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Hepatocyte E4BP4 promotes liver fibrosis via enhancing hepatic stellate cells activation

ABSTRACT: To investigate the role of E4bp4 during non-alcholic liver diseases, we subjected the WT mice and E4bp4 liver specific knockout (E4bp4-LKO) mice to NASH diet for 20 weeks.

ORGANISM(S): Mus musculus

PROVIDER: GSE223518 | GEO | 2024/03/01

REPOSITORIES: GEO

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Hepatocyte E4BP4 promotes liver fibrosis via enhancing hepatic stellate cells activation

Project description:Hepatocyte E4BP4 promotes liver fibrosis via enhancing hepatic stellate cells activation

| PRJNA926631 | ENA

OPN-Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH-Associated Liver Fibrosis.

Project description:Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra-hepatocyte players that facilitate such cell-to-cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high-fat diet-induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH-associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet- or CCl4-induced liver fibrosis. Hepatocyte-specific E4bp4 deletion protected mice against NASH diet-induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA-Seq analysis identified the pro-fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4-induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad-E4bp4-injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet-induced MASH. Inhibition of the hepatocyte E4BP4-OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH.

| S-EPMC11653607 | biostudies-literature

Fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication in metabolic associated liver fibrosis

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

ChIP-seq for E4BP4 in the liver from transgenic mouse with liver specific E4BP4 overexpression

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

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

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.

2022-11-25 | GSE197111 | GEO

Gene expression altered by E4bp4 deficiency of mice on high-fat diet feeding

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

ChIP_seq for E4BP4 in RAW264.7 cells [RAW_ChIP-seq]

2024-03-31 | GSE183079 | GEO

ChIP-seq for E4BP4 in the liver from transgenic mouse with liver specific E4BP4 overexpression

Project description:ChIP-seq for E4BP4 in the liver from transgenic mouse with liver specific E4BP4 overexpression

| PRJNA634326 | ENA

ChIP-seq for E4BP4 in CD4+ T cell

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

A cyclic peptide-grafted Fc with hepatocyte growth factor functionality ameliorates hepatic fibrosis in a non-alcoholic steatohepatitis mouse model.

Project description:Although growth factors have significant therapeutic potential because of their regenerative functions, their poor pharmacokinetics and low stability hinder their therapeutic application. Nonalcoholic steatohepatitis (NASH) is characterized by lipid accumulation, inflammation, and fibrosis in the liver, which can progress to life-threatening conditions such as cirrhosis and liver cancer. The hepatocyte growth factor (HGF)-Met receptor pathway has been proposed as a potential therapy for liver diseases including NASH due to its effects on liver regeneration, but the short half-life of recombinant HGF limits its clinical use. Here, we designed a Met agonist with a long half-life by grafting two Met-binding macrocyclic peptides into loops of the crystallizable region (Fc) of immunoglobulin. This surrogate Met agonist ameliorated liver fibrosis and inflammation in a mouse model of NASH, indicating its potential therapeutic use. This study provides a foundation to develop growth factor and cytokine mimetics and to expand their therapeutic applications.

2024-07-04 | GSE233051 | GEO

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