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Hepatocyte E4BP4 promotes liver fibrosis via enhancing hepatic stellate cells activation

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

PROVIDER: PRJNA926631 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23194216.fastq.gz	Fastqsanger.gz
	SRR23194217.fastq.gz	Fastqsanger.gz
	SRR23194218.fastq.gz	Fastqsanger.gz
	SRR23194219.fastq.gz	Fastqsanger.gz
	SRR23194220.fastq.gz	Fastqsanger.gz

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Hepatocyte E4BP4 promotes liver fibrosis via enhancing hepatic stellate cells activation

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

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Project description:Activation and migration of hepatic stellate cells (HSCs) followed by matrix deposition are characteristics of liver fibrosis. Several studies have shown the importance of hepatocyte and endothelial cell-derived extracellular vesicles (EVs) in liver pathobiology. However, less is known about the role of HSC-derived EVs in liver diseases. In this study, we investigated the molecules released through HSC-derived EVs and whether these can promote fibrosis.

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Project description:Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nano-sized extracellular vesicles (EVs) and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated upregulation of EV-related pathways in the liver pericentral zone, which was abrogated by the glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs upregulated the expression of EV-related genes such as RAB31 by enhancing histone-3-lysine-9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.

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