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Dietary supplementation with geranylgeraniol suppresses lipopolysaccharide-induced inflammation via inhibition of nuclear factor-κB activation in rats

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Abstract

Purpose

The isoprenoid geranylgeraniol (GGOH) inhibits nuclear factor-kappa B (NF-κB) activation in the liver, yet the mechanism remains unclear. We investigated the modulation and inhibition of lipopolysaccharide (LPS)-induced NF-κB signaling in the liver of rats fed a GGOH-supplemented diet.

Methods

Rats were fed a diet supplemented with or without GGOH for 10 days. Rats were then intraperitoneally injected with 0.5 mg/kg LPS or vehicle (sterilized saline) and fasted for 18 h. Plasma levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, and the liver damage indicators alanine and aspartate aminotransferases (ALT and AST) were assessed. Liver mRNA and proteins were assayed for changes in NF-κB target genes and signal transduction genes.

Results

Rats fed a high-dose, GGOH-supplemented diet showed significantly lower levels of plasma inflammatory cytokines and ALT and AST activities. In the liver, GGOH significantly suppressed NF-κB activation and mRNA expression of its pro-inflammatory target genes. Furthermore, GGOH supplementation substantially suppressed mRNA expression of signal transducer genes upstream of the IκB kinase complex. Western blotting of liver extracts further demonstrated the substantial decrease in total IL-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6), leading to lower signal transduction and inhibition of NF-κB after LPS.

Conclusion

A 10-day, high-dose, GGOH-supplemented diet was sufficient to inhibit LPS-induced inflammation and activation of NF-κB in rat livers. GGOH significantly modulated NF-κB signaling molecules, inhibiting its signal transduction and activation in the liver, thus protecting against liver damage.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

FOH:

Farnesol

GOH:

Geraniol

GGOH:

Geranylgeraniol

GGPP:

Geranylgeranyl pyrophosphate

Irak1 :

Interleukin-1 receptor-associated kinase 1

Tak1 :

TGF-beta activated kinase 1

TLR:

Toll-like receptor

Traf6 :

TNF receptor-associated factor 6

References

  1. Bengmark S (2009) Control of systemic inflammation and chronic diseases-the use of turmeric and curcuminoids. In: Mine Y, Miyashita K, Shahidi F (eds) Nutrigenomics and proteomics in health and disease: food factors and gene interactions. Wiley, New York, pp 161–163

    Chapter  Google Scholar 

  2. Pan MH, Lai CS, Dushenkov S, Ho CT (2009) Modulation of inflammatory genes by natural dietary bioactive compounds. J Agric Food Chem 57:4467–4477

    Article  CAS  Google Scholar 

  3. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS et al (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481:243–268

    Google Scholar 

  4. Muraguchi T, Okamoto K, Mitake M, Ogawa H, Shidoji Y (2010) Polished rice as natural sources of cancer-preventing geranylgeranoic acid. J Clin Biochem Nutr 49:8–15

    Article  Google Scholar 

  5. Frenkel J, Rijkers GT, Mandey SH, Buurman SW, Houten SM et al (2002) Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum 46:2794–2803

    Article  CAS  Google Scholar 

  6. Haas D, Hoffman GF (2007) Mevalonate kinase deficiency and autoinflammatory disorders. N Engl J Med 356:2671–2673

    Article  CAS  Google Scholar 

  7. Crick DC, Andres DA, Waechter CJ (1995) Farnesol is utilized for protein isoprenylation and the biosynthesis of cholesterol in mammalian cells. Biochem Biophys Res Commun 211:590–599

    Article  CAS  Google Scholar 

  8. Ohsaki Y, Shirakawa H, Miura A, Giriwono PE, Sato S et al (2010) Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor kappaB through the repression of IKKalpha/beta phosphorylation. J Nutr Biochem 21:1120–1126

    Article  CAS  Google Scholar 

  9. Marcuzzi A, Tommasini A, Crovella S, Pontillo A (2010) Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes. Int Immunopharmacol 10:639–642

    Article  CAS  Google Scholar 

  10. Mandey SH, Kuijk LM, Frenkel J, Waterham HR (2006) A role for geranylgeranylation in interleukin-1beta secretion. Arthritis Rheum 54:3690–3695

    Article  CAS  Google Scholar 

  11. De Moura Espindola R, Mazzantini RP, Ong TP, de Conti A, Heidor R et al (2005) Geranylgeraniol and beta-ionone inhibit hepatic preneoplastic lesions, cell proliferation, total plasma cholesterol and DNA damage during the initial phases of hepatocarcinogenesis, but only the former inhibits NF-kappaB activation. Carcinogenesis 26:1091–1099

    Article  Google Scholar 

  12. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB (2003) Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 63:4375–4383

    CAS  Google Scholar 

  13. Ohsaki Y, Shirakawa H, Hiwatashi K, Furukawa Y, Mizutani T et al (2006) Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci Biotechnol Biochem 70:926–932

    Article  CAS  Google Scholar 

  14. Adams SD, Delano BA, Helmer KS, Mercer DW (2009) Fasting exacerbates and feeding diminishes LPS-induced liver injury in the rat. Dig Dis Sci 54:767–773

    Article  Google Scholar 

  15. Ozaki I, Zhang H, Mizuta T, Ide Y, Eguchi Y et al (2007) Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. Clin Cancer Res 13:2236–2245

    Article  CAS  Google Scholar 

  16. Houten SM, Frenkel J, Waterham HR (2003) Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation. Cell Mol Life Sci 60:1118–1134

    CAS  Google Scholar 

  17. Memon RA, Shechter I, Moser AH, Shigenaga JK, Grunfeld C et al (1997) Endotoxin, tumor necrosis factor and interleukin-1 decrease hepatic squalene synthase activity, protein and mRNA levels in Syrian hamsters. J Lipid Res 38:1620–1629

    CAS  Google Scholar 

  18. Jirillo E, Caccavo D, Magrone T, Piccigallo E, Amati L, Lembo A, Kalis C, Guamenscheimer M (2002) Review: the role of the liver in the response to LPS: experimental and clinical findings. J Endotoxin Res 8:319–327

    CAS  Google Scholar 

  19. Wang YD, Chen WD, Wang M, Yu D, Forman BM et al (2008) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48:1632–1643

    Article  CAS  Google Scholar 

  20. Ghosh S, Hayden MS (2008) New regulators of NF-kappaB in inflammation. Nat Rev Immunol 8:837–848

    Article  CAS  Google Scholar 

  21. Ravi R, Bedi A (2004) NF-kappaB in cancer-a friend turned foe. Drug Resist Updat 7:53–67

    Article  CAS  Google Scholar 

  22. Ahn KS, Sethi G, Krishnan K, Aggarwal BB (2007) Gamma-Tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J Biol Chem 282:809–820

    Article  CAS  Google Scholar 

  23. Medzhitov R, Horng T (2009) Transcriptional control of the inflammatory response. Nat Rev Immunol 9:692–703

    Article  CAS  Google Scholar 

  24. Yip KH, Zheng MH, Feng HT, Steer JH, Joyce DA et al (2004) Sesquiterpene lactone parthenolide blocks lipopolysaccharide-induced osteolysis through the suppression of NF-kappaB activity. J Bone Miner Res 19:1905–1916

    Article  CAS  Google Scholar 

  25. Sethi G, Ahn KS, Pandey MK, Anggarwal BB (2007) Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation. Blood 109:2727–2735

    CAS  Google Scholar 

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Acknowledgments

This work was partially supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science to HS (#20380071).

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The authors declare no conflicts of interest.

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Correspondence to Hitoshi Shirakawa.

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Giriwono, P.E., Shirakawa, H., Ohsaki, Y. et al. Dietary supplementation with geranylgeraniol suppresses lipopolysaccharide-induced inflammation via inhibition of nuclear factor-κB activation in rats. Eur J Nutr 52, 1191–1199 (2013). https://doi.org/10.1007/s00394-012-0429-y

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  • DOI: https://doi.org/10.1007/s00394-012-0429-y

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