Tripterygium wilfordii protects against an animal model of autoimmune hepatitis

  • J Ethnopharmacol. 2023 Mar 10;116365. doi: 10.1016/j.jep.2023.116365.
Ting Zhang  1 ,  Qianru Rao  2 ,  Manyun Dai  1 ,  Zhanxuan E Wu  2 ,  Qi Zhao  2 ,  Fei Li  3
Affiliations
  • 1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Laboratory of Metabolomics and Drug-induced Liver Injury, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2. Laboratory of Metabolomics and Drug-induced Liver Injury, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; Laboratory of Metabolomics and Drug-induced Liver Injury, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 36907478 DOI: 10.1016/j.jep.2023.116365
Abstract

Ethnopharmacological relevance: Tripterygium wilfordii tablets (TWT) is widely used to treat autoimmune diseases such as rheumatoid arthritis. Celastrol, one main active ingredient in TWT, has been shown to produce a variety of beneficial effects, including anti-inflammatory, anti-obesity, anti-cancer, and immunomodulatory. However, whether TWT could protect against Concanavalin A (Con A)-induced hepatitis remains unclear.

The aim of the study: This study aims to investigate the protective effect of TWT against Con A-induced hepatitis and elucidate the underlying mechanism.

Materials and methods: Metabolomic analysis, pathological analysis, biochemical analysis, qPCR and Western blot analysis and the Pxr-null mice were used in this study.

Results: The results indicated that TWT and its active ingredient celastrol could protect against Con A-induced acute hepatitis. Plasma metabolomics analysis revealed that metabolic perturbations related to bile acid and fatty acid metabolism induced by Con A were reversed by celastrol. The level of itaconate in the liver was increased by celastrol and speculated as an active endogenous compound mediating the protective effect of celastrol. Administration of 4-octanyl itaconate (4-OI) as a cell-permeable itaconate mimicker was found to attenuate Con A-induced liver injury through activation of the pregnane X receptor (PXR) and enhancement of the transcription factor EB (TFEB)-mediated Autophagy.

Conclusions: Celastrol increased itaconate and 4-OI promoted activation of TFEB-mediated lysosomal Autophagy to protect against Con A-induced liver injury in a PXR-dependent manner. Our study reported a protective effect of celastrol against Con A-induced AIH via an increased production of itaconate and upregulation of TFEB. The results highlighted that PXR and TFEB-mediated lysosomal autophagic pathway may offer promising therapeutic target for the treatment of autoimmune hepatitis.

Keywords
Autophagy; Celastrol; Concanavalin A; PXR; TFEB; Tripterygium wilfordii tablets.
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