Transcriptome analysis of activated fibroblasts isolated from fibrotic livers
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE134512 | GEO | 2019/12/31
REPOSITORIES: GEO
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Project description:In chronic liver diseases, hepatic stellate cells (HSCs) are induced to form the myofibroblasts responsible for scar formation, leading to liver fibrosis and cirrhosis. Here, single-cell RNA sequencing with in vivo lineage tracing in non-alcoholic steatohepatitis (NASH) model mice reveals a subpopulation of HSCs transitioning back to a state resembling their developmental precursors, mesothelial cells (MCs), after liver injury. These damage-associated intermediates between HSCs and MCs (DIHMs) can be traced with a dual recombinase system by labeling Krt19-expressing cells within pre-labeled Pdgfrb-positive HSCs, and DIHMs highly express inflammation- and fibrosis-associated genes. Cre and Dre-inducible depletion of DIHMs by administering diphtheria toxin reduces liver fibrosis and alleviates liver damage in NASH model mice. Importantly, knockdown of Osr1, a zinc finger transcription factor of the OSR gene family, can block DIHM induction in vitro. Conditional knockout Osr1 in Pdgfrb-expressing mesenchymal cells in NASH model mice can reduce liver fibrosis in vivo. Our study collectively uncovers an injury-induced developmental reversion process wherein HSCs undergo what we term a mesenchymal-to-mesothelial transition (MMesoT), which can be targeted to develop interventions to treat chronic liver diseases.
2024-01-12 | GSE252999 | GEO
Project description:Hepatocyte death plays a critical role in the disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH). We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated free cholesterol was accumulated in macrophages around dead hepatocytes containing cholesterol crystals. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.
2023-06-20 | GSE235024 | GEO
Project description:The lack of a preclinical model of nonalcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC) that recapitulates human disease is a major barrier to therapeutic development. We report a high fat-high sugar diet-induced NASH and HCC in a stable isogenic 129S1/SvImJ crossed with C57Bl/6J mice. Following diet initiation, there was sequential development of steatosis (4-8 weeks), steatohepatitis with ballooning and Mallory-Denk bodies (12-16 weeks), progressive fibrosis (16 week onwards) and spontaneous HCC (32-52 weeks). The mice developed obesity, insulin resistance and dyslipidemia. There was concordance with the human NASH transcriptome (FDR 0.001) with activation of lipogenic, inflammatory and apoptotic pathways relevant in humans. The HCC gene signature resembled S1 and S2 human HCC subclass (FDR 0.01 for both). This simple model of NASH and HCC that resembles human disease in terms of its triggers, physiological and biochemical parameters, histology, transcriptomic profile, and outcomes can facilitate preclinical development for these conditions. 129S1/SvImJ;C57Bl/6J (129/B6) mice were fed with high-fat diet (Western Diet) and high fructose-glucose solution (Sugar Water) (WD SW) or chow diet (CD) for 8 weeks, and total RNA samples were isolated from liver tissues for genome-wide expression profiling.
2016-07-25 | E-GEOD-67678 | biostudies-arrayexpress
Project description:The lack of a preclinical model of nonalcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC) that recapitulates human disease is a major barrier to therapeutic development. We report a high fat-high sugar diet-induced NASH and HCC in a stable isogenic 129S1/SvImJ crossed with C57Bl/6J mice. Following diet initiation, there was sequential development of steatosis (4-8 weeks), steatohepatitis with ballooning and Mallory-Denk bodies (12-16 weeks), progressive fibrosis (16 week onwards) and spontaneous HCC (32-52 weeks). The mice developed obesity, insulin resistance and dyslipidemia. There was concordance with the human NASH transcriptome (FDR 0.001) with activation of lipogenic, inflammatory and apoptotic pathways relevant in humans. The HCC gene signature resembled S1 and S2 human HCC subclass (FDR 0.01 for both). This simple model of NASH and HCC that resembles human disease in terms of its triggers, physiological and biochemical parameters, histology, transcriptomic profile, and outcomes can facilitate preclinical development for these conditions. 129S1/SvImJ;C57Bl/6J (129/B6) mice were fed with high-fat diet (Western Diet) and high fructose-glucose solution (Sugar Water) (WD SW) or chow diet (CD) for 52 weeks, and total RNA samples were isolated from liver and tumor tissues for genome-wide expression profiling.
2016-07-25 | E-GEOD-67679 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. METHODS: Microarray was performed to identify differentially expressed genes in NASH. Quantitative real time PCR (qRT-PCR) was used to examine gene expression levels. Western blotting and immunofluorescence staining were employed to examine hemoglobin proteins. Flow cytometry was used to measure intracellular oxidative stress. RESULTS: Analysis of microarray gene expression data has revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopspies from NASH patients. Increased hemoglobin expression in NASH was validated by qRT-PCR. However, the expression of erythrocyte specific marker genes such as SPTA, SPTB, GYPA, GATA1, and ALAS2 did not change, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, induced a dose dependent increase in HBA1 expression in HepG2 cells. Intriguingly, forced hemoglobin expression suppressed oxidative stress. CONCLUSIONS: Oxidative stress upregulates hemoglobin expression in hepatocytes. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage. These findings suggest that hemoglobin is an inducible antioxidant in hepatocytes in response to increased oxidative stress as found in NASH livers. Twelve biopsy diagnosed NASH patients were included in this study. For control groups, total RNA from 5 different subjects were purchased from ADMET. These subjects are free from liver disease.
2010-10-20 | E-GEOD-24807 | biostudies-arrayexpress
Project description:Obesity-associated lipid overload triggers non-alcoholic fatty liver diseases (NAFLD), which in part may be driven by alterations of regulatory transcription networks and hepatocyte-selective epigenomes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR)/ histone deacetylase 3 (HDAC3) complex, is a central component of such networks and accelerates the progression of non-alcoholic steatohepatitis (NASH). In hepatocyte-specific Gps2 knockout mice, loss of GPS2 alleviated the development of diet-induced steatosis and fibrosis and caused activation of lipid catabolic genes. By determining differential cistromes, epigenomes and transcriptomes in wild-type, single and double knockout mice, we identified the lipid-sensing nuclear receptor PPARa as a direct target of GPS2. We also provide evidence that in hepatocytes, unlike in macrophages, GPS2 acts in concert with the NCOR subunit of the corepressor complex. By analyzing the liver transcriptomes of human patients, we found that GPS2 expression positively correlated with the expression of NASH/fibrosis signature genes. Collectively, our data suggest that the GPS2-PPARa partnership in hepatocytes may influence the development of NASH/fibrosis in mice and in humans.
2019-03-12 | GSE113157 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity, where insulin resistance and hepatocyte fat deposition may progress to steatohepatitis (NASH) and fibrosis/ cirrhosis. NASH has no approved treatment. Consequent upon hepatic fat deposition, NF-κB activation in hepatic myeloid cells mediates inflammation and NASH progression. We delivered micro-doses of liposome-encapsulated lipophilic NF-κB inhibitors, curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol), to the pro-fibrogenic inflammatory liver macrophages and dendritic cells (DCs) in diet-induced NASH. After i.v. administration, liver was the primary organ targeted. MHC class-II+ hepatic DCs taking up liposomes in mice and human were F4/80+ and CD14+ respectively, were lipid-laden and expressed pro-inflammatory genes. Curcumin or calcitriol liposomes suppressed hepatic inflammation, fibrosis and fat accumulation, and reduced insulin resistance associated with suppression of immune activation, cell cycle and collagen deposition pathways in vivo. Thus, hepatic inflammatory DCs passively targeted with liposomes encapsulating lipophilic NF-κB inhibitors are beneficial in NASH.
2020-01-22 | GSE94593 | GEO
Project description:Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease worldwide with limited treatment options. Liver fibrosis, driven by chronic inflammation and hepatic stellate cells (HSCs) activation, critically determines morbidity and mortality in patients with NASH. Pyruvate kinase M2 (PKM2) is involved in immune activation and inflammatory liver diseases; however, its role and therapeutic potential in NASH fibrosis remain largely unexplored. By bioinformatic screening and analysis of human and murine NASH livers, we found that PKM2 was specifically upregulated in non-parenchymal cells (NPCs) in fibrotic NASH livers, especially in macrophages. Macrophage-specific Pkm2 knockout (Pkm2fl/flLysMCre) significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by methionine–choline-deficient (MCD) diet, high-fat high-cholesterol (HFHC) diet and western diet plus weekly carbon tetrachloride injection (WD/CCl4). Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophage reduced profibrotic Ly6Chigh macrophage infiltration. Mechanistically, PKM2-dependent glycolysis promotes NLRP3 activation in proinflammatory macrophages, thus inducing HSCs activation and fibrogenesis. Pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo. Translationally, ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides, a novel oligonucleotide drug that preferentially accumulated in the liver, dose-dependently reversed NASH fibrosis without observable hepatotoxicity. Our study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis. Therapeutic modulation of PKM2 in a macrophage-specific or liver-specific fashion may serve as a novel strategy to combat NASH fibrosis.
2024-05-08 | GSE266040 | GEO
Project description:Glutaredoxin-1 (Glrx) controls redox signaling and has an anti-apoptotic function. We evaluated the role of Glrx on hepatic cell damage and fibrosis induced by a high-fat diet. We fed mice a high-fat high-fructose diet to induce non-alcoholic steatohepatitis (NASH) and injected AAV-Glrx to express hepatocyte-specific Glrx in diet-induced NASH mice. AAV-Glrx suppressed fibrosis and improved liver function in the NASH liver. We used microarrays to profile gene expression in the NASH liver and find pathways that AAV-Glrx mediated to attenuate fibrosis and NASH progression.
2022-06-01 | GSE198961 | GEO
Project description:Background/Aims: There is a major unmet need to assess prognostic impact of anti-fibrotics in clinical trials due to the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. Methods: A Fibrosis Progression Signature (FPS) was defined to predict fibrosis progression within 5 years in HCV and NAFLD patients with no to minimal fibrosis at baseline (n=421), and validated in an independent NAFLD cohort (n=78). The FPS was used to assess response to 13 candidate anti-fibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n=78), and cenicriviroc in NASH patients enrolled in a clinical trial (n=19, NCT02217475). A serum-protein-based surrogate FPS (FPSec) was developed and technically evaluated in a liver disease patient cohort (n=79). Results: A 20-gene FPS was defined and validated in an independent NAFLD cohort (aOR=10.93, AUROC=0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacological target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate anti-fibrotics identified rational combination therapies based on epigallocatechin gallate, some of which were validated for enhanced anti-fibrotic effect in ex vivo culture of clinical liver tissues. In NASH patients treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of PPAR-alfa pathway was absent in patients without fibrosis improvement, suggesting benefit of combining PPAR-alfa agonism to improve anti-fibrotic efficacy of cenicriviroc. A 7-protein FPSec panel showed concordant prognostic prediction with FPS. Conclusion: FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform anti-fibrotic drug development.
2021-12-22 | GSE182065 | GEO