Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis
- 주제(기타) Medicine, Research & Experimental
- 설명문(일반) [He, Yong; Rodrigues, Robim M.; Wang, Xiaolin; Seo, Wonhyo; Ma, Jing; Hwang, Seonghwan; Fu, Yaojie; Ren, Ruixue; Feng, Dechun; Gao, Bin] NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA; [Trojnar, Eszter; Matyas, Csaba; Zhao, Suxian; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD USA; [Kunos, George] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA
- 등재 SCIE, SCOPUS
- 발행기관 AMER SOC CLINICAL INVESTIGATION INC
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000182527
- 본문언어 영어
- Published As http://dx.doi.org/10.1172/JCI141513
초록/요약
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.
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