Skip to main content
SpringerLink
Log in

Development and application of a comprehensive lipidomic analysis to investigate Tripterygium wilfordii-induced liver injury

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

Lipid metabolic pathways play pivotal roles in liver function, and disturbances of these pathways are associated with various diseases. Thus, comprehensive characterization and measurement of lipid metabolites are essential to deciphering the contributions of lipid network metabolism to diseases or its responses to drug intervention. Here, we report an integrated lipidomic analysis for the comprehensive detection of lipid metabolites. To facilitate the characterization of untargeted lipids through fragmentation analysis, nine formulas were proposed to identify the fatty acid composition of lipids from complex MSn spectrum information. By these formulas, the co-eluted isomeric compounds could be distinguished. In total, 250 lipids were detected and characterized, including diacylglycerols, triacylglycerols, glycerophosphoethanolamines, glycerophosphocholines, glycerophosphoserines, glycerophosphoglycerols, glycerophosphoinositols, cardiolipins, ceramides, and sphingomyelins. Integrated with the targeted lipidomics, a total of 27 inflammatory oxylipins were also measured. To evaluate the aberrant lipid metabolism involved in liver injury induced by Tripterygium wilfordii, lipid network metabolism was further investigated. Results indicated that energy lipid modification, membrane remodeling, potential signaling lipid alterations, and abnormal inflammation response were associated with injury. Because of the important roles of lipids in liver metabolism, this new method is expected to be useful in analyzing other lipid metabolism diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Cajka T, Fiehn O. Toward merging untargeted and targeted methods in mass spectrometry-based metabolomics and lipidomics. Anal Chem. 2015;88(1):524–45.

    Article  Google Scholar 

  2. Brites P, Waterham HR, Wanders RJ. Functions and biosynthesis of plasmalogens in health and disease. Biochim Biophys Acta. 2004;1636(2–3):219–31.

    Article  CAS  Google Scholar 

  3. Numata M, Chu HW, Dakhama A, Voelker DR. Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus-induced inflammation and infection. Proc Natl Acad Sci U S A. 2010;107(1):320–5.

    Article  CAS  Google Scholar 

  4. Chen S, Kong H, Lu X, Li Y, Yin P, Zeng Z, et al. Pseudotargeted metabolomics method and its application in serum biomarker discovery for hepatocellular carcinoma based on ultra high-performance liquid chromatography/triple quadrupole mass spectrometry. Anal Chem. 2013;85(17):8326–33.

    Article  CAS  Google Scholar 

  5. Wolfer AM, Gaudin M, Taylor-Robinson SD, Holmes E, Nicholson JK. Development and validation of a high-throughput ultrahigh-performance liquid chromatography–mass spectrometry approach for screening of oxylipins and their precursors. Anal Chem. 2015;87(23):11721–31.

    Article  CAS  Google Scholar 

  6. Garate J, Fernandez R, Lage S, Bestard-Escalas J, Lopez DH, Reigada R, et al. Imaging mass spectrometry increased resolution using 2-mercaptobenzothiazole and 2,5-diaminonaphthalene matrices: application to lipid distribution in human colon. Anal Bioanal Chem. 2015;407(16):4697–708.

    Article  CAS  Google Scholar 

  7. Thomas A, Charbonneau JL, Fournaise E, Chaurand P. Sublimation of new matrix candidates for high spatial resolution imaging mass spectrometry of lipids: enhanced information in both positive and negative polarities after 1,5-diaminonapthalene deposition. Anal Chem. 2012;84(4):2048–54.

    Article  CAS  Google Scholar 

  8. Kind T, Liu KH, Lee do Y, DeFelice B, Meissen JK, Fiehn O. LipidBlast in silico tandem mass spectrometry database for lipid identification. Nat Methods. 2013;10(8):755–8.

    Article  CAS  Google Scholar 

  9. Narvaez-Rivas M, Zhang Q. Comprehensive untargeted lipidomic analysis using core-shell C30 particle column and high field orbitrap mass spectrometer. J Chromatogr A. 2016;1440:123–34.

    Article  CAS  Google Scholar 

  10. Chen F, Ma YL, Ding H, Chen BP. Effects of Tripterygium wilfordii glycosides on regulatory T cells and Th17 in an IgA nephropathy rat model. Genet Mol Res. 2015;14(4):14900–7.

    Article  CAS  Google Scholar 

  11. Li XJ, Jiang ZZ, Zhang LY. Triptolide: progress on research in pharmacodynamics and toxicology. J Ethnopharmacol. 2014;155(1):67–79.

    Article  CAS  Google Scholar 

  12. Suciu M, Gruia AT, Nica DV, Azghadi SMR, Mic AA, Mic FA. Acetaminophen-induced liver injury: implications for temporal homeostasis of lipid metabolism and eicosanoid signaling pathway. Chem Biol Interact. 2015;242:335–44.

    Article  CAS  Google Scholar 

  13. Cajka T, Fiehn O. Comprehensive analysis of lipids in biological systems by liquid chromatography-mass spectrometry. Trends Anal Chem. 2014;61:192–206.

    Article  CAS  Google Scholar 

  14. Yang P, Chan D, Felix E, Madden T, Klein RD, Shureiqi I, et al. Determination of endogenous tissue inflammation profiles by LC/MS/MS: COX- and LOX-derived bioactive lipids. Prostaglandins Leukot Essent Fat Acids. 2006;75(6):385–95.

    Article  CAS  Google Scholar 

  15. Bird SS, Marur VR, Sniatynski MJ, Greenberg HK, Kristal BS. Serum lipidomics profiling using LC-MS and high-energy collisional dissociation fragmentation: focus on triglyceride detection and characterization. Anal Chem. 2011;83(17):6648–57.

    Article  CAS  Google Scholar 

  16. Godzien J, Ciborowski M, Martínez-Alcázar MP, Samczuk P, Kretowski A, Barbas C. Rapid and reliable identification of phospholipids for untargeted metabolomics with LC–ESI–QTOF–MS/MS. J Proteome Res. 2015;14(8):3204–16.

    Article  CAS  Google Scholar 

  17. Liebisch G, Vizcaino JA, Kofeler H, Trotzmuller M, Griffiths WJ, Schmitz G, et al. Shorthand notation for lipid structures derived from mass spectrometry. J Lipid Res. 2013;54(6):1523–30.

    Article  CAS  Google Scholar 

  18. Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G, Lass A, et al. FAT SIGNALS—lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 2012;15(3):279–91.

    Article  CAS  Google Scholar 

  19. Saponaro C, Gaggini M, Carli F, Gastaldelli A. The subtle balance between lipolysis and lipogenesis: a critical point in metabolic homeostasis. Nutrients. 2015;7(11):9453–74.

    Article  Google Scholar 

  20. Sapiro JM, Mashek MT, Greenberg AS, Mashek DG. Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor alpha activity. J Lipid Res. 2009;50(8):1621–9.

    Article  CAS  Google Scholar 

  21. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45(6):1366–74.

    Article  CAS  Google Scholar 

  22. Mantzaris MD, Tsianos EV, Galaris D. Interruption of triacylglycerol synthesis in the endoplasmic reticulum is the initiating event for saturated fatty acid-induced lipotoxicity in liver cells. FEBS J. 2011;278(3):519–30.

    Article  CAS  Google Scholar 

  23. Liu J, Han L, Zhu L, Yu Y. Free fatty acids, not triglycerides, are associated with non-alcoholic liver injury progression in high fat diet induced obese rats. Lipids Health Dis. 2016;15(1):27.

    Article  CAS  Google Scholar 

  24. Nakamura MT, Yudell BE, Loor JJ. Regulation of energy metabolism by long-chain fatty acids. Prog Lipid Res. 2014;53:124–44.

    Article  CAS  Google Scholar 

  25. Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281(17):12093–101.

    Article  CAS  Google Scholar 

  26. Holzer RG, Park EJ, Li N, Tran H, Chen M, Choi C, et al. Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell. 2011;147(1):173–84.

    Article  CAS  Google Scholar 

  27. Duwaerts CC, Maher JJ. Mechanisms of liver injury in non-alcoholic steatohepatitis. Curr Hepatol Rep. 2014;13(2):119–29.

    Article  Google Scholar 

  28. Kusunoki N, Yamazaki R, Kitasato H, Beppu M, Aoki H, Kawai S. Triptolide, an active compound identified in a traditional Chinese herb, induces apoptosis of rheumatoid synovial fibroblasts. BMC Pharmacol. 2004;4:2.

    Article  Google Scholar 

  29. Wang J, Miao M, Qu L, Cui Y, Zhang Y. Protective effects of geniposide against Tripterygium glycosides (TG)-induced liver injury and its mechanisms. J Toxicol Sci. 2016;41(1):165–73.

    Article  Google Scholar 

  30. Yang X, Sheng W, Sun GY, Lee JC. Effects of fatty acid unsaturation numbers on membrane fluidity and alpha-secretase-dependent amyloid precursor protein processing. Neurochem Int. 2011;58(3):321–9.

    Article  CAS  Google Scholar 

  31. Ariyama H, Kono N, Matsuda S, Inoue T, Arai H. Decrease in membrane phospholipid unsaturation induces unfolded protein response. J Biol Chem. 2010;285(29):22027–35.

    Article  CAS  Google Scholar 

  32. Steenbergen R, Nanowski TS, Beigneux A, Kulinski A, Young SG, Vance JE. Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects. J Biol Chem. 2005;280(48):40032–40.

    Article  CAS  Google Scholar 

  33. Dumas JF, Goupille C, Julienne CM, Pinault M, Chevalier S, Bougnoux P, et al. Efficiency of oxidative phosphorylation in liver mitochondria is decreased in a rat model of peritoneal carcinosis. J Hepatol. 2011;54(2):320–7.

    Article  CAS  Google Scholar 

  34. Manganelli V, Capozzi A, Recalchi S, Signore M, Mattei V, Garofalo T, et al. Altered traffic of cardiolipin during apoptosis: exposure on the cell surface as a trigger for “antiphospholipid antibodies”. J Immunol Res. 2015;2015:847985.

    Article  Google Scholar 

  35. Dumas JF, Peyta L, Couet C, Servais S. Implication of liver cardiolipins in mitochondrial energy metabolism disorder in cancer cachexia. Biochimie. 2013;95(1):27–32.

    Article  CAS  Google Scholar 

  36. Patrussi L, Mariggio S, Corda D, Baldari CT. The glycerophosphoinositols: from lipid metabolites to modulators of T-cell signaling. Front Immunol. 2013;4:213.

    Article  CAS  Google Scholar 

  37. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9(2):139–50.

    Article  CAS  Google Scholar 

  38. Rodemer C, Thai TP, Brugger B, Kaercher T, Werner H, Nave KA, et al. Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice. Hum Mol Genet. 2003;12(15):1881–95.

    Article  CAS  Google Scholar 

  39. Berger J, Dorninger F, Forss-Petter S, Kunze M. Peroxisomes in brain development and function. Biochim Biophys Acta. 2015;S0167–4889(15):00426–7.

    Google Scholar 

Download references

Acknowledgments

This study was financially supported by the Natural Science Foundation of China (Grants No. 81303295, 81373688, 81573869); the Natural Science Foundation of Jiangsu Province, China (Grant No. BK20130959); The Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20133237120001); colleges and universities in Jiangsu Province Natural Science Research (Grant No. 13KJB360005), and the Open Project Program of Jiangsu Key Laboratory of Pediatric Respiratory Disease, Nanjing University of Chinese Medicine (Grant No. JKLPRD201407).

Author information

Authors and Affiliations

  1. Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China

    Tong Xie, Shouchuan Wang, Jianya Xu, Cunsi Shen & Jinjun Shan

  2. The First Clinical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China

    Xueping Zhou & Yan Lu

  3. Jiangsu Engineering Research Center for Efficient Delivery System of TCM, College of Pharmacy, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Nanjing, Jiangsu, 210023, China

    Huaxu Zhu, An Kang, Haishan Deng & Liuqing Di

Authors
  1. Tong Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xueping Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shouchuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huaxu Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. An Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haishan Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jianya Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cunsi Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Liuqing Di
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jinjun Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Tong Xie or Jinjun Shan.

Ethics declarations

Animal experiments were carried out in compliance with the standard ethical guidelines and under the control of the university ethical committee.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 969 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, T., Zhou, X., Wang, S. et al. Development and application of a comprehensive lipidomic analysis to investigate Tripterygium wilfordii-induced liver injury. Anal Bioanal Chem 408, 4341–4355 (2016). https://doi.org/10.1007/s00216-016-9533-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-016-9533-9

Keywords

Search

Navigation