CDA-HFD induced NASH liver fibrosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA857447 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20073700.fastq.gz | Fastqsanger.gz | |||
| SRR20073701.fastq.gz | Fastqsanger.gz | |||
| SRR20073702.fastq.gz | Fastqsanger.gz | |||
| SRR20073703.fastq.gz | Fastqsanger.gz | |||
| SRR20073704.fastq.gz | Fastqsanger.gz |
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Project description:To understand the fibrotic response in the CDA-HFD induced NASH fibrosis model, we performed RNA-seq on liver samples collected from mice fed with normal chow (week 0) or CDA-HFD chow (weeks 8 and 16).
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Project description:Six-week old Fah−/−/Rag2−/−/Il2rg −/− (FRG) –NOD breeding mice were intravenously injected with 1.5 x 10^9 plaque forming units (pfu) of an adenoviral vector encoding the secreted form of the human urokinase-like plasminogen activator (Ad-uPA). Forty-eight hours later, 10^6 PHH were injected intrasplenically. Successfully transplanted mice were fed with CDA-HFD for 16 weeks and then treated with humanized CLDN1 specific mAb 500 µg or vehicle for additional 8 weeks. RNA was extracted from non-tumorous liver tissue of 4 NASH fibrosis mice treated with CLDN1 mAb, 3 vehicle Control treated NASH fibrosis mice as well as 3 humanized mice fed by regular diet. Libraries were sequenced on the Illumina HiSeq 4000 as Single-Read 50 base reads.
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Project description:Seven-week old male C57BL/6J mice received a single i.p. injection of DEN (100 mg/kg) and were subsequently fed with CDA-HFD after 3 weeks. After 6 weeks of diet, the mice were randomized in 2 groups, receiving weekly i.p. injections of 500 µg of either CLDN1 specific mAb or vehicle control for 16 weeks. RNA was extracted from non-tumorous liver tissue of 6 DEN-CDA-HFD mice treated with CLDN1 mAb, 6 DEN-CDA-HFD mice treated with vehicle Control as well as 5 C57BL/6J Control mice fed by regular diet. Libraries were sequenced on the Illumina HiSeq 4000 as Single-Read 50 base reads.
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Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to a potential application of bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and onset of fibrosis) to assess its potential effectiveness for the treatment of NASH and liver fibrosis. I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization through RNA-sequencing pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis following treatment, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.
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Project description:BET Inhibition Improves NASH and Liver Fibrosis
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Project description:Exposure to high fat diet (HFD) and persistent organic pollutants including polychlorinated biphenyls (PCBs) is associated with liver injury in human populations and with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. Exposure of HFD-fed male mice to the non-dioxin-like (NDL) PCB mixture Aroclor1260 or to dioxin-like (DL) PCB126 or to the combination caused steatohepatitis and differentially altered the liver proteome with pathways involving epigenetic regulation of gene expression. Here unbiased RNA sequencing of miRNA (miRNA-seq) and subsequent network analysis to characterize the biological pathways altered by HFD and PCB exposure compared to HFD alone. Distinct miRNA expression patterns reveald a potential role of miRNAs in the pathogenesis of NAFLD. These results demonstrate miRNA and transcriptome pathways in PCB-related hepatic inflammation and fibrosis in a mouse model of NAFLD.
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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.
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Project description:Necroptosis contributes to hepatocyte death (HC) in non-alcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) in NASH remain unknown. We show here that the accumulation of necHCs is associated with worsening NASH in humans and in mice with diet-induced NASH and that NASH liver showed evidence of impaired necHC clearance by liver macrophages. Further, the "don't-eat-me" ligand CD47 on HCs and its receptor, SIRPα, on liver macrophages, were markedly upregulated in human and mouse NASH. In vitro, anti-CD47 or anti-SIRPα promoted necHC engulfment by primary liver macrophages. In a proof-of-concept mouse model of inducible HC necroptosis, anti-CD47 increased necHC uptake by liver macrophages and inhibited hepatic stellate cell (HSC) activation, which is responsible for liver fibrogenesis. Most importantly, treatment of two mouse models of diet-induced NASH with anti-CD47 or anti-SIRPα increased the uptake of necHC by liver macrophages and decreased HSC activation and liver fibrosis. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRPα upregulation contributes to fibrotic NASH and suggest therapeutic blockade of the CD47-SIRPα axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.
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Project description:Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease; yet the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely under-stood. Using a cell type-resolved genomics approach, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a partial loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a net-work of NASH-activated transcription factors (TFs), as exemplified by Elf3 and Glis2. Indeed, Elf3 and Glis2 controlled hepatocyte identity and fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell (HSC) gene programs. Thus, interconnected TF networks not only promoted hepatocyte dysfunction, but also directed the intra-hepatic crosstalk with HSCs necessary for NASH and fibrosis progression implying molecular “hub-centered” targeting strategies to be superior to existing mono-target approaches as currently used in NASH therapy.
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Project description:Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning and fibrosis and inhibits activation of hepatic stellate cells. Glucagon like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared to clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
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