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We hypothesized that superior therapeutic effects might be achieved by combining treatments that reduce the bile acid pool size with one that blocks inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Bile duct\u2010ligated (<jats:styled-content style=\"fixed-case\">BDL<\/jats:styled-content>) rats and <jats:italic>Mdr2<\/jats:italic>(<jats:italic>Abcb4<\/jats:italic>)<jats:sup>\u2212\/\u2212<\/jats:sup> mice were treated with all\u2010trans retinoic acid (at<jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>), a potent inhibitor of bile acid synthesis, 5\u00a0mg\/kg\/d by gavage, or Cenicriviroc (<jats:styled-content style=\"fixed-case\">CVC<\/jats:styled-content>), a known antagonist of <jats:styled-content style=\"fixed-case\">CCR<\/jats:styled-content>2 and <jats:styled-content style=\"fixed-case\">CCR<\/jats:styled-content>5, 50\u00a0mg\/kg\/d alone or in combination for 14 days and 1\u00a0month respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All\u2010trans retinoic acid alone reduced bile acid pool size and liver necrosis in <jats:styled-content style=\"fixed-case\">BDL<\/jats:styled-content> rats. However, the combination with <jats:styled-content style=\"fixed-case\">CVC<\/jats:styled-content> further reduced liver to body weight ratio, bile acid pool size, plasma liver enzyme, bilirubin, liver necrosis and fibrosis when compared to the at<jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> treatment. The assessment of hepatic hydroxyproline content further confirmed the reduced liver injury concurrent with reduction of pro\u2010inflammatory cytokines emphasizing the synergistic effects of these two agents. Profiling of hepatic inflammatory cells revealed that combination therapy reduced neutrophils and T cells but not macrophages. The superior therapeutic effects of combination treatment were also confirmed in <jats:italic>Mdr2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice where a significant reduction in plasma liver enzymes, bilirubin, liver fibrosis, bile duct proliferation and hepatic infiltration of neutrophils and T cells and expression of cytokines were found.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Multitargeted therapy is an important paradigm for treating cholestatic liver injury. The combination of <jats:styled-content style=\"fixed-case\">CVC<\/jats:styled-content> with at<jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> or other <jats:styled-content style=\"fixed-case\">FXR<\/jats:styled-content> activators may warrant a clinical trial in patients with cholestatic liver disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.13698","type":"journal-article","created":{"date-parts":[[2018,1,22]],"date-time":"2018-01-22T15:30:38Z","timestamp":1516635038000},"page":"1128-1138","source":"Crossref","is-referenced-by-count":41,"title":["Cenicriviroc, a cytokine receptor antagonist, potentiates all\u2010trans retinoic acid in reducing liver injury in cholestatic rodents"],"prefix":"10.1111","volume":"38","author":[{"given":"Dongke","family":"Yu","sequence":"first","affiliation":[{"name":"Liver Center Yale University School of Medicine  New Haven CT 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