{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:41:56Z","timestamp":1788892916198,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T00:00:00Z","timestamp":1701043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP23fk0210125"],"award-info":[{"award-number":["JP23fk0210125"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["5\/4\/8\u201018\/Obs\/SPP\/2022\u2010NCD\u2010II"],"award-info":[{"award-number":["5\/4\/8\u201018\/Obs\/SPP\/2022\u2010NCD\u2010II"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Hepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. This study aimed to identify the specific cells expressing THBS2\/TSP2 in non\u2010alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2\/TSP2 upregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Comprehensive NAFLD liver gene datasets, including single\u2010cell RNA sequencing (scRNA\u2010seq), in\u2010house NAFLD liver tissue, and LX\u20102 cells derived from human hepatic stellate cells (HSCs), were analysed using a combination of computational biology, genetic, immunological, and pharmacological approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction (qPCR) examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (<jats:italic>r<\/jats:italic>\u2009=\u2009.349, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). In support of this, scRNA\u2010seq data and in\u00a0situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGF\u03b2) pathway and collagen gene activation. Moreover, the activation of LX\u20102 cells with TGF\u03b2 increased THBS2\/TSP2 and collagen expression independently of the TGF\u03b2\u2010SMAD2\/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX\u20102 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>THBS2\/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2\/TSP2 may therefore represent a potential target for anti\u2010fibrotic therapy in NAFLD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15792","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T01:18:24Z","timestamp":1701134304000},"page":"483-496","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Thrombospondin 2 is a key determinant of fibrogenesis in non\u2010alcoholic fatty liver disease"],"prefix":"10.1111","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1481-1029","authenticated-orcid":false,"given":"Takefumi","family":"Kimura","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology and Hepatology Shinshu University School of Medicine  Matsumoto Japan"},{"name":"Consultation Center for Liver Diseases Shinshu University Hospital  Matsumoto 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