{"doi":"10.1172/jci135919","title":"Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity","abstract":"Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA-PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress. We showed that obese mice, like humans, had reduced fibrinolysis and increased plasma PAI-1 and tPA, due largely to their increased hepatocyte expression. A decrease in the PAI-1 (SERPINE1) gene corepressor Rev-Erbα increased PAI-1, which then increased the tPA gene PLAT via a PAI-1/LRP1/PKA/p-CREB1 pathway. This pathway was partially counterbalanced by increased DACH1, a PLAT-negative regulator. We focused on the PAI-1/PLAT pathway, which mitigates the reduction in fibrinolysis in obesity. Thus, silencing hepatocyte PAI-1, CREB1, or tPA in obese mice lowered plasma tPA and further impaired fibrinolysis. The PAI-1/PLAT pathway was present in primary human hepatocytes, and associations among PAI-1, tPA, and PLAT in livers from obese and lean humans were consistent with these findings. Knowledge of PAI-1 and tPA regulation in hepatocytes in obesity may suggest therapeutic strategies for improving fibrinolysis and lowering the risk of thrombosis in this setting.","journal":"Journal of Clinical Investigation","year":2020,"id":67374,"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":47,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"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":356752,"name":"Keiko Nakamura","orcid":"0000-0002-5678-2625","position":1,"is_corresponding":false},{"id":357679,"name":"Shana Gershbaum","orcid":null,"position":2,"is_corresponding":false},{"id":226771,"name":"Xiaobo Wang","orcid":"0000-0001-6044-914X","position":3,"is_corresponding":false},{"id":357680,"name":"Sherry Thomas","orcid":null,"position":4,"is_corresponding":false},{"id":308856,"name":"Marc Bessler","orcid":"0009-0001-4291-2222","position":5,"is_corresponding":false},{"id":347520,"name":"Beth Schrope","orcid":"0000-0003-0313-8120","position":6,"is_corresponding":false},{"id":308855,"name":"Abraham Krikhely","orcid":"0009-0000-0809-2999","position":7,"is_corresponding":false},{"id":228867,"name":"Rui-Ming Liu","orcid":"0000-0003-0281-6102","position":8,"is_corresponding":false},{"id":356753,"name":"Lale Özcan","orcid":"0000-0002-2710-7057","position":9,"is_corresponding":false},{"id":356754,"name":"José A. López","orcid":"0000-0002-2550-5131","position":10,"is_corresponding":false},{"id":109693,"name":"Ira Tabas","orcid":"0000-0003-3429-1515","position":11,"is_corresponding":false},{"id":226776,"name":"Ze Zheng","orcid":"0000-0002-4453-224X","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-18T21:15:12.020735Z","pmid":"32657780","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":[]}