Hepatocytes demarcated by EphB2 contribute to the progression of non-alcoholic steatohepatitis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA783863 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17044641_1.fastq.gz | Fastqsanger.gz | |||
| SRR17044641_2.fastq.gz | Fastqsanger.gz | |||
| SRR17044642_1.fastq.gz | Fastqsanger.gz | |||
| SRR17044642_2.fastq.gz | Fastqsanger.gz | |||
| SRR17044643_1.fastq.gz | Fastqsanger.gz |
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Project description:Current therapeutic strategies for treating non-alcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mouse and human. At the non-alcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which was mainly demarcated by receptor tyrosine kinase EphB2. EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomously inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in NASH. Thus, EphB2 expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.
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Project description:Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mice and humans. At the nonalcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which were mainly demarcated by receptor tyrosine kinase ephrin type B receptor 2 (EphB2). EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomous inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH. Thus, EphB2-expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.
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Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.
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