Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1-FXR Signaling[S]

• Published in: Molecular & cellular proteomics Vol. 18; no. 3; pp. 520 - 533
• Main Authors: Zhao, Qi, Liu, Fang, Cheng, Yan, Xiao, Xue-Rong, Hu, Dan-Dan, Tang, Ying-Mei, Bao, Wei-Min, Yang, Jin-Hui, Jiang, Tao, Hu, Jia-Peng, Gonzalez, Frank J., Li, Fei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019; The American Society for Biochemistry and Molecular Biology
• Subjects: 1-Naphthylisothiocyanate - adverse effects; Adult; Animals; Cholestasis, Intrahepatic - blood; Cholestasis, Intrahepatic - chemically induced; Cholestasis, Intrahepatic - drug therapy; Cholestasis, Intrahepatic - genetics; Disease Models, Animal; Female; Gene Expression Profiling - methods; Hepatotoxicity; Humans; Male; Mass Spectrometry; Mechanism of action; Metabolites; Metabolomics; Metabolomics - methods; Mice; Middle Aged; Pentacyclic Triterpenes; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction - drug effects; Sirtuin 1 - metabolism; Thioacetamide - adverse effects; Treatment Outcome; Triterpenes - administration & dosage; Triterpenes - pharmacology; Metabolomics; Metabolites; Mechanism of action; Hepatotoxicity; Mass Spectrometry
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1074/mcp.RA118.000817

The present study used metabolomics, transcriptomics, protein analysis by immunoblots, chemical inhibition and gene knockout mice to determine the effects of celastrol on cholestasis and its mechanisms. Samples from patients were used to validate our findings, and the data supported the conclusions that celastrol protected against cholestatic liver injury through modulation of the SIRT1 and FXR. [Display omitted] Highlights •1. Celastrol alleviated cholestatic liver injury.•2. Celastrol inhibited the decrease of SIRT1 induced by deoxycholic acid.•3. SIRT1-FXR signaling pathway mediated the effect of celastrol. Celastrol, derived from the roots of the Tripterygium Wilfordi, shows a striking effect on obesity. In the present study, the role of celastrol in cholestasis was investigated using metabolomics and transcriptomics. Celastrol treatment significantly alleviated cholestatic liver injury in mice induced by α-naphthyl isothiocyanate (ANIT) and thioacetamide (TAA). Celastrol was found to activate sirtuin 1 (SIRT1), increase farnesoid X receptor (FXR) signaling and inhibit nuclear factor-kappa B and P53 signaling. The protective role of celastrol in cholestatic liver injury was diminished in mice on co-administration of SIRT1 inhibitors. Further, the effects of celastrol on cholestatic liver injury were dramatically decreased in Fxr-null mice, suggesting that the SIRT1-FXR signaling pathway mediates the protective effects of celastrol. These observations demonstrated a novel role for celastrol in protecting against cholestatic liver injury through modulation of the SIRT1 and FXR.