{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:10:09Z","timestamp":1791216609924,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012176","name":"Project 211","doi-asserted-by":"publisher","award":["CPU2022QZ31(Y Dai)"],"award-info":[{"award-number":["CPU2022QZ31(Y Dai)"]}],"id":[{"id":"10.13039\/501100012176","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Silibinin is used to treat non\u2010alcohol fatty liver disease (NAFLD) despite having rapid liver metabolism. Therefore, we investigated the role of the intestine in silibinin mechanism of action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>NAFLD mice model was established by feeding them with a high\u2010fat diet (HFD). Liver pathological were examined using H&amp;E and oil red O staining. Tissue distribution of silibinin was detected by LC\u2013MS\/MS. SiRNA was employed for gene silencing and plasmid was used for gene overexpression. ChIP\u2010qPCR assay was performed to detect the levels of histone acetylation. Recombinant adeno\u2010associated virus 9\u2010short hairpin\u2010fibroblast growth factor (FGF)\u201015 and \u2010farnesoid X receptor (FXR; NR1H4) were used to knockdown expression of FGF\u201015 and FXR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Oral silibinin significantly reversed NAFLD in mice, although liver concentration was insufficient for reduction of lipid accumulation in hepatocytes. Among endogenous factors capable of reversing NAFLD, the expression of Fgf\u201015 was selectively up\u2010regulated by silibinin in ileum and colon of mice. When intestinal expression of Fgf\u201015 was knocked down, protection of silibinin against lipid accumulation and injury of livers nearly disappeared. Silibinin could reduce activity of histone deacetylase 2 (HDAC2), enhance histone acetylation in the promoter region of FXR and consequently increase intestinal expression of FGF\u201015\/19.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Oral silibinin selectively promotes expression of FGF\u201015\/19 in ileum by enhancing transcription of FXR via reduction of HDAC2 activity, and FGF\u201015\/19 enters into circulation to exert anti\u2010NAFLD action. As the site of action is the intestine this would explain the discrepancy between pharmacodynamics and pharmacokinetics of silibinin.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16431","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T22:16:12Z","timestamp":1717625772000},"page":"3663-3684","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Silibinin, a commonly used therapeutic agent for non\u2010alcohol fatty liver disease, functions through upregulating intestinal expression of fibroblast growth factor 15\/19"],"prefix":"10.1111","volume":"181","author":[{"given":"Yujie","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing 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