{"doi":"10.1172/jci143690","title":"Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis","abstract":"Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSECs) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that VCAM-1 mediates monocyte adhesion to LSECs. However, the pathogenic role of VCAM-1 in NASH is unclear. Herein, we report that VCAM-1 was a top upregulated adhesion molecule in the NASH mouse liver transcriptome. Open chromatin landscape profiling combined with genome-wide transcriptome analysis showed robust transcriptional upregulation of LSEC VCAM-1 in murine NASH. Moreover, LSEC VCAM-1 expression was significantly increased in human NASH. LSEC VCAM-1 expression was upregulated by palmitate treatment in vitro and reduced with inhibition of the mitogen-activated protein 3 kinase (MAP3K) mixed lineage kinase 3 (MLK3). Likewise, LSEC VCAM-1 expression was reduced in the Mlk3-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing Ab or pharmacological inhibition attenuated diet-induced NASH in mice, mainly via reducing the proinflammatory monocyte hepatic population as examined by mass cytometry by time of flight (CyTOF). Moreover, endothelium-specific Vcam1 knockout mice were also protected against NASH. In summary, lipotoxic stress enhances the expression of LSEC VCAM-1, in part, through MLK3 signaling. Inhibition of VCAM-1 was salutary in murine NASH and might serve as a potential therapeutic strategy for human NASH.","journal":"Journal of Clinical Investigation","year":2021,"id":148044,"datarank":0.7390880527735809,"base_score":4.927253685157205,"endowment":4.927253685157205,"self_citation_contribution":0.7390880527735809,"citation_network_contribution":0.0,"self_endowment_contribution":0.7390880527735809,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":137,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":250278,"name":"Qianqian Guo","orcid":"0000-0003-4968-7782","position":1,"is_corresponding":false},{"id":230194,"name":"Kevin D. Pavelko","orcid":"0000-0001-7555-1315","position":2,"is_corresponding":false},{"id":70826,"name":"Jeong‐Heon Lee","orcid":"0000-0003-4007-9166","position":3,"is_corresponding":false},{"id":630042,"name":"Keith D. Robertson","orcid":"0000-0002-7508-3328","position":4,"is_corresponding":false},{"id":250273,"name":"Yasuhiko Nakao","orcid":"0000-0002-9353-2780","position":5,"is_corresponding":false},{"id":630043,"name":"Jan Melek","orcid":"0000-0003-2357-1116","position":6,"is_corresponding":false},{"id":235928,"name":"Vijay H. Shah","orcid":"0000-0001-7620-573X","position":7,"is_corresponding":false},{"id":282125,"name":"Petra Hirsova","orcid":"0000-0003-0494-0924","position":8,"is_corresponding":false},{"id":235925,"name":"Samar H. Ibrahim","orcid":"0000-0001-8470-8337","position":9,"is_corresponding":false},{"id":457153,"name":"Kunimaro Furuta","orcid":"0000-0001-6440-5929","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:42:41.063423Z","pmid":"33476308","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":[]}