{"doi":"10.1172/jci.insight.165369","title":"Notch-mediated hepatocyte MCP-1 secretion causes liver fibrosis","abstract":"Patients with nonalcoholic steatohepatitis (NASH) have increased expression of liver monocyte chemoattractant protein-1 (MCP-1), but its cellular source and contribution to various aspects of NASH pathophysiology remain debated. We demonstrated increased liver CCL2 (which encodes MCP-1) expression in patients with NASH, and commensurately, a 100-fold increase in hepatocyte Ccl2 expression in a mouse model of NASH, accompanied by increased liver monocyte-derived macrophage (MoMF) infiltrate and liver fibrosis. To test repercussions of increased hepatocyte-derived MCP-1, we generated hepatocyte-specific Ccl2-knockout mice, which showed reduced liver MoMF infiltrate as well as decreased liver fibrosis. Forced hepatocyte MCP-1 expression provoked the opposite phenotype in chow-fed wild-type mice. Consistent with increased hepatocyte Notch signaling in NASH, we observed a close correlation between markers of Notch activation and CCL2 expression in patients with NASH. We found that an evolutionarily conserved Notch/recombination signal binding protein for immunoglobulin kappa J region binding site in the Ccl2 promoter mediated transactivation of the Ccl2 promoter in NASH diet-fed mice. Increased liver MoMF infiltrate and liver fibrosis seen in opposite gain-of-function mice was ameliorated with concomitant hepatocyte Ccl2 knockout or CCR2 inhibitor treatment. Hepatocyte Notch activation prompts MCP-1-dependent increase in liver MoMF infiltration and fibrosis.","journal":"JCI Insight","year":2023,"id":317603,"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":75,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":820680,"name":"Jorge Postigo","orcid":"0009-0008-0350-9810","position":1,"is_corresponding":false},{"id":444990,"name":"KyeongJin Kim","orcid":"0000-0001-6865-9141","position":2,"is_corresponding":false},{"id":218295,"name":"Changyu Zhu","orcid":"0000-0003-3583-3638","position":3,"is_corresponding":false},{"id":444991,"name":"Junjie Yu","orcid":"0000-0001-5603-6094","position":4,"is_corresponding":false},{"id":1023252,"name":"Marica Meroni","orcid":"0000-0002-4161-4178","position":5,"is_corresponding":false},{"id":914095,"name":"Brent Mayfield","orcid":null,"position":6,"is_corresponding":false},{"id":315356,"name":"Alberto Bartolomé","orcid":"0000-0002-3382-0553","position":7,"is_corresponding":false},{"id":316240,"name":"Dianne H. Dapito","orcid":null,"position":8,"is_corresponding":false},{"id":2965,"name":"Anthony W. Ferrante","orcid":"0000-0001-9272-2593","position":9,"is_corresponding":false},{"id":667809,"name":"Paola Dongiovanni","orcid":"0000-0003-4343-7213","position":10,"is_corresponding":false},{"id":246029,"name":"Luca Valenti","orcid":"0000-0001-8909-0345","position":11,"is_corresponding":false},{"id":369807,"name":"Rémi J. Creusot","orcid":"0000-0002-8328-8155","position":12,"is_corresponding":false},{"id":109694,"name":"Utpal B. Pajvani","orcid":"0000-0001-5991-2723","position":13,"is_corresponding":false},{"id":1023738,"name":"Jinku Kang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:06:50.336418Z","pmid":"36752206","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":[]}