Biological Trace Element Research

, Volume 154, Issue 2, pp 268–274 | Cite as

The Alteration of Copper Homeostasis in Inflammation Induced by Lipopolysaccharides

  • Ming HanEmail author
  • Zhexuan Lin
  • Yuan Zhang


Significant changes of copper homeostasis were triggered by lipopolysaccharides, which result in systemic inflammatory response and contribute to hepatic injury. Administration of lipopolysaccharides resulted in the increase of plasma “free” copper and total copper concentrations, whereas, the decrease of “free” copper and total copper contents in liver tissue. Copper-associated proteins were detected and showed a down-regulation of X-linked inhibitor of apoptosis protein, and up-regulation of copper metabolism domain containing 1 and copper transporter 1. The alteration of these proteins would lower the apoptotic threshold. Meanwhile, the increasing of circulation copper might cause oxidative injury through Fenton reaction and contribute to tissue injury. Our findings underscored the possibility that these changes in systemic copper homeostasis might provide a novel insight of the characteristic of the acute phase of inflammatory response and the underlying influence on tissue injury.


“Free” copper Total copper Lipopolysaccharides Copper transport associated proteins  



This work is supported by the National Natural Science Foundation of China (project number:81172088), the Joint Scientific Special foundation of Guandong Provincial Department of Science and Technology-Academy of Traditional Chinese Medicine (2012A032500009), and the Natural Science Foundation of Guangdong Province (project number S2012040007604).


  1. 1.
    Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251PubMedCrossRefGoogle Scholar
  2. 2.
    Jeschke MG, Klein D, Bolder U, Einspanier R (2004) Insulin attenuates the systemic inflammatory response in endotoxemic rats. Endocrinology 145:4084–4093PubMedCrossRefGoogle Scholar
  3. 3.
    Berger MM, Chiolero RL (2007) Antioxidant supplementation in sepsis and systemic inflammatory response syndrome. Crit Care Med 35:S584–590PubMedCrossRefGoogle Scholar
  4. 4.
    Ding HQ, Zhou BJ, Liu L, Cheng S (2002) Oxidative stress and metallothionein expression in the liver of rats with severe thermal injury. Burns: J Int Soc Burn Inj 28:215–221CrossRefGoogle Scholar
  5. 5.
    Delves HT (2001) Effect of inflammatory response on trace element and vitamin status. Ann Clin Biochem 38:289–291PubMedGoogle Scholar
  6. 6.
    Sakr Y, Reinhart K, Blood F, Marx G, Russwurm S, Bauer M, Brunkhorst F (2007) Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure. Brit J Anaesth 98:775–784PubMedCrossRefGoogle Scholar
  7. 7.
    Percival SS (1998) Copper and immunity. Am J Clin Nutr 67:1064S–1068SPubMedGoogle Scholar
  8. 8.
    Babu U, Failla ML (1990) Copper status and function of neutrophils are reversibly depressed in marginally and severely copper-deficient rats. J Nutr 120:1700–1709PubMedGoogle Scholar
  9. 9.
    Pan Q, Kleer CG, van Golen KL, Irani J, Bottema KM, Bias C, De Carvalho M, Mesri EA, Robins DM, Dick RD, Brewer GJ, Merajver SD (2002) Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res 62:4854–4859PubMedGoogle Scholar
  10. 10.
    Su GL (2002) Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283:G256–265PubMedGoogle Scholar
  11. 11.
    Zhang Y, Lin ZX, Li H, Peng L, Luo HJ, Li WQ, Luo WH (2010) Determination of serum copper and zinc in different chemical forms by graphite furnace atomic absorption spectrometry with ethanol-EDTA precipitation method. Spectrosc Spect Anal 30:816–819Google Scholar
  12. 12.
    Lin Z, Li H, Luo H, Zhang Y, Luo W (2011) Benzylamine and methylamine, substrates of semicarbazide-sensitive amine oxidase, attenuate inflammatory response induced by lipopolysaccharide. Int Immunopharmacol 11:1079–1089PubMedCrossRefGoogle Scholar
  13. 13.
    Venelinov TI, Davies IM, Beattie JH (2004) Dialysis-Chelex method for determination of exchangeable copper in human plasma. Anal Bioanal Chem 379:777–780PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang YA, Lin ZX, Li H, Luo WH (2004) Determination of cobalt in mouse tissue by graphite furnace atomic absorption spectrometry-micro-digestion with acid. Chinese J Anal Chem 32:1498–1500Google Scholar
  15. 15.
    Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138PubMedCrossRefGoogle Scholar
  16. 16.
    Maria C, Linder MH-A (1996) Copper biochemistry and molecular biology. Am J Clin Nutr 63:797s–811sGoogle Scholar
  17. 17.
    Pall HS, Williams AC, Blake DR, Lunec J, Gutteridge JM, Hall M, Taylor A (1987) Raised cerebrospinal-fluid copper concentration in Parkinson’s disease. Lancet 2:238–241PubMedCrossRefGoogle Scholar
  18. 18.
    Solomons NW (1985) Biochemical, metabolic, and clinical role of copper in human nutrition. J Am Coll Nutr 4:83–105PubMedGoogle Scholar
  19. 19.
    Walter RM Jr, Uriu-Hare JY, Olin KL, Oster MH, Anawalt BD, Critchfield JW, Keen CL (1991) Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus. Diabetes Care 14:1050–1056PubMedCrossRefGoogle Scholar
  20. 20.
    Singh KK, Kumar M, Kumar P, Gupta MK, Jha DK, Kumari S, Roy BK, Kumar S (2012) "Free" copper: a new endogenous chemical mediator of inflammation in birds. Biol Trace Elem Res 145:338–348PubMedCrossRefGoogle Scholar
  21. 21.
    Noto R, Alicata R, Sfogliano L, Neri S, Bifarella M (1983) A study of cupremia in a group of elderly diabetics. Acta Diabetol Lat 20:81–85PubMedCrossRefGoogle Scholar
  22. 22.
    Inagaki K, Mikuriya N, Morita S, Haraguchi H, Nakahara Y, Hattori M, Kinosita T, Saito H (2000) Speciation of protein-binding zinc and copper in human blood serum by chelating resin pre-treatment and inductively coupled plasma mass spectrometry. Analyst 125:197–203PubMedCrossRefGoogle Scholar
  23. 23.
    Lopez-Avila V, Sharpe O, Robinson WH (2006) Determination of ceruloplasmin in human serum by SEC-ICPMS. Anal Bioanal Chem 386:180–187PubMedCrossRefGoogle Scholar
  24. 24.
    Wallace JL (2005) Nitric oxide as a regulator of inflammatory processes. Mem Inst Oswaldo Cruz 100(Suppl 1):5–9PubMedGoogle Scholar
  25. 25.
    Tsuji K, Kwon AH, Yoshida H, Qiu Z, Kaibori M, Okumura T, Kamiyama Y (2005) Free radical scavenger (edaravone) prevents endotoxin-induced liver injury after partial hepatectomy in rats. J Hepatol 42:94–101PubMedCrossRefGoogle Scholar
  26. 26.
    Knight TR, Fariss MW, Farhood A, Jaeschke H (2003) Role of lipid peroxidation as a mechanism of liver injury after acetaminophen overdose in mice. Toxicol Sci 76:229–236PubMedCrossRefGoogle Scholar
  27. 27.
    Mufti AR, Burstein E, Csomos RA, Graf PCF, Wilkinson JC, Dick RD, Challa M, Son J-K, Bratton SB, Su GL, Brewer GJ, Jakob U, Duckett CS (2006) XIAP Is a copper binding protein deregulated in Wilson’s disease and other copper toxicosis disorders. Mol Cell 21:775–785PubMedCrossRefGoogle Scholar
  28. 28.
    Burstein E, Ganesh L, Dick RD, van De Sluis B, Wilkinson JC, Klomp LWJ, Wijmenga C, Brewer GJ, Nabel GJ, Duckett CS (2004) A novel role for XIAP in copper homeostasis through regulation of MURR1. EMBO J 23:244–254PubMedCrossRefGoogle Scholar
  29. 29.
    Russell JC, Whiting H, Szuflita N, Hossain MA (2008) Nuclear translocation of X-linked inhibitor of apoptosis (XIAP) determines cell fate after hypoxia ischemia in neonatal brain. J Neurochem 106:1357–1370PubMedCrossRefGoogle Scholar
  30. 30.
    Tao TY, Liu F, Klomp L, Wijmenga C, Gitlin JD (2003) The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein. J Biol Chem 278:41593–41596PubMedCrossRefGoogle Scholar
  31. 31.
    Narindrasorasak S, Kulkarni P, Deschamps P, She Y-M, Sarkar B (2007) Characterization and copper binding properties of human COMMD1 (MURR1). Biochemistry 46:3116–3128PubMedCrossRefGoogle Scholar
  32. 32.
    Lee J, Prohaska JR, Dagenais SL, Glover TW, Thiele DJ (2000) Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant. Gene 254:87–96PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Second Affiliated Hospital of Shantou University Medical CollegeShantouPeople’s Republic of China
  2. 2.The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouChina

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