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Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE183899 | GEO | 2023/05/02

REPOSITORIES: GEO

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Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease.

Project description: Not available

| S-EPMC10066269 | biostudies-literature

Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease [mouse data set]

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

Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease [human data set]

2023-05-02 | GSE183754 | GEO

Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease

Project description:Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease

| PRJNA762302 | ENA

Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease [human data set]

| PRJNA761973 | ENA

Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease [mouse data set]

| PRJNA762281 | ENA

Adaptive downregulation of Cl-/HCO3- exchange activity in rat hepatocytes under experimental obstructive cholestasis.

Project description:In obstructive cholestasis, there is an integral adaptive response aimed to diminish the bile flow and minimize the injury of bile ducts caused by increased intraluminal pressure and harmful levels of bile salts and bilirrubin. Canalicular bicarbonate secretion, driven by the anion exchanger 2 (AE2), is an influential determinant of the canalicular bile salt-independent bile flow. In this work, we ascertained whether AE2 expression and/or activity is reduced in hepatocytes from rats with common bile duct ligation (BDL), as part of the adaptive response to cholestasis. After 4 days of BDL, we found that neither AE2 mRNA expression (measured by quantitative real-time PCR) nor total levels of AE2 protein (assessed by western blot) were modified in freshly isolated hepatocytes. However, BDL led to a decrease in the expression of AE2 protein in plasma membrane fraction as compared with SHAM control. Additionally, AE2 activity (JOH-, mmol/L/min), measured in primary cultured hepatocytes from BDL and SHAM rats, was decreased in the BDL group versus the control group (1.9 ± 0.3 vs. 3.1 ± 0.2, p<0.005). cAMP-stimulated AE2 activity, however, was not different between SHAM and BDL groups (3.7 ± 0.3 vs. 3.5 ± 0.3), suggesting that cAMP stimulated insertion into the canalicular membrane of AE2-containing intracellular vesicles, that had remained abnormally internalized after BDL. In conclusion, our results point to the existence of a novel adaptive mechanism in cholestasis aimed to reduce biliary pressure, in which AE2 internalization in hepatocytes might result in decreased canalicular HCO3- output and decreased bile flow.

| S-EPMC6383990 | biostudies-literature

Analysis of Flavonoids Bioactivity for Cholestatic Liver Disease: Systematic Literature Search and Experimental Approaches.

Project description:Flavonoids are naturally occurring compounds that show health benefits on the liver. However, there is little investigation about identification and evaluation of new flavonoid-containing drugs for cholestatic liver disease, one of the most common liver illnesses. We aimed to a systematic search regarding efficacy of flavonoids for treatment of cholestatic liver disease, and then evaluate naringenin (NG) as representative flavonoid in an obstructive cholestasis model. We searched for information of experimental and clinical studies in four major databases without time and language limits. Intervention was defined as any flavonoid derivate compared with other flavonoid, placebo, or without comparator. In addition, we evaluated NG on a bile duct-ligated model in order to contribute evidence of its actions. Eleven experimental reports that support the efficacy of flavonoids in cholestatic liver disease were identified. However, there was no homogeneity in efficacy endpoints evaluated and methodology. On the other hand, NG showed beneficial effects by improving specific metabolic (cholesterol and lipoproteins) and liver damage (bilirubin and alkaline phosphatase) biomarkers. The review lacks homogeneous evidence about efficacy of flavonoids in experimental settings, and is susceptible to risk for bias. NG only showed improvements in specific disease biomarkers. More investigation is still needed to determine its potential for drug development.

| S-EPMC6468533 | biostudies-literature

Benefit of farnesoid X receptor inhibition in obstructive cholestasis.

Project description:The nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor have been implicated in regulating bile acid, lipid, carbohydrate, and xenobiotic metabolism. Bile duct ligation was used to increase endogenous bile acids and evaluate the roles of these receptors in modulating cholestatic liver injury. FXR knockout (KO) mice were found to be protected from obstructive cholestasis. Concurrent deletion of FXR also could ameliorate an increase in liver injury that is seen usually in pregnane X receptor KO mice with cholestasis. Mechanisms proposed for this protection include the lowering of bile acid concentrations and altered expression of the hepatic transporters Mdr1, Mdr2, BSEP, and Mrp4. FXR KO mice also exhibit a biphasic lipid profile after bile duct ligation, with an increase in high-density lipoprotein cholesterol and triglycerides by day 6. The expression of apolipoprotein AV was reduced in these mice, implicating FXR in triglyceride regulation. We show that FXR modulates cholestasis by controlling bile acids within the hepatocyte and is involved in bile acid synthesis, bile excretion via BSEP, and serum export via Mrp4. This study strongly suggests a potential clinical role for FXR antagonists in the treatment of obstructive cholestatic liver disorders.

| S-EPMC1544085 | biostudies-literature

A comparison of gene expression in mouse liver and kidney in obstructive cholestasis utilizing high-density oligonucleotide microarray technology.

Project description:AimTo assess the effects of obstructive cholestasis on a wider range of gene expression using microarray technology.MethodsMale C57BL/6J mice underwent common bile duct ligation (BDL) and were matched with pair-fed sham-operated controls. After 7 d, the animals were sacrificed and total RNA was isolated from livers and kidneys. Equal amounts of RNA from each tissue were pooled for each group and hybridized to Affymetrix GeneChip MG-U74Av2 containing a total of 12488 probe sets. Data analysis was performed using GeneSpring 6.0 software. Northern analysis and immunofluorescence were used for validation.ResultsIn sham-operated and BDL mice, 44 and 50% of 12488 genes were expressed in livers, whereas 49 and 51% were expressed in kidneys, respectively. Seven days after BDL, 265 liver and 112 kidney genes with GeneOntology annotation were up-regulated and 113 liver and 36 kidney genes were down-regulated in comparison with sham-operated controls. Many genes were commonly regulated in both tissues and metabolism-related genes represented the largest functional group.ConclusionFollowing BDL, microarray analysis reveals a broad range of gene alterations in both liver and kidney.

| S-EPMC4087986 | biostudies-literature

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