Transcriptomic profiling of induced steatosis in mouse precision-cut liver slices
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ABSTRACT:
PROVIDER: PRJNA824462 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18675500_1.fastq.gz | Fastqsanger.gz | |||
| SRR18675500_2.fastq.gz | Fastqsanger.gz | |||
| SRR18675501_1.fastq.gz | Fastqsanger.gz | |||
| SRR18675501_2.fastq.gz | Fastqsanger.gz | |||
| SRR18675502_1.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptomic profiling of induced steatosis in precision-cut liver slices
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Project description:Transcriptomic profiling of induced steatosis in human precision-cut liver slices
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Project description:Progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) is a major cause of end-stage liver diseases. There is a high need for predictive human ex vivo models to translate preclinical findings for potential new NAFLD drugs to human disease. About a decade ago, precision cut liver slices (PCLSs) have been established as an ex vivo assay for humans and other organisms. The molecular and functional baseline characteristics of PCLSs have been extensively described previously. In the present study, we provide a comprehensive RNA-Seq based molecular characterization of a new assay for NAFLD that induces steatosis in human and mouse PCLSs culture by incremental supplementation of sugars (glucose and fructose), insulin, and fatty acids (palmitate, oleate). Independent of the triglyceride levels of the human donor liver organs at baseline, the nutrient over-supplementation leads to an increase of triglyceride synthesis and cytokine release to the culture supernatant and thus recapitulates hallmark features of steatosis and inflammation in NAFLD. The mirrored design of human vs. mouse liver slices cultured at the exact same conditions allows a comprehensive assessment of donor variability and the contribution of time vs. nutrient factors to the overall observed molecular pattern and the investigation of conserved and species-specific transcriptional pathways that are involved in steatosis and inflammation of the liver.
2023-05-09 | GSE200418 | GEO
Project description:Progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) is a major cause of end-stage liver diseases. There is a high need for predictive human ex vivo models to translate preclinical findings for potential new NAFLD drugs to human disease. About a decade ago, precision cut liver slices (PCLSs) have been established as an ex vivo assay for humans and other organisms. The molecular and functional baseline characteristics of PCLSs have been extensively described previously. In the present study, we provide a comprehensive RNA-Seq based molecular characterization of a new assay for NAFLD that induces steatosis in human and mouse PCLSs culture by incremental supplementation of sugars (glucose and fructose), insulin, and fatty acids (palmitate, oleate). Independent of the triglyceride levels of the human donor liver organs at baseline, the nutrient over-supplementation leads to an increase of triglyceride synthesis and cytokine release to the culture supernatant and thus recapitulates hallmark features of steatosis and inflammation in NAFLD. The mirrored design of human vs. mouse liver slices cultured at the exact same conditions allows a comprehensive assessment of donor variability and the contribution of time vs. nutrient factors to the overall observed molecular pattern and the investigation of conserved and species-specific transcriptional pathways that are involved in steatosis and inflammation of the liver.
2023-05-09 | GSE200408 | GEO
Project description:The objective of this study is to map early time-response in of estrogen regulated genes using precision cut liver slices (PCLS). PCLS from juvenile male cod were exposed to ethynylestradiol (EE2) in culture for 12, 24 and 48 h and the transcriptome responses were studied using RNA-seq
2023-02-23 | E-MTAB-12605 | biostudies-arrayexpress
Project description:This study was done to show the utility of precision-cut lung slices (PCLS) in supporting the survival of Pneumocystis murina in vitro.
2024-01-24 | GSE247615 | GEO
Project description:There is a high need for predictive human ex vivo models for non-alcoholic fatty liver disease (NAFLD). About a decade ago, precision-cut liver slices (PCLSs) have been established as an ex vivo assay for humans and other organisms. In the present study, we use transcriptomics by RNASeq to profile a new human and mouse PCLSs based assay for steatosis in NAFLD. Steatosis as quantified by an increase of triglycerides after 48 h in culture, is induced by incremental supplementation of sugars (glucose and fructose), insulin, and fatty acids (palmitate, oleate). We mirrored the experimental design for human vs. mouse liver organ derived PCLSs and profiled each organ at eight different nutrient conditions after 24 h and 48 h time in culture. Thus, the provided data allows a comprehensive analysis of the donor, species, time, and nutrient factor specific regulation of gene expression in steatosis, despite the heterogeneity of the human tissue samples. Exemplified this is demonstrated by ranking homologous gene pairs by convergent or divergent expression pattern across nutrient conditions.
| S-EPMC10199090 | biostudies-literature
Project description:miRNA profiling in human precision-cut lung slices (PCLS)
| PRJNA705600 | ENA
Project description:Background: Studies in mice have shown that PPARα is an important regulator of lipid metabolism in liver and a key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARα in human liver. Here we set out to study the function of PPARα in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARα agonist Wy14643. Results: Quantitative PCR indicated that PPARα is well expressed in human liver and human liver slices and that the classical PPARα targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARα activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARα activation (q value<0.05). Many genes induced by PPARα activation were involved in lipid metabolism (ACSL5, AGPAT9, FADS1, SLC27A4), xenobiotic metabolism (POR, ABCC2, CYP3A5) or the unfolded protein response, whereas most of the downregulated genes were involved in immune-related pathways. Among the most highly repressed genes upon PPARα activation were several chemokines (e.g. CXCL9-11, CCL8, CX3CL1, CXCL6), interferon γ-induced genes (e.g. IFITM1, IFIT1, IFIT2, IFIT3) and numerous other immune-related genes (e.g. TLR3, NOS2, and LCN2). Comparative analysis of gene regulation by Wy14643 between human liver slices and primary human hepatocytes showed that down-regulation of gene expression by PPARα is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARα activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARα were identified that were commonly induced by PPARα activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L. Conclusion: Our manuscript demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARα in human liver. Our data underscore the major role of PPARα in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARα in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease. Precision-cut liver slices, prepared from liver biopsies obtained from obese subjects undergoing bariatric surgery, were incubated with the peroxisome proliferator-activated receptor alpha (PPARα) agonist Wy14643 or vehicle for 24hrs, after which gene expression was profiled by array.
2015-11-23 | E-GEOD-71731 | biostudies-arrayexpress
Project description:Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNFM-NM-1 signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1M-NM-1 and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis. Liver slices (diameter 4 mm, thickness 250 M-BM-5m) were pre-incubated at 37M-BM-0C for 1h individually in a well containing 1.3 ml WilliamsM-bM-^@M-^Y medium E with glutamax-1 (Gibco, Paisley, UK), supplemented with 25 mM D-glucose and 50 M-BM-5g/ml gentamicin (Gibco, Paisley, UK) (WEGG medium) in a 12-well plate with shaking (90 times/min) under saturated carbogen atmosphere.
2014-01-22 | E-GEOD-54255 | biostudies-arrayexpress