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The Protective Roles of PPARα Activation in Triptolide-Induced Liver Injury
Dan-Dan Hu1,2, Qi Zhao1, Yan Cheng1
1State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
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. Triptolide-induced liver injury could be alleviated by treatment of mice with the PPARα agonist fenofibrate, whereas 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 in long-chain acylcarnitines was observed in the serum of patients with cholestatic liver injury compared with healthy volunteers. These data demonstrated the role of PPARα and long-chain acylcarnitines in TP-induced hepatotoxicity, and suggested that modulation of PPARα may protect against drug-induced liver injury.
Insights
Triptolide causes liver injury by disrupting peroxisome proliferator-activated receptor alpha (PPARα) signaling. Long-chain acylcarnitines and PPARα activation may protect against this drug-induced liver injury.
Area of Science:
- Pharmacology
- Toxicology
- Metabolomics
Background:
- Triptolide (TP), derived from Tripterygium wilfordii Hook F, treats immune diseases but causes liver injury.
- Identifying biomarkers and understanding mechanisms of TP-induced hepatotoxicity is crucial.
Purpose of the Study:
- Investigate biomarkers for TP-induced hepatotoxicity in mice.
- Determine the mechanisms underlying TP-induced liver injury.
- Explore the role of peroxisome proliferator-activated receptor alpha (PPARα) signaling.
Main Methods:
- LC/MS-based metabolomics to identify altered metabolites in TP-induced liver injury.
- In vivo studies using PPARα agonist (fenofibrate) and antagonist (GW6471).
- Studies in Ppara-/- mice to confirm PPARα's role.
- Analysis of NOTCH-NRF2 pathway activation in hepatocytes and in vivo.
- Comparison with human patient serum samples (cholestatic liver injury).
Main Results:
- Accumulation of long-chain acylcarnitines in serum indicated disrupted PPARα signaling.
- Fenofibrate alleviated TP-induced liver injury, while GW6471 exacerbated it.
- Protective effects of fenofibrate were absent in Ppara-/- mice.
- Elevated long-chain acylcarnitines activated the NOTCH-NRF2 pathway, potentially protecting against liver injury.
- Increased long-chain acylcarnitines were observed in human cholestatic liver injury patients.
Conclusions:
- PPARα signaling and long-chain acylcarnitines play key roles in TP-induced hepatotoxicity.
- Modulating PPARα may offer protection against drug-induced liver injury.
- Long-chain acylcarnitines may serve as biomarkers for drug-induced liver injury.
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