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Cenicriviroc, a cytokine receptor antagonist, potentiates all‐trans retinoic acid in reducing liver injury in cholestatic rodents
Author(s) -
Yu Dongke,
Cai ShiYing,
Men Albert,
Vig Pamela,
Boyer James L.
Publication year - 2018
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.13698
Subject(s) - liver injury , bile acid , cholestasis , medicine , retinoic acid , fibrosis , bilirubin , pharmacology , endocrinology , chemistry , biochemistry , gene
Background & Aims Cholestatic liver injury is mediated by bile acid‐induced inflammatory responses. We hypothesized that superior therapeutic effects might be achieved by combining treatments that reduce the bile acid pool size with one that blocks inflammation. Methods Bile duct‐ligated ( BDL ) rats and Mdr2 ( Abcb4 ) −/− mice were treated with all‐trans retinoic acid (at RA ), a potent inhibitor of bile acid synthesis, 5 mg/kg/d by gavage, or Cenicriviroc ( CVC ), a known antagonist of CCR 2 and CCR 5, 50 mg/kg/d alone or in combination for 14 days and 1 month respectively. Results All‐trans retinoic acid alone reduced bile acid pool size and liver necrosis in BDL rats. However, the combination with CVC further reduced liver to body weight ratio, bile acid pool size, plasma liver enzyme, bilirubin, liver necrosis and fibrosis when compared to the at RA treatment. The assessment of hepatic hydroxyproline content further confirmed the reduced liver injury concurrent with reduction of pro‐inflammatory 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 Mdr2 −/− 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. Conclusions Multitargeted therapy is an important paradigm for treating cholestatic liver injury. The combination of CVC with at RA or other FXR activators may warrant a clinical trial in patients with cholestatic liver disease.