{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:58:53Z","timestamp":1753891133546,"version":"3.41.2"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T00:00:00Z","timestamp":1706832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 111-2314-B-039-010"],"award-info":[{"award-number":["MOST 111-2314-B-039-010"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Non-alcoholic fatty liver disease (NAFLD) is prevalent among rheumatoid arthritis (RA) patients, but its pathogenesis has rarely been explored. Galectin-9 (Gal-9) interacts with T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3) expressed on hepatocytes and thus regulates T cell proliferation in a murine model of NAFLD. We aimed to examine the pathogenic role of the Gal-9\/TIM-3 pathway in RA-NAFLD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Serum levels of Gal-9, soluble TIM-3 (sTIM-3), fatty acid-binding proteins (FABP)1, and FABP4 were determined by ELISA in forty-five RA patients and eleven healthy participants. Using Oil-red O staining and immunoblotting, we examined the effects of Gal-9 and free fatty acid (FFA) on lipid accumulation in human hepatocytes and FABP1 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Serum Gal-9, sTIM-3 and FABP1 level were significantly higher in RA patients (median 5.02\u2009ng\/mL, 3.42\u2009ng\/mL, and 5.76\u2009ng\/mL, respectively) than in healthy participants (1.86\u2009ng\/mL, 0.99\u2009ng\/mL, and 0.129\u2009ng\/mL, all <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001). They were also significantly higher in patients with moderate-to-severe NAFLD compared with none-to-mild NAFLD (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01; <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.05; and <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01, respectively). Serum Gal-9 levels were positively correlated with sTIM-3, FABP1, FABP4 levels, and ultrasound-fatty liver score, respectively, in RA patients. Multivariate regression analysis revealed that Gal-9 (cut-off&amp;gt;3.30) was a significant predictor of NAFLD development, and Gal-9 and sTIM-3 were predictors of NAFLD severity (both <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.05). The cell-based assay showed that Gal-9 and FFA could upregulate FABP1 expression and enhance lipid droplet accumulation in hepatocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Elevated levels of Gal-9 and sTIM3 in RA patients with NAFLD and their positive correlation with NAFLD severity suggest the pathogenic role of Gal-9 signaling in RA-related NAFLD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2024.1347268","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T04:52:28Z","timestamp":1706849548000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Significant association of elevated serum galectin-9 levels with the development of non-alcoholic fatty liver disease in patients with rheumatoid arthritis"],"prefix":"10.3389","volume":"11","author":[{"given":"Po-Ku","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Fan","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Yuan","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsai-Ling","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shih-Hsin","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsin-Hua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chu-Huang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Der-Yuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1111\/j.1365-2036.2011.04724.x","article-title":"Systematic 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