2. Academic Validation
  3. The Protective Roles of PPARα Activation in Triptolide-induced Liver Injury

The Protective Roles of PPARα Activation in Triptolide-induced Liver Injury

  • Toxicol Sci. 2019 Jun 26;kfz146. doi: 10.1093/toxsci/kfz146.
Dan-Dan Hu 1 2,  Qi Zhao 1,  Yan Cheng 1,  Xue-Rong Xiao 1,  Jian-Feng Huang 1,  Yan Qu 1,  Xian Li 2,  Ying-Mei Tang 3,  Wei-Min Bao 4,  Jin-Hui Yang 3,  Tao Jiang 3,  Jia-Peng Hu 5,  Frank J Gonzalez 6,  Fei Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
  • 2 School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology of Natural Products, Kunming Medical University, Kunming, China.
  • 3 Department of Gastroenterology, The 2nd Affiliated Hospital of Kunming Medical University, Yunnan Research Center for Liver Diseases, Kunming, China.
  • 4 Department of General Surgery, Yunnan Provincial 1st People's Hospital, Kunming, China.
  • 5 Clinical Laboratory, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 6 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
PMID: 31241159 DOI: 10.1093/toxsci/kfz146
Abstract

Triptolide (TP), one of the main active ingredients in Tripterygium wilfordii Hook F, is clinically used to treat immune diseases but is known to cause liver injury. The aim of this study was to investigate the biomarkers for TP-induced hepatotoxicity in mice and to determine potential mechanisms of its liver injury. LC/MS-based metabolomics was used to determine the metabolites that were changed in TP-induced liver injury. The accumulation of long-chain acylcarnitines in serum indicated that TP exposure disrupted endogenous Peroxisome Proliferator-activated Receptor α (PPARα) signaling. TP-induced liver injury could be alleviated by treatment of mice with the PPARα Agonist fenofibrate, while the PPARα Antagonist GW6471 increased hepatotoxicity. Furthermore, fenofibrate did not protect Ppara-/- mice from TP-induced liver injury, suggesting an essential role for the PPARα in the protective effect of fenofibrate. Elevated long-chain acylcarnitines may protect TP-induced liver injury through activation of the NOTCH-NRF2 pathway as revealed in primary mouse hepatocytes and in vivo. In agreement with these observations in mice, the increase of long-chain acylcarnitines was observed in the serum of patients with cholestatic liver injury compared to heathy volunteers. These data demonstrated the role of PPARα and long-chain acylcarnitines in TP-induced hepatotoxicity, and suggest that modulation of PPARα may protect against drug-induced liver injury.

Keywords

PPARα; acylcarnitines; liver injury; metabolomics.

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