High-throughput sequencing reveals induction of drug metabolism in various cholestatic livers
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE116627 | GEO | 2020/06/01
REPOSITORIES: GEO
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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:Cholestatic liver diseases are characterized by excessive accumulation of bile acids in the liver. The involvement of local tissue microenvironment in cholestatic diseases remains poorly understood. Here, we performed a comprehensive analysis of liver single-cell transcriptomic study of human cholestatic liver diseases. Our study involved 9 liver samples obtained from 7 patients diagnosed with hepatatrophia resulting from cholestasis. By utilizing single-cell data, we gained valuable insights into the specific functions of endothelial cells (EC) in response to chenodeoxycholic acid during cholestasis. The findings from our study hold the potential to lay the groundwork for personalized therapeutic approaches in the future, tailored to the individual needs of patients.
2023-07-22 | GSE237622 | GEO
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.
2010-12-10 | E-GEOD-20599 | 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:Bile acid accumulation and subsequent liver damage is a frequent adverse effect induced by drugs. Considerable efforts have therefore been focused on the introduction and characterization of tools that allow reliable prediction of this type of drug-induced liver injury. Among those are the cholestatic index and transcriptomic profiling, which are typically assessed in in vitro settings. The present study was set up to test the applicability of both tools to non-pharmaceutical compounds with cholestatic potential, including the industrial compound bis(2-ethylhexyl)phthalate, the cosmetic ingredients triclosan and octynoic acid, the herbicides paraquat and quizalofop-para-ethyl, and the food additives sunset yellow and tartrazine, in a human hepatoma cell culture model of cholestatic liver injury. The cholestatic index method showed cholestatic liability of sunset yellow, tartrazine and triclosan. Of those, tartrazine induced transcriptional changes reminiscent of the transcriptional profile of cholestatic drugs. Furthermore, a number of genes were found to be uniquely modulated by tartrazine, in accordance with the cholestatic drugs atazanavir, cyclosporin A and nefazodone, which may have potential as novel transcriptomic biomarkers of chemical-induced cholestatic liver injury. In conclusion, unambiguous identification of the non-pharmaceutical compounds tested in this study as inducers of cholestasis could not be achieved.
2021-03-18 | GSE169072 | GEO
Project description:Liver cholestasis is a chronic liver disease (CLD) which belongs to a major health problem. Cholestasis is characterised by a decrease in bile flow due to impaired secretion by hepatocytes or by obstruction of bile flow through intra- or extrahepatic bile ducts. Thereby cholestasis can induce ductal proliferation, hepatocyte injury and liver fibrosis. Notch signalling promotes the formation and maturation of ductular reactions. We investigated the liver regeneration process in the context of cholestasis induced by disruption of the Notch signalling pathway. Liver-specific deletion of Rbpj, which represents a key regulator of Notch signalling, induces severe cholestasis through impaired IHBD maturation, severe necrosis and increased lethality. Deregulation of the biliary compartment and cholestasis are associated with change of several signalling pathways including the Hippo pathway resulting in upregulation of SOX9, which is associated with transdifferentiation of hepatocytes. SOX9 upregulation in cholestatic liver injury in vitro is independent of Notch signalling. We could comprehensively address that Rbpj depletion is followed by deregulation of YAP/TEAD, which influences transdifferentiation of hepatocytes and thereby contributing to liver regeneration. In this study the liver regeneration process was analyzed in 4 weeks old Rbpj knockout mice and compared to 4 weeks old Rbpj wildtype mice.
2018-10-17 | GSE121302 | GEO
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation.
2010-12-10 | GSE20599 | GEO
Project description:We performed high-throughput RNA-sequencing on livers from hepatocyte specific Fxr-/- Shp-/- double knockout mice, and identified upregulation of N-glycan protein modification machinery. This correlated positively with Golgi structural defects and alterations in the hepatic secretome. This study identifies a new role for hepatic FXR-SHP axis in Golgi dynamics and N-glycosylation, apart from its traditional function in nutrient metabolism.
2021-03-09 | GSE164447 | GEO
Project description:Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in development of drug targets. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXRα during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains (TAD) and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, TADs, intra-chromosomal and inter-chromosomal Foxa2-anchored loops, drastically changes upon addition of FXR agonist. Hence, we determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.
2023-10-16 | GSE229049 | GEO
Project description:Cholelithiasis-induced cholestasis is one of the most common causes of hospitalization due to gastrointestinal disease, yet considerable knowledge gaps exist in the pathogenesis of this disease. This can partially be explained by inadequate characterization of experimental cholestasis models. Therefore, we compared the transcriptional profile of commonly used mouse models for obstructive cholestasis and benchmarked them to human disease to identify the model(s) best suited for cholelithiasis-induced cholestasis research and to uncover conserved mechanisms involved in human and murine cholestasis. Selected mouse models included bile duct ligation (BDL) surgery, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet, associated with extra- and intrahepatic obstructive cholestasis, respectively, and a drug-induced cholestasis model relying on cyclosporin A (CsA), in an acute and chronic setting. Human samples were collected from patients with cholelithiasis-induced cholestasis of an acute and recurrent nature. RNA sequencing was performed on mouse and human liver tissue. Both the BDL and DDC models, but not the CsA model, were shown to be applicable for studying cholelithiasis-induced cholestasis, with transcriptomic profiles that highly correspond to acute cholestasis in human patients. In particular, the conservation of canonical pathways related to the inflammatory response and cytoskeleton organization, in which the Rho family GTPase is involved, were identified. This study furthermore revealed some promising mechanistic-based transcriptomic biomarkers relevant for murine and human cholestasis, which could potentially be useful for robust prediction and detection of diverse types of cholestatic liver disease.
2023-05-02 | GSE183882 | GEO