Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis
| Autor: | Suxian Zhao, Dechun Feng, Jing Ma, Yaojie Fu, Ruixue Ren, Pal Pacher, Csaba Mátyás, Robim Marcelino Rodrigues, Bin Gao, Wonhyo Seo, Seonghwan Hwang, Eszter Trojnar, George Kunos, Xiaolin Wang, Yong He |
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| Přispěvatelé: | Pharmaceutical and Pharmacological Sciences, Experimental in vitro toxicology and dermato-cosmetology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Apolipoprotein E mice Neutrophils Mice Obese Non-alcoholic Fatty Liver Disease/genetics Cell Communication 03 medical and health sciences Extracellular Vesicles 0302 clinical medicine Non-alcoholic Fatty Liver Disease medicine Receptors LDL/genetics Animals Neutrophils/metabolism Receptor Mice Knockout Chemistry nutritional and metabolic diseases Extracellular Vesicles/genetics Hepatocytes/metabolism General Medicine Extracellular vesicle medicine.disease Cell biology MicroRNAs MicroRNAs/genetics 030104 developmental biology medicine.anatomical_structure Receptors LDL 030220 oncology & carcinogenesis Hepatocyte LDL receptor Hepatocytes Kexin lipids (amino acids peptides and proteins) Steatosis Lipoprotein Research Article |
| Zdroj: | J Clin Invest |
| Popis: | Neutrophil infiltration around lipotoxic hepatocytes is a hallmark of nonalcoholic steatohepatitis (NASH); however, how these 2 types of cells communicate remains obscure. We have previously demonstrated that neutrophil-specific microRNA-223 (miR-223) is elevated in hepatocytes to limit NASH progression in obese mice. Here, we demonstrated that this elevation of miR-223 in hepatocytes was due to preferential uptake of miR-223-enriched extracellular vesicles (EVs) derived from neutrophils as well other types of cells, albeit to a lesser extent. This selective uptake was dependent on the expression of low-density lipoprotein receptor (LDLR) on hepatocytes and apolipoprotein E (APOE) on neutrophil-derived EVs, which was enhanced by free fatty acids. Once internalized by hepatocytes, the EV-derived miR-223 acted to inhibit hepatic inflammatory and fibrogenic gene expression. In the absence of this LDLR- and APOE-dependent uptake of miR-223-enriched EVs, the progression of steatosis to NASH was accelerated. In contrast, augmentation of this transfer by treatment with an inhibitor of proprotein convertase subtilisin/kexin type 9, a drug used to lower blood cholesterol by upregulating LDLR, ameliorated NASH in mice. This specific role of LDLR and APOE in the selective control of miR-223-enriched EV transfer from neutrophils to hepatocytes may serve as a potential therapeutic target for NASH. |
| Databáze: | OpenAIRE |
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