Rosiglitazone ameliorates bile duct ligation-induced liver fibrosis by down-regulating NF-κB-TNF-α signaling pathway in a PPARγ-dependent manner

Liver fibrosis is a major cause of morbidity and mortality worldwide. One of its therapeutic targets is peroxisome proliferator-activated receptor gamma (PPAR gamma), with its ligands including rosiglitazone being tested in pre-clinical and clinical studies. However, the effects of rosiglitazone on bile duct ligation (BDL)-induced liver fibrosis and the involved mechanisms remain unknown. Herein, we used floxed control (PPAR gamma(fl/fl)) and hepatocyte-specific PPAR gamma deficient (HepPPAR gamma KO) mice to conduct BDL to induce liver fibrosis and treated the animals with rosiglitazone. After one week of BDL, mice in BDL group displayed liver injury evidenced by increased collagen content, fibrosis area, necrosis area and apoptotic cells, and elevated alkaline phosphatase and alanine transaminase activities in serum. Interestingly, rosiglitazone ameliorated BDL-induced liver injury in PPAR gamma(fl/fl) mice but not in HepPPAR gamma KO mice. Mechanistically, rosiglitazone reduced BDL-induced collagen content by downregulating fibrotic related genes including transforming growth factor beta 1, alpha-smooth muscle actin and collagen type I alpha 1, and decreased inflammation cytokine tumor necrosis factor alpha level by inhibiting phosphorylation of nuclear factor-kappa B in a PPAR gamma-dependent manner. Based on findings above, we demonstrated that rosiglitazone can ameliorate BDL-induced liver fibrosis in mice and confirmed its critical functions on fibrosis by regulating NF-kappa B-TNIF-alpha pathway in a PPAR gamma-dependent manner. (C) 2019 Elsevier Inc. All rights reserved.