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J Proteome Res. 2019 Mar 1;18(3):1133-1144. doi: 10.1021/acs.jproteome.8b00797. Epub 2019 Feb 12.

Modulation of Lipid Metabolism by Celastrol.

Zhang T1,2, Zhao Q1,2, Xiao X1, Yang R1,2, Hu D1, Zhu X1,2, Gonzalez FJ3, Li F1,4.

Author information

1
State Key Laboratory of Phytochemistry and Plant Resources in West China , Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201 , China.
2
University of Chinese Academy of Sciences , Beijing 100049 , China.
3
Laboratory of Metabolism, Center for Cancer Research , National Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , United States.
4
Jiangxi University of Traditional Chinese Medicine , Nanchang 330004 , China.

Abstract

Hyperlipidemia, characterized by high serum lipids, is a risk factor for cardiovascular disease. Recent studies have identified an important role for celastrol, a proteasome inhibitor isolated from Tripterygium wilfordii Hook. F., in obesity-related metabolic disorders. However, the exact influences of celastrol on lipid metabolism remain largely unknown. Celastrol inhibited the terminal differentiation of 3T3-L1 adipocytes and decreased the levels of triglycerides in wild-type mice. Lipidomics analysis revealed that celastrol increased the metabolism of lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), sphingomyelins (SMs), and phosphatidylethanolamines (PEs). Further, celastrol reversed the tyloxapol-induced hyperlipidemia induced associated with increased plasma LPCs, PCs, SMs, and ceramides (CMs). Among these lipids, LPC(16:0), LPC(18:1), PC(22:2/15:0), and SM(d18:1/22:0) were also decreased by celastrol in cultured 3T3-L1 adipocytes, mice, and tyloxapol-treated mice. The mRNAs encoded by hepatic genes associated with lipid synthesis and catabolism, including Lpcat1, Pld1, Smpd3, and Sptc2, were altered in tyloxapol-induced hyperlipidemia, and significantly recovered by celastrol treatment. The effect of celastrol on lipid metabolism was significantly reduced in Fxr-null mice, resulting in decreased Cers6 and Acer2 mRNAs compared to wild-type mice. These results establish that FXR was responsible in part for the effects of celastrol in controlling lipid metabolism and contributing to the recovery of aberrant lipid metabolism in obesity-related metabolic disorders.

KEYWORDS:

LC−MS; celastrol; hyperlipidemia; lipidomics

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