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Leukotriene B4 (LTB4) is a potent pro-inflammatory chemoattractant that drives macrophage and neutrophil chemotaxis, and genetic loss or inhibition of its high-affinity receptor, leukotriene B4 receptor 1 (BLT1), results in improved insulin sensitivity and decreased hepatic steatosis. To validate the therapeutic efficacy of BLT1 inhibition in an inflammatory and pro-fibrotic mouse model of MASH and fibrosis, mice were challenged with a choline-deficient, l-amino acid-defined, high-fat diet and treated with a BLT1 antagonist at 30 or 90\u2005mg\/kg for 8 weeks. Liver function, histology, and gene expression were evaluated at the end of the study. Treatment with the BLT1 antagonist significantly reduced plasma lipids and liver steatosis but had no impact on liver injury biomarkers or histological endpoints such as inflammation, ballooning, or fibrosis compared to control. Artificial intelligence-powered digital pathology analysis revealed a significant reduction in steatosis co-localized fibrosis in livers treated with the BLT1 antagonist. Liver RNA-seq and pathway analyses revealed significant changes in fatty acid, arachidonic acid, and eicosanoid metabolic pathways with BLT1 antagonist treatment; however, these changes were not sufficient to impact inflammation and fibrosis endpoints. Targeting this LTB4\u2013BLT1 axis with a small molecule inhibitor in animal models of chronic liver disease should be considered with caution, and additional studies are warranted to understand the mechanistic nuances of BLT1 inhibition in the context of MASH and liver fibrosis.<\/jats:p>","DOI":"10.1042\/bcj20230422","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T09:31:55Z","timestamp":1701163915000},"page":"177-190","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Leukotriene B4 receptor 1 does not mediate disease progression in a mouse model of liver fibrosis"],"prefix":"10.1042","volume":"481","author":[{"given":"Erin S.","family":"Coyne","sequence":"first","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yilin","family":"Nie","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Desiree","family":"Abdurrachim","sequence":"additional","affiliation":[{"name":"2MSD, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlene Zhi Lin","family":"Ong","sequence":"additional","affiliation":[{"name":"2MSD, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongqi","family":"Zhou","sequence":"additional","affiliation":[{"name":"2MSD, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asad Abu Bakar","family":"Ali","sequence":"additional","affiliation":[{"name":"2MSD, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacey","family":"Meyers","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff","family":"Grein","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy","family":"Blumenschein","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendan","family":"Gongol","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cedric","family":"Hugelshofer","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ester","family":"Carballo-Jane","sequence":"additional","affiliation":[{"name":"3Merck & Co., Inc., Rahway, NJ, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3042-0025","authenticated-orcid":false,"given":"Saswata","family":"Talukdar","sequence":"additional","affiliation":[{"name":"1Merck & Co., Inc., South San Francisco, CA, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"2024020516553283500_BCJ-2023-0422C1","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/S2468-1253(22)00165-0","article-title":"The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis","volume":"7","year":"2022","journal-title":"Lancet Gastroenterol. 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