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

• Published in: Biochemical and biophysical research communications 2019-11, Vol.519 (4), p.854-860
• Main Authors: Wei, Zhuo, Zhao, Dan, Zhang, Ye, Chen, Yuanli, Zhang, Shuang, Li, Qi, Zeng, Peng, Li, Xiaoju, Zhang, Wenwen, Duan, Yajun, Han, Jihong, Yang, Xiaoxiao
• Format: Article
• Language: English
• Subjects: Bile duct ligation; Inflammation; Liver fibrosis; PPARγ; Rosiglitazone
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.09.084

Liver fibrosis is a major cause of morbidity and mortality worldwide. One of its therapeutic targets is peroxisome proliferator-activated receptor γ (PPARγ), 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 (PPARγfl/fl) and hepatocyte-specific PPARγ deficient (HepPPARγ 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 PPARγfl/fl mice but not in HepPPARγ KO mice. Mechanistically, rosiglitazone reduced BDL-induced collagen content by downregulating fibrotic related genes including transforming growth factor β1, α-smooth muscle actin and collagen type I α1, and decreased inflammation cytokine tumor necrosis factor α level by inhibiting phosphorylation of nuclear factor-κB in a PPARγ-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-κB-TNF-α pathway in a PPARγ-dependent manner. [Display omitted] •Rosiglitazone ameliorates BDL-induced gallbladder enlargement and jaundice in mice.•Rosiglitazone reduces BDL-induced liver injury in wild type mice.•Rosiglitazone inhibits liver fibrosis PPARγ-dependently by inactivating NF-κB-TNF-α.