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

PROVIDER: PRJNA762302 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15837400.fastq.gz	Fastqsanger.gz
	SRR15837401.fastq.gz	Fastqsanger.gz
	SRR15837402.fastq.gz	Fastqsanger.gz
	SRR15837403.fastq.gz	Fastqsanger.gz
	SRR15837404.fastq.gz	Fastqsanger.gz

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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 [human 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 | GSE183754 | GEO

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

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]

Project description: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

Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury

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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-02 | GSE183899 | GEO

Discrimination of etiologically different cholestasis by modeling proteomics datasets

Project description:Cholestasis is characterized by disrupted bile flow from the liver to the small intestine. Although etiologically different cholestasis display similar symptoms, diverse factors can contribute to the progression of the disease and determines the appropriate therapeutic option. Therefore, stratifying cholestatic patients is essential for the development of tailor-made treatment strategies. Here, we have analyzed the liver proteome from cholestatic patients of different etiology. 7,161 proteins were identified and quantified, of which 263 were differentially expressed between control and cholestasis groups. These differential proteins point to deregulated cellular processes that explain part of the molecular framework of cholestasis progression. However, the clustering of different cholestasis types was limited. Therefore, a machine learning pipeline was designed to identify a panel of 20 differential proteins that segregate different cholestasis groups with high accuracy and sensitivity. In summary, proteomics combined with machine learning algorithms provides valuable insights into the molecular mechanisms of cholestasis progression and a panel of proteins to discriminate across different types of cholestasis. This strategy may prove useful to develop precision medicine approaches for patient care.

2024-05-22 | PXD047823 | Pride

single-cell transcriptional profiling of human cholestatic livers

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

Obstructive cholestasis compromises balance and alters brain lipid composition in neonatal piglets

Project description:Infants with neonatal cholestasis are prone to neurodevelopmental deficits including neuromotor function. Accumulation of potentially neurotoxic molecules in the bloodstream including ammonia and bile acids and malabsorption of lipids may affect neurodevelopment in these patients. This study examined neuromotor function and bile acid and lipid composition of the brain in a piglet model of obstructive neonatal cholestasis via bile duct ligation (BDL) surgery. Results showed that BDL piglets had compromised balance and increased liver enzyme levels, liver fibrosis and bile duct proliferation compared to SHAM piglets. Plasma and cerebellum bile acid profiles differed between BDL and SHAM piglets with hyocholic acid and conjugated bile acid forms dominating in the BDL group. In the cerebellum there were different lipid profiles, but similar gene expression profiles between the two groups.

2022-06-01 | GSE180600 | GEO

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