{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:21:13Z","timestamp":1790392873319,"version":"4.1.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T00:00:00Z","timestamp":1505779200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:p>The farnesoid X receptor (FXR) agonist, a bile acid\u2010activated nuclear receptor, has been shown to improve the histologic features of nonalcoholic steatohepatitis (NASH); however, a satisfactory effect on hepatic fibrosis has not been achieved. We aimed to investigate the combined effect of FXR agonist and angiotensin II type 1 receptor blocker on hepatic fibrogenesis in rat models of NASH. For 8 weeks, two rat models of NASH were developed. Otsuka Long\u2010Evans Tokushima Fatty (OLETF) rats were administered intraperitoneal injections of 1\u2009mL\/kg pig serum (PS) twice a week, whereas Fischer\u2010344 rats were fed a choline\u2010deficient, L\u2010amino acid\u2010defined diet (CDAA). The <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic> effects of an FXR agonist (INT747) and an angiotensin II type 1 receptor blocker (losartan) on hepatic fibrogenesis were evaluated. In PS\u2010administered OLETF rats, INT747 and losartan had potent inhibitory effects on hepatic fibrogenesis with suppression of hepatic stellate cell (HSC) activation and expression of transforming growth factor \u03b21 and toll\u2010like receptor 4. INT747 decreased intestinal permeability by ameliorating zonula occuludens\u20101 disruption, whereas losartan directly suppressed activated\u2010HSC (Ac\u2010HSC) regulation. The <jats:italic toggle=\"yes\">in vitro<\/jats:italic> inhibitory effects of INT747 and losartan on messenger RNA expressions of transforming growth factor \u03b21, toll\u2010like receptor 4, and myeloid differentiation factor 88 and phosphorylation of nuclear factor\u2010\u03baB and mothers against decapentaplegic homolog 3 in Ac\u2010HSC were almost in parallel. Losartan directly inhibited the regulation of Ac\u2010HSC. Likewise, INT747 in combination with losartan was beneficial on hepatic fibrogenesis in rats fed with CDAA diet. The therapeutic effects of these agents were almost comparable between PS\u2010administered OLETF and CDAA\u2010treated rats. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: INT747 and losartan synergistically suppressed hepatic fibrogenesis by reversing gut barrier dysfunction and inhibiting Ac\u2010HSC proliferation. Combined therapy may represent a promising novel approach for NASH. (<jats:italic toggle=\"yes\">Hepatology Communications<\/jats:italic> 2017;1:928\u2013945)<\/jats:p>","DOI":"10.1002\/hep4.1104","type":"journal-article","created":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T12:42:47Z","timestamp":1505824967000},"page":"928-945","source":"Crossref","is-referenced-by-count":15,"title":["Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on hepatic fibrosis"],"prefix":"10.1097","volume":"1","author":[{"given":"Tadashi","family":"Namisaki","sequence":"first","affiliation":[{"name":"Third Department of Internal Medicine,Nara Medical University,Kashihara,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Moriya","sequence":"additional","affiliation":[{"name":"Third Department of Internal Medicine,Nara Medical 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