{"doi":"10.7554/elife.89136.3","title":"Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis","abstract":"Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1 fl/fl mice on a choline-deficient, high-fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri- N -acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.","journal":"eLife","year":2024,"id":467671,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":292017,"name":"Batuhan Yenilmez","orcid":"0000-0001-8798-3676","position":1,"is_corresponding":false},{"id":292012,"name":"Mark Kelly","orcid":"0000-0001-9018-594X","position":2,"is_corresponding":false},{"id":398074,"name":"Dimas Echeverria","orcid":"0000-0002-1040-0855","position":3,"is_corresponding":false},{"id":1093580,"name":"Michael Elleby","orcid":"0009-0005-7947-5686","position":4,"is_corresponding":false},{"id":284598,"name":"Lawrence M. Lifshitz","orcid":"0000-0001-6197-6638","position":5,"is_corresponding":false},{"id":878015,"name":"Naideline Raymond","orcid":null,"position":6,"is_corresponding":false},{"id":633972,"name":"Emmanouela Tsagkaraki","orcid":"0000-0001-7754-8945","position":7,"is_corresponding":false},{"id":1093943,"name":"Shauna M. Harney","orcid":null,"position":8,"is_corresponding":false},{"id":668507,"name":"Chloe DiMarzio","orcid":null,"position":9,"is_corresponding":false},{"id":1093581,"name":"Hui Wang","orcid":"0000-0001-7189-7087","position":10,"is_corresponding":false},{"id":302204,"name":"Nicholas McHugh","orcid":"0000-0003-2004-0811","position":11,"is_corresponding":false},{"id":1030866,"name":"Brianna Bramato","orcid":"0000-0001-6966-7696","position":12,"is_corresponding":false},{"id":298333,"name":"Brett M. Morrison","orcid":"0000-0001-5404-3899","position":13,"is_corresponding":false},{"id":1093944,"name":"Jeffery D. Rothstein","orcid":null,"position":14,"is_corresponding":false},{"id":302206,"name":"Anastasia Khvorova","orcid":"0000-0001-6928-8071","position":15,"is_corresponding":false},{"id":238439,"name":"Michael Czech","orcid":"0000-0003-4075-7350","position":16,"is_corresponding":false},{"id":667630,"name":"Kyounghee Min","orcid":"0000-0002-2546-0236","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T02:05:15.025255Z","pmid":null,"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":[]}