Triptolide increases resistance to bile duct ligation-induced liver injury and fibrosis in mice by inhibiting RELB

Zihang Yuan; Jie Wang; Haoran Zhang; Yingying Miao; Qianhui Tang; Ziqiao Yuan; Cheng Nong; Zhicheng Duan; Luyong Zhang; Zhenzhou Jiang; Qinwei Yu

doi:10.3389/fnut.2022.1032722

Triptolide increases resistance to bile duct ligation-induced liver injury and fibrosis in mice by inhibiting RELB

Front Nutr. 2022 Oct 13:9:1032722. doi: 10.3389/fnut.2022.1032722. eCollection 2022.

Authors

Zihang Yuan¹, Jie Wang¹, Haoran Zhang¹, Yingying Miao¹, Qianhui Tang¹, Ziqiao Yuan¹, Cheng Nong¹, Zhicheng Duan¹, Luyong Zhang^{1

2}, Zhenzhou Jiang^{1

3}, Qinwei Yu¹

Affiliations

¹ New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
² Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China.
³ Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, China.

Abstract

Cholestasis is a common, chronic liver disease that may cause fibrosis and cirrhosis. Tripterygium wilfordii Hook.f (TWHF) is a species in the Euonymus family that is commonly used as a source of medicine and food in Eastern and Southern China. Triptolide (TP) is an epoxy diterpene lactone of TWHF, as well as the main active ingredient in TWHF. Here, we used a mouse model of common bile duct ligation (BDL) cholestasis, along with cultured human intrahepatic biliary epithelial cells, to explore whether TP can relieve cholestasis. Compared with the control treatment, TP at a dose of 70 or 140 μg/kg reduced the serum levels of the liver enzymes alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in mice; hematoxylin and eosin staining also showed that TP reduced necrosis in tissues. Both in vitro and in vivo analyses revealed that TP inhibited cholangiocyte proliferation by reducing the expression of RelB. Immunohistochemical staining of CK19 and Ki67, as well as measurement of Ck19 mRNA levels in hepatic tissue, revealed that TP inhibited the BDL-induced ductular reaction. Masson 3 and Sirius Red staining for hepatic hydroxyproline showed that TP alleviated BDL-induced hepatic fibrosis. Additionally, TP substantially inhibited BDL-induced hepatic inflammation. In summary, TP inhibited the BDL-induced ductular reaction by reducing the expression of RelB in cholangiocytes, thereby alleviating liver injury, fibrosis, and inflammation.

Keywords: RelB; TNFSF14; bile duct ligation (BDL); cholangiocyte; triptolide.