Hepatocyte E4BP4 promotes liver fibrosis via enhancing hepatic stellate cells activation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE223518 | GEO | 2024/03/01
REPOSITORIES: GEO
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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.
2021-07-13 | PXD025691 | Pride
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:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to evaluate the effects of liver-specific E4BP4 overexpression under mouse albumin promoter on the liver glucose and lipid metabolism. Methods: We generated transgenic mice (TG) with liver-specific E4BP4 overexpression, and harvested two livers with one TG mouse each. After cervical dislocation, mouse liver was perfused with a buffer containing Hanks' balanced salt solution, and cross-inked for 30 minutes with 2mM DSG and for 10 minutes with 1% formaldehyde by perfusion, followed by frozen at -80C. Then, Liver was homogenated by gentleMACS Dissociators. Nuclei were isolated and protein-DNA complexes were incubated with antibodies against two kinds of E4BP4 and immunoprecipitated with IgG paramagnetic beads. Results: There were many significant peaks at the promoter/enhancer or intronic region of many genes. Conclusions: E4BP4 possibly regulates the expression of some genes linked to lipid metabolism in the liver.
2021-05-01 | GSE150988 | GEO
Project description:To identify hepatic genes specifically regulated by E4bp4. Lipid droplet binding genes are downregulated in the liver of E4bp4 liver specific knockout mice.
2022-07-31 | GSE200528 | GEO
Project description:ChIP-seq for E4BP4 in the liver from transgenic mouse with liver specific E4BP4 overexpression
| PRJNA634326 | ENA
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to evaluate the effects of liver-specific E4BP4 overexpression under mouse albumin promoter on the liver glucose and lipid metabolism.
2024-03-31 | GSE183079 | GEO
Project description:Here, using ChIP-seq, we demonstrate that the transcriptional repressor Adenovirus E4 promoter-binding protein (E4BP4) binds directly to the Bcl6 promoter, which a key transcription factor controlling Tfh cell differentiation. By obtaining sequence from chromatin immunoprecipitated DNA of E4BP4 overexpressing CD4+T cells, we generated genome-wide binding gene spectrums of E4BP4. These results reveal that E4BP4 interacts with BCL6 and E4BP4 directly modulated the expression of Bcl6 to reveal the mechanism downstream of E4BP4 that regulates Tfh cell differentiation.
2021-01-19 | GSE121387 | GEO
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.
2023-08-09 | GSE240406 | GEO
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to evaluate the gene expression of E4BP4 knockout (KO) RAW264.7 cells. Methods: We generated E4BP4-KO RAW264.7 Cell Line using CRISPR-CAS9 system. Control plasmid was encoding the Cas9 nuclease without gRNA sequence. Total RNA of E4BP4-KO and Control (CTRL) RAW264.7 cells was extracted. RAW264.7 cells RNA profiles were generated by deep sequencing for two groups (E4BP4-KO versus CTRL RAW264.7 cells) with three samples each. Results: There were significant differences between E4BP4-KO and CTRL RAW264.7 cells. Conclusions: Deletion of E4BP4 in RAW264.7 cells induced various changes at the transcription level.
2024-03-31 | GSE183076 | GEO
Project description:Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions world-wide and is the strongest predictor of mortality in non-alcoholic steatohepatitis (NASH), yet there are no approved anti-fibrotic therapies. To identify novel anti-fibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single nuclear RNA sequencing and tissue clearing in a robust, murine NASH model. In advanced fibrosis, an autocrine HSC signaling circuit emerges that is comprised of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions are supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, NTRK3-NTF3, inhibits human HSC activation in culture and reverses advanced murine NASH-fibrosis in vivo. We have uncovered a novel repertoire of previously uncharacterized anti-fibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a novel therapeutic paradigm in which stage-specific therapies could yield enhanced anti-fibrotic efficacy in patients with advanced fibrosis.
2022-10-21 | GSE212837 | GEO