1. Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis
- Author
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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, Pharmaceutical and Pharmacological Sciences, and Experimental in vitro toxicology and dermato-cosmetology
- Subjects
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 - Abstract
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.
- Published
- 2021