{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:21:26Z","timestamp":1790392886205,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,7,15]],"date-time":"2019-07-15T00:00:00Z","timestamp":1563148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hepatology Research"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>Non\u2010alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase\u20104 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fifty Fischer 344 rats were fed a choline\u2010deficient L\u2010amino\u2010acid\u2010defined (CDAA) diet for 12\u00a0weeks. The <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> effects of OCA\u2009+\u2009sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide\u2013Toll\u2010like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA\u2009+\u2009sitagliptin on activated hepatic stellate cells (Ac\u2010HSCs) were assessed <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Treatment with OCA\u2009+\u2009sitagliptin potentially inhibited hepatic fibrogenesis along with Ac\u2010HSC proliferation and hepatic transforming growth factor (TGF)\u2010\u03b21, \u03b11(I)\u2010procollagen, and tissue inhibitor of metalloproteinase\u20101 (TIMP\u20101) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase\u20102 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet\u2010induced zonula occludens\u20101 disruption, whereas sitagliptin directly inhibited Ac\u2010HSC proliferation. The <jats:italic>in vitro<\/jats:italic> suppressive effects of OCA\u2009+\u2009sitagliptin on TGF\u2010\u03b21 and \u03b11(I)\u2010procollagen mRNA expression and p38 phosphorylation in Ac\u2010HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac\u2010HSC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Treatment with OCA\u2009+\u2009sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac\u2010HSC proliferation. Thus, OCA\u2009+\u2009sitagliptin could be a promising therapeutic strategy for NASH.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hepr.13385","type":"journal-article","created":{"date-parts":[[2019,6,9]],"date-time":"2019-06-09T06:33:17Z","timestamp":1560061997000},"page":"1147-1161","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase\u20104 inhibitor on hepatic fibrosis"],"prefix":"10.1111","volume":"49","author":[{"given":"Naotaka","family":"Shimozato","sequence":"first","affiliation":[{"name":"Third Department of Internal Medicine Nara Medical University  Kashihara Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Namisaki","sequence":"additional","affiliation":[{"name":"Third Department of Internal Medicine Nara Medical University  Kashihara Nara 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