RNA sequencing of whole mouse liver
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB81328 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13847400_1.fastq.gz | Fastqsanger.gz | |||
| ERR13847400_2.fastq.gz | Fastqsanger.gz | |||
| ERR13847401_1.fastq.gz | Fastqsanger.gz | |||
| ERR13847401_2.fastq.gz | Fastqsanger.gz | |||
| ERR13847402_1.fastq.gz | Fastqsanger.gz |
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Project description:Background & Aims: Liver fibrosis, a serious medical condition with limited therapies, frequently progresses to cirrhosis and other severe complications. Here, we report that cell cycle-related and expression elevated protein in tumor (CREPT) is up-regulated in liver fibrosis. CREPT preferentially enhances transforming growth factor-β (TGF-β)-activated Smad2/3, rather than the canonical Smad2/3-Smad4 complex, thereby facilitating liver fibrosis progression. Methods: We analyzed public transcriptomic and proteomic datasets from patients with liver fibrosis. Human tissue arrays and mouse models of fibrosis were used to investigate CREPT expression patterns. Hepatocyte-specific overexpression (TG-CREPT) and deletion (CREPThep-/-) mice were subjected to acute liver injury (24 h, high-dose CCl4), chronic fibrosis (28 d, low-dose CCl4), and bile duct ligation (BDL) to induce liver fibrosis. Histological, biochemical, and RNA-sequencing (RNA-seq) analyses and CUT&Tag experiments were conducted. Results: CREPT is predominantly enriched in hepatocytes and upregulated in fibrotic liver tissues from patients and mice induced by CCl4 or BDL. Overexpression of CREPT in hepatocytes exacerbates liver injury and fibrosis in mice under acute or chronic CCl4 exposure and BDL challenge. In contrast, hepatocyte-specific deletion of CREPT significantly alleviates liver fibrosis. Mechanistically, CREPT aggravates TGF-β/Smad signaling pathway, preferentially interacting with Smad2/3, but not Smad4, to promote inflammatory responses, and up-regulates fibrogenic genes, including Cebpd, Fosl2 and Fn1. Intriguingly, targeting CREPT with LNP-delivered siRNA (LNP-siCREPT) and GalNAc-delivered siRNA (GalNAc-siCREPT) significantly reduces pre-existing liver fibrosis in mice. Conclusions: Our findings identify a promoting effect of CREPT on liver fibrosis through TGF-β-activated Smad2/3 but not Smad4. Targeting CREPT represents a potential therapeutic strategy for liver fibrosis.
2025-08-28 | GSE306355 | GEO
Project description:To gain insight into the differential signaling pathways triggered in N-RAS-/- versus N-RAS+/+ mice during liver injury and fibrosis, we performed microarray analyses of livers 28 days after CCl4 treatment and BDL surgery, respectively. Our findings suggested that increased cell proliferation and matrix deposition as well as loss of cell homeostasis were characteristic of N-RAS-/- after experimental fibrosis. We used microarrays to detail the global programme of gene expression underlying CCl4 and BDL challenge,
2023-07-15 | GSE236915 | GEO
Project description:Liver fibrosis is a common pathological complication of end-stage liver disease, which is usually associated with chronic liver inflammation and injury. Liver fibrosis was induced by bile duct ligation (BDL) in rats. The differentially expressed genes in liver tissue of BDL rats were identified by microarray technique.
2021-05-09 | GSE174099 | GEO
Project description:PPARδ is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle and liver. The aim of our study was to assess the effect of either the well-validated PPARδ agonist GW501516, or a novel PPARδ agonist KD3010 in mouse models of liver fibrosis. KD3010, but not GW501516, treated mice had markedly less liver injury induced by carbon tetrachloride (CCl4) injections. Deposition of extracellular matrix proteins was lower in the KD3010 group as compared to the vehicle or GW501516 treated group. Interestingly, profibrogenic CTGF was significantly induced by GW501516, but not KD3010, following CCl4 treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for three weeks. Hepatocytes were identified as targets for PPARδ agonist, and primary hepatocytes treated with KD3010 showed decreased serum starvation or CCl4-induced cell death, while GW501516 treated hepatocytes were not protected. KD3010 treatment of hepatocytes decreased reactive oxygen species (ROS) production after CCl4 exposure. In conclusion, our data demonstrate that a novel PPARδ agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis. Given the oral availability and the favorable pharmacologic profile of KD3010, ligand activation of PPARδ represents an attractive and promising target for patients with chronic liver diseases. Total RNA was extracted from primary mouse hepatocytes treated with DMSO or PPARd agonists (KD3010, GW1516)
2012-04-18 | E-GEOD-32121 | biostudies-arrayexpress
Project description:Background: It is poorly understood what cellular types participate in ductular reaction (DR) andwhether DR facilitates recovery from injury or accelerates hepatic fibrosis. The aim of this study is to gaininsights into the role of hepatic progenitor cell (HPC)-originated DR during fibrotic progression.Methods: DR in liver specimens of PBC, chronic HBV infection (CHB) or NAFLD, and four rodentfibrotic models by different pathogenic processes was evaluated. Gli1 expression was inhibited in rodentmodels or cell culture and organoid models by AAV-shGli1 or treating with GANT61.Results: Severity of liver fibrosis was positively correlated with DR extent in patients with PBC, CHB orNAFLD. HPCs were activated, expanded, differentiated into reactive cholangiocytes and constituted“HPC-originated DR”, accompanying with exacerbated fibrosis in rodent models of HPC activation &proliferation (CCl4/2-AAF-treated), Μdr2-/- spontaneous PSC, BDL-cholestatic fibrosis orWD-fed/CCl4-treated NASH-fibrosis. Gli1 expression was significantly increased in enriched pathways invivo and in vitro. Enhanced Gli1 expression was identified in KRT19+-reactive cholangiocytes. SuppressingGli1 expression by administration of AAV-shGli1 or GANT61 ameliorated HPC-originated DR andfibrotic extent. KRT19 expression was reduced after GANT61 treatment in sodium butyrate-stimulated WB-F344 cells or organoids or in cells transduced with Gli1 knockdown lentiviral vectors. In contrast,KRT19 expression was elevated after transducing Gli1 overexpression lentiviral vectors in these cells.Conclusions: During various modes of chronic injury, Gli1 acted as an important mediator of HPCactivation, expansion, differentiation into reactive cholangiocytes that formed DR, and subsequentlyprovoked hepatic fibrogenesis.
2025-08-01 | GSE273215 | GEO
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.
2015-02-19 | E-GEOD-52253 | biostudies-arrayexpress
Project description:Aims Biliary diseases represent around 10% of all chronic liver diseases and affect both adults and children. Currently available biochemical tests detect cholestasis but not early liver fibrosis. Circulating extracellular vesicles (EVs) provide a real-time molecular snapshot of the injured organ in a non-invasive way. We thus aimed at searching for a panel of EV-based biomarkers for cholestasis-induced early liver fibrosis using mice models. Results: Progressive and detectable histological evidence of collagen deposition and liver fibrosis was observed as from Day 8 after bile duct ligation (BDL) in mice. Whole transcriptome and small RNA-seq analyses of circulating EVs revealed differentially enriched RNA species after BDL versus sham controls. Unsupervised hierarchical clustering identified a signature that allowed for discrimination between BDL and controls. In particular, 151 microRNAs enriched in BDL-derived EVs were identified, of which 66 were conserved in humans. The liver was an important source of circulating EVs in BDL animals as evidenced by the enrichment of several hepatic mRNAs, such as Albumin, Haptoglobin, Transferrin receptor 1 and Alas2. Interestingly, among experimentally validated miRNAs, miR194-5p and miR29-3p showed similar enrichment patterns also in EVs derived from DDC-treated (drug-induced cholestasis) and MDR2-/- (genetic cholestasis) mice. Innovation A panel of mRNAs and miRNAs contained in circulating EVs, when combined, provides sensitive biomarkers for the early detection of hepatic damage and fibrosis. Conclusion Analysis of EVs for enrichment in miR29-3p and miR194-5p, in combination with hepatic injury RNA markers, could represent a sensitive biomarker panel for the early detection of cholestasis-induced liver fibrosis.
2022-02-28 | GSE166753 | GEO
Project description:Aims Biliary diseases represent around 10% of all chronic liver diseases and affect both adults and children. Currently available biochemical tests detect cholestasis but not early liver fibrosis. Circulating extracellular vesicles (EVs) provide a real-time molecular snapshot of the injured organ in a non-invasive way. We thus aimed at searching for a panel of EV-based biomarkers for cholestasis-induced early liver fibrosis using mice models. Results: Progressive and detectable histological evidence of collagen deposition and liver fibrosis was observed as from Day 8 after bile duct ligation (BDL) in mice. Whole transcriptome and small RNA-seq analyses of circulating EVs revealed differentially enriched RNA species after BDL versus sham controls. Unsupervised hierarchical clustering identified a signature that allowed for discrimination between BDL and controls. In particular, 151 microRNAs enriched in BDL-derived EVs were identified, of which 66 were conserved in humans. The liver was an important source of circulating EVs in BDL animals as evidenced by the enrichment of several hepatic mRNAs, such as Albumin, Haptoglobin, Transferrin receptor 1 and Alas2. Interestingly, among experimentally validated miRNAs, miR194-5p and miR29-3p showed similar enrichment patterns also in EVs derived from DDC-treated (drug-induced cholestasis) and MDR2-/- (genetic cholestasis) mice. Innovation A panel of mRNAs and miRNAs contained in circulating EVs, when combined, provides sensitive biomarkers for the early detection of hepatic damage and fibrosis. Conclusion Analysis of EVs for enrichment in miR29-3p and miR194-5p, in combination with hepatic injury RNA markers, could represent a sensitive biomarker panel for the early detection of cholestasis-induced liver fibrosis.
2022-02-28 | GSE166752 | GEO
Project description:BACKGROUND & AIMS: c-Jun N-terminal kinase (JNK)1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated, via phosphorylation, in response to acetaminophen- or CCl4-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissues from patients and in mice with genetic deletion of JNK in hepatocytes. METHODS: We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, non-steroidal anti-inflammatory drugs or autoimmune hepatitis), or patients without acute liver failure (controls), collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1Îhepa) or combination of Jnk1 and Jnk2 (JnkÎhepa), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray, and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes. RESULTS: Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to JnkÎhepa mice produced a greater level of liver injury than that observed in Jnk1Îhepa or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in JnkÎhepa mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared to Jnk1Îhepa or control mice. Hepatocytes from JnkÎhepa mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of AMPK, total protein AMPK levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected JnkÎhepa and control mice from liver injury. CONCLUSIONS: In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects. Livers and primary hepatocytes were isolated from wild type and JNKÎhepa (Jnk1Îhepa/global Jnk2-/-) double-knockout mice and subjected to gene expression profiling.
2016-01-04 | E-GEOD-59602 | biostudies-arrayexpress
Project description:TGFβ/BMP family member Bone Morphogenetic Protein 8b (Bmp8b) is upregulated in NASH (Western Diet -WD- Model), acute liver damage (CCl4 model) and by Partial Hepatectomy (PH). Absence of Bmp8b reduces liver inflammation and fibrosis in the NASH model (WD). In the acute (3days) CCl4 model, absence of Bmp8b impacts acute inflammatory responses, hepatic stellate cells (HSC) activation, and compensatory hepatocyte proliferation; defective inflammatory pathways and hepatocytes proliferation is also observed in the Partial hepatectomy model. BMP8b is thus a pathophysiologically relevant target to modulate the responses to damage in acute and chronic liver disease.
2020-04-01 | GSE110404 | GEO