Skip to main content
SpringerLink
Log in

n-3 Polyunsaturated Fatty Acids Improve Inflammation via Inhibiting Sphingosine Kinase 1 in a Rat Model of Parenteral Nutrition and CLP-Induced Sepsis

  • Original Article
  • Published:
Lipids

Abstract

The sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) pathway plays a key role in inflammation. Parenteral nutrition containing n-3 polyunsaturated fatty acids (n-3 PUFA) may regulate inflammatory reactions. The aim of this study is to determine whether n-3 PUFA may improve inflammatory responses by neutralizing SphK1 signaling. Rat models of parenteral nutrition, cecal ligation and puncture (CLP)-induced sepsis were generated. Male Sprague–Dawley rats were operated for CLP on day 2 after venous catheterization. The rats were randomized to receive normal saline (NS; n = 20), parenteral nutrition (PN; n = 20), or PN + fish oil (FO; n = 20) for 5 days. The daily intake of fish oil (1.25–2.82 g EPA and 1.44–3.09 g DHA per 100 ml) in the FO group was approximately 1.8 g/kg body weight/day. Rats in the control group (n = 10) were subjected to sham operation and received a chow diet. Spleen tissues were collected for SphK1 and S1P receptor expression analysis. Our data showed that n-3 PUFA ameliorated the survival rate. SphK1 expression and its enzymatic activity were significantly upregulated in sepsis rats. Furthermore, mRNA and protein levels of S1PR3, but not S1PR1, were also facilitated after CLP. However, PN + FO dramatically decreased SphK1 mRNA level and its enzymatic activity. S1PR3 expression was also attenuated by FO addition. In conclusion, the anti-inflammatory effect of n-3 PUFA may be linked to the inhibition of the SphK1/S1P pathway in a rat model of parenteral nutrition and CLP-induced sepsis.

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

Similar content being viewed by others

Abbreviations

SphK1:

Sphingosine kinase 1

S1P:

Sphingosine-1-phosphate

n-3 PUFA:

n-3 polyunsaturated fatty acids

EPA:

Eicosapentaenoic acid

DHA:

Docosahexaenoic acid

CLP:

Cecal ligation and puncture

HMGB-1:

High-mobility group box 1

S1PRs:

Sphingosine-1-phosphate receptors

Sph:

Sphingosine

TPN:

Total parenteral nutrition

References

  1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R, Surviving Sepsis Campaign Guidelines Committee including The Pediatric S (2013) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39:165–228

    Article  CAS  PubMed  Google Scholar 

  2. Lanza-Jacoby S, Flynn JT, Miller S (2001) Parenteral supplementation with a fish-oil emulsion prolongs survival and improves rat lymphocyte function during sepsis. Nutrition 17:112–116

    Article  CAS  PubMed  Google Scholar 

  3. Calder PC (2006) n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 83:1505S–1519S

    CAS  PubMed  Google Scholar 

  4. Barbosa VM, Miles EA, Calhau C, Lafuente E, Calder PC (2010) Effects of a fish oil containing lipid emulsion on plasma phospholipid fatty acids, inflammatory markers, and clinical outcomes in septic patients: a randomized, controlled clinical trial. Crit Care 14:R5

    Article  PubMed  PubMed Central  Google Scholar 

  5. Li Q, Zhang Q, Wang M, Zhao S, Xu G, Li J (2008) n-3 polyunsaturated fatty acids prevent disruption of epithelial barrier function induced by proinflammatory cytokines. Mol Immunol 45:1356–1365

    Article  CAS  PubMed  Google Scholar 

  6. Chapkin RS, Wang N, Fan YY, Lupton JR, Prior IA (2008) Docosahexaenoic acid alters the size and distribution of cell surface microdomains. Biochim Biophys Acta 1778:466–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Galli C, Calder PC (2009) Effects of fat and fatty acid intake on inflammatory and immune responses: a critical review. Ann Nutr Metab 55:123–139

    Article  CAS  PubMed  Google Scholar 

  8. Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8:349–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lo CJ, Chiu KC, Fu M, Lo R, Helton S (1999) Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity. J Surg Res 82:216–221

    Article  CAS  PubMed  Google Scholar 

  10. Proia RL, Hla T (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379–1387

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pettus BJ, Bielawski J, Porcelli AM, Reames DL, Johnson KR, Morrow J, Chalfant CE, Obeid LM, Hannun YA (2003) The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. FASEB J 17:1411–1421

    Article  CAS  PubMed  Google Scholar 

  12. Grin’kina NM, Karnabi EE, Damania D, Wadgaonkar S, Muslimov IA, Wadgaonkar R (2012) Sphingosine kinase 1 deficiency exacerbates LPS-induced neuroinflammation. PLoS One 7:e36475

    Article  PubMed  PubMed Central  Google Scholar 

  13. Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY, Maceyka M, Jiang H, Luo C, Kordula T, Milstien S, Spiegel S (2010) Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465:1084–1088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wu W, Mosteller RD, Broek D (2004) Sphingosine kinase protects lipopolysaccharide-activated macrophages from apoptosis. Mol Cell Biol 24:7359–7369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dejager L, Pinheiro I, Dejonckheere E, Libert C (2011) Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol 19:198–208

    Article  CAS  PubMed  Google Scholar 

  16. Scarlett CJ, O’Leary MJ, Kee AJ, Nielsen A, Sevette A, Baxter RC, Smith RC (2004) A study of parenteral versus enteral nutrition following caecal ligation and puncture in the rat: influence on survival and tissue protein turnover. Clin Nutr 23:1135–1145

    Article  CAS  PubMed  Google Scholar 

  17. Lai YN, Yeh SL, Lin MT, Shang HF, Yeh CL, Chen WJ (2004) Glutamine supplementation enhances mucosal immunity in rats with Gut-Derived sepsis. Nutrition 20:286–291

    Article  CAS  PubMed  Google Scholar 

  18. Lanza-Jacoby S (1986) Effect of continuous and discontinuous intravenous or intragastric total parenteral nutrition in rats on serum lipids, liver lipids and liver lipogenic rates. J Nutr 116:733–741

    CAS  PubMed  Google Scholar 

  19. Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA (2009) Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 4:31–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cao S, Ren J, Sun L, Gu G, Yuan Y, Li J (2011) Fish oil-supplemented parenteral nutrition prolongs survival while beneficially altering phospholipids’ fatty acid composition and modulating immune function in rat sepsis. Shock 36:184–190

    Article  CAS  PubMed  Google Scholar 

  21. Waitzberg DL, Torrinhas RS (2009) Fish oil lipid emulsions and immune response: what clinicians need to know. Nutr Clin Pract 24:487–499

    Article  PubMed  Google Scholar 

  22. Wang X, Zhang DM, Gu TT, Ding XQ, Fan CY, Zhu Q, Shi YW, Hong Y, Kong LD (2013) Morin reduces hepatic inflammation-associated lipid accumulation in high fructose-fed rats via inhibiting sphingosine kinase 1/sphingosine 1-phosphate signaling pathway. Biochem Pharmacol 86:1791–1804

    Article  CAS  PubMed  Google Scholar 

  23. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  24. Hasan NM, Longacre MJ, Stoker SW, Kendrick MA, Druckenbrod NR, Laychock SG, Mastrandrea LD, MacDonald MJ (2012) Sphingosine kinase 1 knockdown reduces insulin synthesis and secretion in a rat insulinoma cell line. Arch Biochem Biophys 518:23–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wamhoff BR, Lynch KR, Macdonald TL, Owens GK (2008) Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 28:1454–1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kakkar P, Das B, Viswanathan PN (1984) A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys 21:130–132

    CAS  PubMed  Google Scholar 

  27. Snider AJ, Orr Gandy KA, Obeid LM (2010) Sphingosine kinase: role in regulation of bioactive sphingolipid mediators in inflammation. Biochimie 92:707–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Maceyka M, Spiegel S (2014) Sphingolipid metabolites in inflammatory disease. Nature 510:58–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Billich A, Bornancin F, Mechtcheriakova D, Natt F, Huesken D, Baumruker T (2005) Basal and induced sphingosine kinase 1 activity in A549 carcinoma cells: function in cell survival and IL-1beta and TNF-alpha induced production of inflammatory mediators. Cell Signal 17:1203–1217

    Article  CAS  PubMed  Google Scholar 

  30. Fernandez-Pisonero I, Duenas AI, Barreiro O, Montero O, Sanchez-Madrid F, Garcia-Rodriguez C (2012) Lipopolysaccharide and sphingosine-1-phosphate cooperate to induce inflammatory molecules and leukocyte adhesion in endothelial cells. J Immunol 189:5402–5410

    Article  CAS  PubMed  Google Scholar 

  31. Hammad SM, Crellin HG, Wu BX, Melton J, Anelli V, Obeid LM (2008) Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages. Prostaglandins Other Lipid Mediat 85:107–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nayak D, Huo Y, Kwang WX, Pushparaj PN, Kumar SD, Ling EA, Dheen ST (2010) Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience 166:132–144

    Article  CAS  PubMed  Google Scholar 

  33. Lai WQ, Irwan AW, Goh HH, Howe HS, Yu DT, Valle-Onate R, McInnes IB, Melendez AJ, Leung BP (2008) Anti-inflammatory effects of sphingosine kinase modulation in inflammatory arthritis. J Immunol 181:8010–8017

    Article  CAS  PubMed  Google Scholar 

  34. Li Q, Wang C, Zhang Q, Tang C, Li N, Li J (2012) The role of sphingosine kinase 1 in patients with severe acute pancreatitis. Ann Surg 255:954–962

    Article  PubMed  Google Scholar 

  35. Snider AJ, Kawamori T, Bradshaw SG, Orr KA, Gilkeson GS, Hannun YA, Obeid LM (2009) A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. FASEB J 23:143–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Spiegel S, Milstien S (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol 11:403–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rosen H, Stevens RC, Hanson M, Roberts E, Oldstone MB (2013) Sphingosine-1-phosphate and its receptors: structure, signaling, and influence. Annu Rev Biochem 82:637–662

    Article  CAS  PubMed  Google Scholar 

  38. Eskan MA, Rose BG, Benakanakere MR, Zeng Q, Fujioka D, Martin MH, Lee MJ, Kinane DF (2008) TLR4 and S1P receptors cooperate to enhance inflammatory cytokine production in human gingival epithelial cells. Eur J Immunol 38:1138–1147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fischer I, Alliod C, Martinier N, Newcombe J, Brana C, Pouly S (2011) Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLoS One 6:e23905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sun X, Singleton PA, Letsiou E, Zhao J, Belvitch P, Sammani S, Chiang ET, Moreno-Vinasco L, Wade MS, Zhou T, Liu B, Parastatidis I, Thomson L, Ischiropoulos H, Natarajan V, Jacobson JR, Machado RF, Dudek SM, Garcia JG (2012) Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury. Am J Respir Cell Mol Biol 47:628–636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Niessen F, Schaffner F, Furlan-Freguia C, Pawlinski R, Bhattacharjee G, Chun J, Derian CK, Andrade-Gordon P, Rosen H, Ruf W (2008) Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 452:654–658

    Article  CAS  PubMed  Google Scholar 

  42. Kono M, Tucker AE, Tran J, Bergner JB, Turner EM, Proia RL (2014) Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo. J Clin Invest 124:2076–2086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by the Medical Science and Technology Innovation Subject of Nanjing Military Region (No. 12Z27).

Author information

Authors and Affiliations

  1. Department of Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China

    Tao Tian, Yunzhao Zhao, Qian Huang & Jieshou Li

Authors
  1. Tao Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yunzhao Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jieshou Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yunzhao Zhao.

Ethics declarations

Conflict of interest

There are no conflicts of interest among the authors.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tian, T., Zhao, Y., Huang, Q. et al. n-3 Polyunsaturated Fatty Acids Improve Inflammation via Inhibiting Sphingosine Kinase 1 in a Rat Model of Parenteral Nutrition and CLP-Induced Sepsis. Lipids 51, 271–278 (2016). https://doi.org/10.1007/s11745-016-4129-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-016-4129-x

Keywords

Search

Navigation