild-type control mice lacked the Cre-recombinase transgene. Microarray analysis was performed on liver RNA collected from both genotypes of mice in the absence and presence of pneumococcal pneumonia. RNA from 4 separate groups of mice (3 mice per group) was analyzed: 1) Uninfected wild-type control mice; 2) Uninfected mutant mice lacking liver STAT3 and RelA; 3) Control mice infected intratracheally for 24h with 10^6 CFU of Streptococcus pneumoniae (serotype 3); and 4) Mutant mice infected intratracheally for 24h with 10^6 CFU of Streptococcus pneumoniae (serotype 3).
2012-02-16 | E-GEOD-32105 | biostudies-arrayexpress
Project description:A common response to physiological duress is the hepatic acute phase response, a process during which the expression of many genes is altered in the liver. Amongst these transcripts are those encoding acute phase proteins, defined as circulating proteins with significantly changed concentrations during an acute phase response. The goal of this study was to determine the influence of two transcription factors, STAT3 and NF-kappaB p65 (RelA), on hepatic gene changes including but not limited to acute phase proteins during bacterial pneumonia. Using the Cre-LoxP system, mice were generated with combined functional deletions of both STAT3 and RelA in hepatocytes. In mutant mice, Cre-recombinase was expressed under transcriptional control of an albumin promoter in the presence of homozygous floxed alleles for both STAT3 and RelA. Wild-type control mice lacked the Cre-recombinase transgene. Microarray analysis was performed on liver RNA collected from both genotypes of mice in the absence and presence of pneumococcal pneumonia.
2012-02-16 | GSE32105 | GEO
Project description:Background and aims: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6 type cytokine signaling required for hepatocyte proliferation and hepatoprotection but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. Methods: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2-/-) as a model for SC. Results: We demonstrate that conditional inactivation of stat3 in hepatocytes and cholangiocytes (stat3 delta hc) of mdr2-/- mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2-/- mice lacking IL-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both, hepatocytes and cholangiocytes. Loss of Stat3 in cholangiocytes led to increased expression of TNFα which might reduce the barrier function of bile ducts. Loss of Stat3 in hepatocytes led to upregulation of bile acid biosynthesis genes and downregulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3deltahc mice were more sensitive to cholic acid-induced liver damage than control mice. Conclusions: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes. Affymetrix microarray analyses was performed to identify metabolic and molecular pathways in stat3Dhc mdr2-/- mice that lead to cholestasis and bile acid-induced liver injury. To avoid false positive results that are due to differential cellular composition, we defined the onset of fibrosis and expression of fibrogenic factors in stat3Dhc mdr2-/- mice.
2010-10-20 | E-GEOD-18759 | biostudies-arrayexpress
Project description:Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have been proposed as potential regulators of energy metabolism. However, numerous aspects of this process remain elusive. In our quest, employing a chemical-genetic screening strategy, we successfully identified the JAK/STAT3 pathway as the primary regulatory mechanism controlling mtDNA G4 dynamics in hypoxic MCF-7 cells. Further proteomic analyses and associated investigations have shed light on the translocation of RelA, a member of the NF-κB family, to the mitochondria upon activation of the JAK/STAT3 pathway. Once localized, RelA directly binds to mtDNA G4s and facilitates their folding, consequently yielding escalated mtDNA instability, impaired mtDNA transcription, and ensuing mitochondrial dysfunction. Ultimately, this intricately orchestrated cascade disrupts the equilibrium of energy metabolism, favoring a more pronounced deviation towards glycolysis. This pioneering revelation introduces an unprecedented and pivotal component to the intricately interconnected framework harnessed by cancer cells, empowering them to undergo metabolic reprogramming and adapt to hypoxic environments.
2024-05-13 | PXD043639 | Pride
Project description:The canonical NF-kB module induces nuclear translocation of RelA heterodimers from the latent cytoplasmic complexes. RelA directs inflammatory immune responses against microbial entities. However, aberrant RelA activity also triggers destructive inflammation, including those associated with inflammatory bowel disease (IBD). What provokes this pathological RelA activity remains unclear. As such, the noncanonical NF-kB pathway activates RelB heterodimers and mediates immune organogenesis. Because NF-kB-activating pathways are interlinked, we asked if noncanonical NF-kB signaling exacerbated intestinal inflammation. Our investigation revealed recurrent engagement of the noncanonical pathway in human IBD. In a mouse model of chemical colitis, the noncanonical NF-kB signaling gene Nfkb2 aggravated inflammation by amplifying the RelA activity induced in intestinal epithelial cells. Our mechanistic studies clarified that noncanonical signaling augmented the abundance of latent RelA complexes leading to hyperactive canonical NF-kB response in the colitogenic gut. In sum, latent dimer homeostasis appears to link noncanonical NF-kB signaling to RelA-driven inflammatory pathologies.
2021-07-07 | GSE148577 | GEO
Project description:Microbial transformation of bile acids affects intestinal immune homeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. Additionally, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.
2024-02-09 | GSE253360 | GEO
Project description:A structure-function study of NF-kB subunit RelA and coactivator CBP/p300 interaction reveals the critical role of CBP/p300 in recruitment of RelA to its target promoter site. mRNA profiles of unstimulated or stimulated with TNFa rela-/- MEF reconstituted with RelA wild type or mutants were generated by deep sequencing, in duplicate
2013-09-09 | E-GEOD-46213 | biostudies-arrayexpress