Intestinal expression of ASBT determines the sclerosing cholangitis phenotype.
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ABSTRACT:
PROVIDER: PRJNA546456 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: Determine the impact of ASBT genotype on the onset and progression of liver disease, using RNA-sequencing to characterize the transcriptome of ASBT wildtype and knockout mice. We assess alterations at the gene and mechanistic-levels. Methods: mRNA profiles were generated in 45-day-old ASBT WT and KO mice (BALB/cJ background). Data were processed using the Tuxedo Pipeline, using the mm10 genome with annotations provided by Ensembl. Results: We identified 1406 differentially expressed transcripts between knockout and wildtype mice, with ontologies heavily weighted toward fibrotic and inflammatory processes, with immune cell infiltration. Conclusions: Knockout of ASBT induces increased liver injury through exposure to elevated bile acids.
2019-06-04 | GSE132168 | 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: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
Project description:Background. Abcb4 (-/-) mice secrete phosphatidylcholine-deficient bile and develop sclerosing cholangitis (SC). The cholangitis involves differential hepatic transcription of genes whose products govern inflammation, activation of hepatic stellate cells and fibrosis. This study was undertaken to test the hypothesis that several genes involved in regulation of tissue inflammation and fibrosis display transcription rates that reflect SC disease activity. Methods. Abcb4 (-/-) mice fed cholic acid (CA) display high SC activity and ursodeoxycholic acid (UDCA) fed mice display low SC activity. Differential hepatic transcription of genes was accordingly measured in abcb4 (-/-) mice maintained on CA- and UDCA-supplemented diets using cDNA microarrays. Abcb4 (+/+) mice served as controls. The differential transcription of selected genes was verified by real time polymerase chain reaction. Liver tissue pathology was quantified by histopathology scoring and immunohistochemistry to visualize bile duct cells and activated hepatic stellate cells. Results. Differential transcription of Ccl2, Ccl20, Cxcl10, Nfκb1, Nfκb2, Tgfβ1, Tgfβ2, Sparc, Ctgf, Lgals3, Elf3, Spp1, Pdgfa, Pdgfrb, Col1a1, Col1a2 and Col4a1 genes paralleled the differing SC activities of cholic acid- and UDCA-fed abcb4 (-/-) mice. Histopathology scores and immunohistochemistry showed greatly enhanced activation of hepatic stellate cells during high SC activity due to CA feeding. Conclusion. Differential transcription of several genes relating to tissue inflammation and hepatic stellate cell activation parallels SC activity in abcb4 (-/-) mice. Data on their differential transcription may be used to gauge SC disease activity.
2008-08-20 | GSE11507 | GEO
Project description:To qualitatively and quantitatively analyze enterohepatically-circulated molecules using targeted bile acid concentrations of peripheral blood collected from primary sclerosing cholangitis (PSC) patients compared to normal and diseased controls. There are three groups of patients. (1) Normal donor controls (ND), (2) Patients with Primary Sclerosing Cholangitis (PSC), and (3) Disease Controls (DC) which are patients with liver disease other than PSC.
2017-07-05 | ST000998 | MetabolomicsWorkbench
Project description:To qualitatively and quantitatively analyze enterohepatically-circulated molecules using targeted acyl carnitines concentrations of peripheral blood collected from primary sclerosing cholangitis (PSC) patients compared to normal and diseased controls. There are three groups of patients. (1) Normal donor controls (ND), (2) Patients with Primary Sclerosing Cholangitis (PSC), and (3) Disease Controls (DC) which are patients with liver disease other than PSC.
2017-07-05 | ST000997 | MetabolomicsWorkbench
Project description:To qualitatively and quantitatively analyze enterohepatically-circulated molecules using targeted amino acid concentrations of peripheral blood collected from primary sclerosing cholangitis (PSC) patients compared to normal and diseased controls. There are three groups of patients. (1) Normal donor controls (ND), (2) Patients with Primary Sclerosing Cholangitis (PSC), and (3) Disease Controls (DC) which are patients with liver disease other than PSC.
2018-07-05 | ST000995 | MetabolomicsWorkbench
Project description:CCL24 is a profibrotic, proinflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Mdr2-/- mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24 neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under profibrotic conditions in primary human cholangiocytes and macrophages and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of PSC patients. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in PSC patients via reduced liver inflammation, fibrosis and cholestasis.
2023-04-30 | GSE228596 | GEO
Project description:To qualitatively and quantitatively analyze enterohepatically-circulated molecules using targeted free fatty acid concentrations of peripheral blood collected from primary sclerosing cholangitis (PSC) patients compared to normal and diseased controls. There are three groups of patients. (1) Normal donor controls (ND), (2) Patients with Primary Sclerosing Cholangitis (PSC), and (3) Disease Controls (DC) which are patients with liver disease other than PSC.
2017-07-05 | ST000996 | MetabolomicsWorkbench
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 (SC) 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 (stat3Δhc) of mdr2-/- mice strongly aggravated bile acid-induced liver injury and fibrosis. Similarly, stat3Δhc mice are more sensitive to cholic acid feeding than control mice. Global gene expression analysis demonstrated that hepatoprotective signals via epidermal growth factor and insulin-like growth factor 1 are affected upon loss of Stat3. Conclusions: Our data suggest that Stat3 protects cholangiocytes and hepatocytes from bile acid-induced damage thereby preventing liver fibrosis in cholestatic diseases.
2010-10-20 | GSE18759 | GEO