{"doi":"10.1002/rth2.12403","title":"Liver fibrosis is driven by protease‐activated receptor‐1 expressed by hepatic stellate cells in experimental chronic liver injury","abstract":"Background Blood coagulation protease activity is proposed to drive hepatic fibrosis through activation of protease-activated receptors (PARs). Whole-body PAR-1 deficiency reduces experimental hepatic fibrosis, and in vitro studies suggest a potential contribution by PAR-1 expressed by hepatic stellate cells. However, owing to a lack of specific tools, the cell-specific role of PAR-1 in experimental hepatic fibrosis has never been formally investigated. Using a novel mouse expressing a conditional PAR-1 allele, we tested the hypothesis that PAR-1 expressed by hepatic stellate cells contributes to hepatic fibrosis. Methods PAR-1flox/flox mice were crossed with mice expressing Cre recombinase controlled by the lecithin retinol acyltransferase (LRAT) promoter, which induces recombination in hepatic stellate cells. Male PAR-1flox/flox/LRATCre and PAR-1flox/flox mice were challenged twice weekly with carbon tetrachloride (CCl4, 1 mL/kg i.p.) for 6 weeks to induce liver fibrosis. Results PAR-1 mRNA levels were reduced (>95%) in hepatic stellate cells isolated from PAR-1flox/flox/LRATCre mice. Hepatic stellate cell activation was evident in CCl4-challenged PAR-1flox/flox mice, indicated by increased α-smooth muscle actin labeling and induction of several profibrogenic genes. CCl4-challenged PAR-1flox/flox mice displayed robust hepatic collagen deposition, indicated by picrosirius red staining and type I collagen immunolabeling. Notably, stellate cell activation and collagen deposition were significantly reduced (>30%) in PAR-1flox/flox/LRATCre mice. Importantly, the reduction in liver fibrosis was not a consequence of reduced acute CCl4 hepatotoxicity in PAR-1flox/flox/LRATCre mice. Conclusions The results constitute the first direct experimental evidence that PAR-1 expressed by stellate cells directly promotes their profibrogenic phenotype and hepatic fibrosis in vivo.","journal":"Research and Practice in Thrombosis and Haemostasis","year":2020,"id":79535,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9442,"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":413341,"name":"Asmita Pant","orcid":"0000-0003-4468-8639","position":1,"is_corresponding":false},{"id":414745,"name":"Holly Cline-Fedewa","orcid":null,"position":2,"is_corresponding":false},{"id":414746,"name":"Kurt J. Williams","orcid":null,"position":3,"is_corresponding":false},{"id":414747,"name":"Bryan L. Copple","orcid":null,"position":4,"is_corresponding":false},{"id":364581,"name":"Joseph S. Palumbo","orcid":"0009-0005-7550-8532","position":5,"is_corresponding":false},{"id":363546,"name":"James P. Luyendyk","orcid":"0000-0003-3174-8583","position":6,"is_corresponding":false},{"id":413340,"name":"Lauren G. Poole","orcid":"0000-0002-5405-5774","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T21:50:57.971597Z","pmid":"32685902","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":[]}