ASBT inhibition alleviates cholangiopathy and hepatic fibrosis development in Cyp2c70-/- mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE183251 | GEO | 2022/08/08
REPOSITORIES: GEO
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Project description:We report the effect of a potent pharmacological inhibition of ASBT in mdr2 -/- mice, compared to genetic and treatment controls using RNA-sequencing. Through quantification of mRNA in liver samples, we found significant upregulation of anti-inflammatory and anti-fibrotic gene signatures in mdr2-/- mice. Additionally, we report downregulation of pro-inflammatory genes invovled in leukocyte recruitment. Mdr2 knockout mice (female, 30 day old) were fed high fat-chow diet containing a potent inhibitor of ASBT for 14 days. Genotypic and dietary controls were included. RNA-sequencing was performed on liver samples taken from the caudate lobe.
2016-02-17 | E-GEOD-66231 | biostudies-arrayexpress
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 (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
Project description:We report the effect of a potent pharmacological inhibition of ASBT in mdr2 -/- mice, compared to genetic and treatment controls using RNA-sequencing. Through quantification of mRNA in liver samples, we found significant upregulation of anti-inflammatory and anti-fibrotic gene signatures in mdr2-/- mice. Additionally, we report downregulation of pro-inflammatory genes invovled in leukocyte recruitment.
2016-02-17 | GSE66231 | 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: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:Escherichia coli strain:ASBT-1 Genome sequencing and assembly
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Project description:Transplantation of pluripotent stem cell (PSC) derived liver organoids have been studied to solve the donor shortage. However, differentiation of unintended cell populations, challenges in generating multi-lineage organoids, and tumorigenicity hinder its uses in clinics. Here, liver assembloids (iHEA) were generated by integrating induced endothelial cells (iEC) and induced hepatic stem cells (iHepSC). iHEA showed enhanced functional maturity iHepSCs derived liver organoids (iHLO) in vitro and had improved therapeutic effects on cholestatic liver fibrosis animals in vivo. Mechanistically, FN1 expressed from iECs led to up-regulation of Itgalph5/beta1 and Hnf4alpha in iHEA and were correlated to decrease of hepatic stellate cells activation genes such as Lox, and Spp1 in the cholestatic liver fibrosis animals. In conclusion, our study demonstrates that directly converted cells can be a promising source for generating transplantable assembloids. This study is designed to generate liver organoids (iHLO) and liver assembloids (iHEA) using induced stem cells generated by direct conversion. Hepatic maturity of iHLO and iHEA were compared by measuring gene expression, albumin/urea secretion and CYP1A2 activity. The experiments were repeated at least three times, and the replicates are indicated in each figure and legend. N values represent the number of animals in the experiment. All animal experimental procedures were approved and conducted under a protocol (UNISTIACUC-20-49) by the Animal Care and Use Committee of Ulsan National Institute of Science and Technology (UNIST, Ulsan, South Korea). The experiments were carried out in accordance with documented standards of the Institutional Review Board of Ulsan National Institute of Science and Technology (UNIST) (UNISTIRB-15–17 C) for human cell experiments.
2022-08-03 | GSE193768 | GEO
Project description:Hepatic fibrosis, a common pathological manifestation of chronic liver injury, is generally considered to be the end result of an increase in extracellular matrix produced by activated hepatic stellate cells (HSCs). Targeting the mechanisms underlying HSC activation may provide a powerful therapeutic strategy for the prevention and treatment of liver fibrosis. A high-throughput screening assay was established, and the histone deacetylase inhibitor givinostat was identified as a potent inhibitor of HSC activation in vitro. Givinostat significantly inhibited HSC activation in vivo, ameliorated carbon tetrachloride-induced mouse liver fibrosis and lowered plasma aminotransferases. Transcriptomic analysis revealed the most significantly regulated genes in the givinostat treatment group in comparison with those in the solvent group, among which, Dmkn, Msln and Upk3b were identified as potential regulators of HSC activation. Givinostat significantly reduced the mRNA expression of Dmkn, Msln and Upk3b in both a mouse liver fibrosis model and in HSC-LX2 cells. Knocking down any of the aforementioned genes inhibited the TGF-β1-induced expression of α-smooth muscle actin and collagen type I, indicating that they are crucial for HSC activation. In summary, using a novel strategy targeting HSC activation, the present study identified a potential epigenetic drug for the treatment of hepatic fibrosis and revealed novel regulators of HSC activation.
2020-12-01 | GSE161981 | GEO