Neuregulin 4 suppresses NASH-associated liver cancer through restraining tumor-prone liver microenvironment
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA767430 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16120500_1.fastq.gz | Fastqsanger.gz | |||
| SRR16120500_2.fastq.gz | Fastqsanger.gz | |||
| SRR16120501_1.fastq.gz | Fastqsanger.gz | |||
| SRR16120501_2.fastq.gz | Fastqsanger.gz | |||
| SRR16120502_1.fastq.gz | Fastqsanger.gz |
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Project description:The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that respond to physiological cues and undergo pathophysiological reprogramming in disease states, such as nonalcoholic steatohepatitis (NASH). Patients with NASH are at increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here we show that diet-induced NASH is characterized by induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic T cells in mouse liver. The adipose-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbates the induction of tumor-prone liver immune microenvironment and NASH-associated HCC, whereas transgenic NRG4 overexpression elicits protective effects in mice. In a therapeutic setting, recombinant NRG4 protein exhibits remarkable efficacy in inhibiting HCC in mice with NASH, thereby paving the way for future therapeutic development.
2022-08-15 | GSE185042 | GEO
Project description:The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that undergo pathophysiological reprogramming in disease states, such as non-alcoholic steatohepatitis (NASH). Patients with NASH are at an increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here, we show that diet-induced NASH is characterized by the induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic CD8+ T cells in the liver. The adipocyte-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbated the induction of tumor-prone liver immune microenvironment and NASH-related HCC, whereas transgenic NRG4 overexpression elicited protective effects in mice. In a therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potency in suppressing HCC and prolonged survival in the treated mice. These findings pave the way for therapeutic intervention of liver cancer by targeting the NRG4 hormonal checkpoint.
| S-EPMC9458631 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays
2011-07-12 | E-MEXP-3291 | biostudies-arrayexpress
Project description:Nrg4 is a brown fat-enriched adipokine that binds to the liver and suppress the process of steatosis-to-NASH progression. Adipose tissue Nrg4 expression was reduced in mice under NASH diet feeding. Nrg4 homozygous knockout mice are prone to diet-induced steatohepatitis We used microarrays to elucidate the pathogenic pathways that are regulated by Nrg4 deficiency in the livers of mice under NASH diet feeding.
2018-02-14 | GSE99753 | GEO
Project description:Assessment of chromatin transcription activity of liver biopsies from individuales who were stratified to either NASH prone (NP) or NASH resistance (NR)
2024-01-01 | GSE182129 | GEO
Project description:We performed RNA-seq analysis of pooled RNA extracted from liver of mice fed normal chow (control), WDF (NASH), and WDF+TH (TH-treated NASH).
2022-03-01 | GSE172297 | GEO
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.
2018-11-27 | GSE114261 | GEO
Project description:Human genetic studies have identified several MARC1 variants as protective against non-alcoholic fatty liver diseases (NAFLD). The MARC1 variants are associated with reduced lipid profiles, liver enzymes, and liver-related mortality. However, the role of mitochondrial amidoxime reducing component 1 (mARC1), encoded by MARC1, in NAFLD is still unknown and the therapeutic potential of this target has never been developed. Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine conjugated mouse mARC1 siRNA to address this. In ob/ob mice, knockdown of mARC1 in mouse hepatocytes resulted in decreased liver weight, serum lipid enzymes, low-density lipoprotein cholesterol, and liver triglycerides. Loss of mARC1 also improved the lipid profiles and attenuated liver pathological changes in two diet-induced nonalcoholic steatohepatitis (NASH) mouse models. A comprehensive analysis of mARC1-deficient liver in NASH by metabolomics, proteomics, and lipidomics showed that mARC1 knockdown partially restored metabolites and lipids altered by diets. Taken together, loss of mARC1 protects mouse liver from NASH, suggesting a potential therapeutic approach of NASH by downregulation of mARC1 in hepatocytes.
2023-04-28 | MSV000091820 | MassIVE
Project description:Gene expression profiling reveals a potential role of isorhamnetin in the mitigation of NASH features including steatosis, liver injury, and fibrosis Microarray gene expression profiling was conducted for technical replicates of healthy liver as control (CTL), NASH-induced (NASH), NASH-induced treated with isorhamnetin for 14 days (50 mg/kg of body weight) (NASH+ISO) liver tissues to identify its effect in the regulation of pathways involved in pathologic features of NASH.
2019-09-19 | GSE137635 | GEO
Project description:Background and Aims: Nonalcoholic steatohepatitis (NASH) will soon become the leading cause of liver transplantation in the US and is also associated with increased COVID-19 mortality. Currently, there are no FDA approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Since animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage NASH patient liver may address current knowledge gaps in human NASH pathology. Approach and Results: We devised methods allowing derivation, proliferation, hepatic differentiation and extensive characterization of bipotent ductal organoids from irreversibly damaged NASH patient liver. The transcriptomes of organoids derived from NASH liver, but not healthy liver show significant upregulation of pro-inflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of upregulation being NASH patient-specific.
2021-07-28 | GSE180882 | GEO