Abstract
Objective and design
To investigate the potential protective effects of chlorogenic acid (CGA) on acute liver injury caused by lipopolysaccharide (LPS) in mice.
Materials and methods
C57BL/6J mice were pretreated with CGA (50 mg/kg, intraperitoneally) once per day for 5 days before an overnight LPS challenge (30 mg/kg, intraperitoneally). Severity of liver injury was assessed by histological analysis and determination of serum ALT and AST levels. Expression and activation of key regulators involved in the inflammatory response were determined, respectively, by real-time RT-PCR and western blotting.
Results
In contrast to the yellow color of the liver in LPS-treated mice, CGA maintained the normal reddish appearance of the liver. Histological analysis indicated that CGA attenuated the infiltration of neutrophil cells and the necrosis of hepatocytes. CGA also decreased the elevated plasma levels of ALT and AST. At the transcriptional level, CGA pretreatment suppressed hepatic mRNA expression of toll-like receptor 4 (TLR4), TNF-α and NF-κB p65 subunit. In contrast, mRNA level of the transcriptional coactivator PGC-1α was restored by CGA. Finally, CGA reduced the phosphorylation of NF-κB p65 subunit in the liver.
Conclusion
Our data suggest that CGA has remarkable hepatoprotective effects on LPS-induced liver injury and that the possible mechanism is related to its anti-inflammatory action.
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References
Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–50.
Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420:885–91.
Ulevitch RJ, Tobias PS. Recognition of gram-negative bacteria and endotoxin by the innate immune system. Curr Opin Immunol. 1999;11:19–22.
Zhang G, Ghosh S. Molecular mechanisms of NF-kappaB activation induced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res. 2000;6:453–7.
Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6853–66.
DiDonato J, Mercurio F, Rosette C, Wu-Li J, Suyang H, Ghosh S. Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Mol Cell Biol. 1996;16:1295–304.
Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1996;16:1295–304.
Minter RM, Bi X, Ben-Josef G, Wang T, Hu B, Arbabi S, et al. LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction. Am J Physiol Gastrointest Liver Physiol. 2009;296:G45–54.
Liaudet L, Murthy KG, Mabley JG, Pacher P, Soriano FG, Salzman AL, et al. Comparison of inflammation, organ damage, and oxidant stress induced by Salmonella enterica serovar muenchen flagellin and serovar enteritidis lipopolysaccharide. Infect Immun. 2002;70:192–8.
Remick DG, Newcomb DE, Bolgos GL, Call DR. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock. 2000;13:110–6.
Clifford MN. Chlorogenic acids and other cinnamates—nature, occurrence and dietary burden. J Sci Food Agric. 1999;79:362–72.
Kono Y, Kobayashi K, Tagawa S, Adachi K, Ueda A, Sawa Y, et al. Antioxidant activity of polyphenolics in diets: rate constants of reactions of chlorogenic acid and caffeic acid with reactive species of oxygen and nitrogen. Biochim Biophys Acta. 1997;1335:335–42.
Kasai H, Fukada S, Yamaizumi Z, Sugie S, Mori H. Action of chlorogenic acid in vegetables and fruits as an inhibitor of 8-hydroxydeoxyguanosine formation in vitro and in a rat carcinogenesis model. Food Chem Toxicol. 2000;38:467–71.
dos Santos MD, Almeida MC, Lopes NP, de Souza GE. Evaluation of the anti-inflammatory, analgesic and antipyretic activities of the natural polyphenol chlorogenic acid. Biol Pharm Bull. 2006;29:2236–40.
Feng R, Lu Y, Bowman LL, Qian Y, Castranova V, Ding M. Inhibition of activator protein-1, NF-kappaB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid. J Biol Chem. 2005;280:27888–95.
Krakauer T. The polyphenol chlorogenic acid inhibits staphylococcal exotoxin-induced inflammatory cytokines and chemokines. Immunopharmacol Immunotoxicol. 2002;24:113–9.
Shan J, Fu J, Zhao Z, Kong X, Huang H, Luo L, et al. Chlorogenic acid inhibits lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 cells through suppressing NF-kappaB and JNK/AP-1 activation. Int Immunopharmacol. 2009;9:1042–8.
Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–112.
Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005;1:361–70.
Yukawa GS, Mune M, Otani H, Tone Y, Liang XM, Iwahashi H, et al. Effects of coffee consumption on oxidative susceptibility of low-density lipoproteins and serum lipid levels in humans. Biochemistry (Moscow). 2004;69:70–4.
Rodriguez de Sotillo DV, Hadley M. Chlorogenic acid modifies plasma and liver concentrations of: cholesterol, triacylglycerol, and minerals in (fa/fa) Zucker rats. J Nutr Biochem. 2002;13:717–26.
Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci. 2002;65:166–76.
Nakama T, Hirono S, Moriuchi A, Hasuike S, Nagata K, Hori T, et al. Etoposide prevents apoptosis in mouse liver with d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure resulting in reduction of lethality. Hepatology. 2001;33:1441–50.
Morikawa A, Sugiyama T, Kato Y, Koide N, Jiang GZ, Takahashi K, et al. Apoptotic cell death in the response of d-galactosamine-sensitized mice to lipopolysaccharide as an experimental endotoxic shock model. Infect Immun. 1996;64:734–8.
Hishinuma I, Nagakawa J, Hirota K, Miyamoto K, Tsukidate K, Yamanaka TK, et al. Involvement of tumor necrosis factor-alpha in development of hepatic injury in galactosamine-sensitized mice. Hepatology. 1990;12:1187–91.
Tiegs G, Wolter M, Wendel A. Tumor necrosis factor is a terminal mediator in galactosamine/endotoxin-induced hepatitis in mice. Biochem Pharmacol. 1989;38:627–31.
Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 1999;11:443–51.
da Silva Correia J, Soldau K, Christen U, Tobias PS, Ulevitch RJ. Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. Transfer from CD14 to TLR4 and MD-2. J Biol Chem. 2001;276:21129–35.
Liu S, Gallo DJ, Green AM, Williams DL, Gong X, Shapiro RA, et al. Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide. Infect Immun. 2002;70:3433–42.
Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–79.
Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002;109(Suppl):S81–96.
Liang G, Zhou H, Wang Y, Gurley EC, Feng B, Chen L, et al. Inhibition of LPS-induced production of inflammatory factors in the macrophages by mono-carbonyl analogues of curcumin. J Cell Mol Med. 2009;13(9B):3370–9.
Chanchevalap S, Nandan MO, McConnell BB, Charrier L, Merlin D, Katz JP, et al. Kruppel-like factor 5 is an important mediator for lipopolysaccharide-induced proinflammatory response in intestinal epithelial cells. Nucleic Acids Res. 2006;34:1216–23.
Vermeulen L, De Wilde G, Notebaert S, Vanden Berghe W, Haegeman G. Regulation of the transcriptional activity of the nuclear factor-kappaB p65 subunit. Biochem Pharmacol. 2002;64:963–70.
Acknowledgments
This work was supported by grants from Chinese National Science Foundation (30870928), Major Program of Educational Commission of Jiangsu Province (09KJA180003), Nanjing Normal University Outstanding Talents Program (2008104XGQ0065), Opening Project of Jiangsu Key Laboratory for Molecular and Medical Biotechnology (MMB09KF05), Mega-projects of Science Research for the 11th Five-year Plan of China (2009ZX09302) and National Science Foundation for Talent Training in Basic Science (J0730650). The authors wish to thank Dr. Jessica Schwartz (University of Michigan) for helping to improve the English writing.
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Responsible Editor: K. Visvanathan.
Y. Xu and J. Chen contributed equally to this work.
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Xu, Y., Chen, J., Yu, X. et al. Protective effects of chlorogenic acid on acute hepatotoxicity induced by lipopolysaccharide in mice. Inflamm. Res. 59, 871–877 (2010). https://doi.org/10.1007/s00011-010-0199-z
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DOI: https://doi.org/10.1007/s00011-010-0199-z