{"doi":"10.1172/jci141513","title":"Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223–enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis","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.","journal":"Journal of Clinical Investigation","year":2020,"id":50864,"datarank":0.7772675325438129,"base_score":5.181783550292085,"endowment":5.181783550292085,"self_citation_contribution":0.7772675325438129,"citation_network_contribution":0.0,"self_endowment_contribution":0.7772675325438129,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":177,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":251604,"name":"Robim M. Rodrigues","orcid":"0000-0003-2927-6791","position":1,"is_corresponding":false},{"id":226855,"name":"Xiaolin Wang","orcid":"0000-0001-9171-4073","position":2,"is_corresponding":false},{"id":253165,"name":"Wonhyo Seo","orcid":null,"position":3,"is_corresponding":false},{"id":251605,"name":"Jing Ma","orcid":"0000-0002-2671-3792","position":4,"is_corresponding":false},{"id":251606,"name":"Seonghwan Hwang","orcid":"0000-0002-9728-3603","position":5,"is_corresponding":false},{"id":251607,"name":"Yaojie Fu","orcid":"0009-0006-5411-6078","position":6,"is_corresponding":false},{"id":251608,"name":"Eszter Trojnár","orcid":"0000-0002-3266-2477","position":7,"is_corresponding":false},{"id":251609,"name":"Csaba Mátyás","orcid":"0000-0001-6095-7611","position":8,"is_corresponding":false},{"id":251610,"name":"Suxian Zhao","orcid":"0000-0001-6674-4721","position":9,"is_corresponding":false},{"id":244217,"name":"Ruixue Ren","orcid":null,"position":10,"is_corresponding":false},{"id":239662,"name":"Dechun Feng","orcid":"0000-0001-7485-762X","position":11,"is_corresponding":false},{"id":251611,"name":"Pál Pacher","orcid":"0000-0001-7036-8108","position":12,"is_corresponding":false},{"id":243202,"name":"George Kunos","orcid":"0000-0003-1788-4976","position":13,"is_corresponding":false},{"id":226858,"name":"Bin Gao","orcid":"0000-0002-0505-2972","position":14,"is_corresponding":false},{"id":226856,"name":"Yong He","orcid":"0009-0006-8681-5287","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T20:39:29.006085Z","pmid":"33301423","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}