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dc.contributor.authorMin, Kyounghee
dc.contributor.authorYenilmez, Batuhan
dc.contributor.authorKelly, Mark
dc.contributor.authorEcheverria, Dimas
dc.contributor.authorElleby, Michael
dc.contributor.authorLifshitz, Lawrence M
dc.contributor.authorRaymond, Naideline
dc.contributor.authorTsagkaraki, Emmanouela
dc.contributor.authorHarney, Shauna M
dc.contributor.authorDiMarzio, Chloe
dc.contributor.authorWang, Hui
dc.contributor.authorMcHugh, Nicholas
dc.contributor.authorBramato, Brianna
dc.contributor.authorMorrison, Brett
dc.contributor.authorRothstein, Jeffery D
dc.contributor.authorKhvorova, Anastasia
dc.contributor.authorCzech, Michael P
dc.date.accessioned2024-05-13T14:11:11Z
dc.date.available2024-05-13T14:11:11Z
dc.date.issued2024-04-02
dc.identifier.citationMin K, Yenilmez B, Kelly M, Echeverria D, Elleby M, Lifshitz LM, Raymond N, Tsagkaraki E, Harney SM, DiMarzio C, Wang H, McHugh N, Bramato B, Morrison B, Rothstein JD, Khvorova A, Czech MP. Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis. Elife. 2024 Apr 2;12:RP89136. doi: 10.7554/eLife.89136. PMID: 38564479; PMCID: PMC10987092.en_US
dc.identifier.eissn2050-084X
dc.identifier.doi10.7554/eLife.89136en_US
dc.identifier.pmid38564479
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53334
dc.description.abstractCirculating 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 MCT1fl/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.en_US
dc.language.isoenen_US
dc.relationThis article is based on a previously available preprint in bioRxiv, https://doi.org/10.1101/2023.05.03.539244en_US
dc.relation.ispartofeLifeen_US
dc.relation.urlhttps://doi.org/10.7554/elife.89136en_US
dc.rights© 2023, Min et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.; Attribution 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectAAVen_US
dc.subjectNAFLDen_US
dc.subjectNASHen_US
dc.subjectRNAi therapeuticsen_US
dc.subjectcell biologyen_US
dc.subjecthumanen_US
dc.subjectliver fibrosisen_US
dc.subjectmouseen_US
dc.subjectstellate cellsen_US
dc.titleLactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitisen_US
dc.typeJournal Articleen_US
dc.source.journaltitleeLife
dc.source.volume12
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland
dc.identifier.journaleLife
refterms.dateFOA2024-05-13T14:11:13Z
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentProgram in Molecular Medicineen_US
dc.contributor.departmentRNA Therapeutics Instituteen_US
dc.contributor.studentKyounghee Min
dc.description.thesisprogramInterdisciplinary Graduate Program


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© 2023, Min et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.; Attribution 4.0 International
Except where otherwise noted, this item's license is described as © 2023, Min et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.; Attribution 4.0 International