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Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis
- Title
- Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis
- Authors
- He, Yong; Rodrigues, Robim M.; Wang, Xiaolin; Seo, Wonhyo; Ma, Jing; Hwang, Seonghwan; Fu, Yaojie; Trojnar, Eszter; Matyas, Csaba; Zhao, Suxian; Ren, Ruixue; Feng, Dechun; Pacher, Pal; Kunos, George; Gao, Bin
- Ewha Authors
- 서원효
- SCOPUS Author ID
- 서원효
- Issue Date
- 2021
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- ISSN
- 0021-9738
1558-8238
- Citation
- JOURNAL OF CLINICAL INVESTIGATION vol. 131, no. 3
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Indexed
- SCIE; SCOPUS
- Document Type
- 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.
- DOI
- 10.1172/JCI141513
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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