Advertisement

Archives of Toxicology

, Volume 93, Issue 2, pp 505–517 | Cite as

The protective role of liver X receptor (LXR) during fumonisin B1-induced hepatotoxicity

  • Marion Régnier
  • Arnaud Polizzi
  • Céline Lukowicz
  • Sarra Smati
  • Frédéric Lasserre
  • Yannick Lippi
  • Claire Naylies
  • Joelle Laffitte
  • Colette Bétoulières
  • Alexandra Montagner
  • Simon Ducheix
  • Pascal Gourbeyre
  • Sandrine Ellero-Simatos
  • Sandrine Menard
  • Justine Bertrand-Michel
  • Talal Al Saati
  • Jean-Marc Lobaccaro
  • Hester M. Burger
  • Wentzel C. Gelderblom
  • Hervé Guillou
  • Isabelle P. OswaldEmail author
  • Nicolas LoiseauEmail author
Organ Toxicity and Mechanisms

Abstract

Fumonisin B1 (FB1), a congener of fumonisins produced by Fusarium species, is the most abundant and most toxicologically active fumonisin. FB1 causes severe mycotoxicosis in animals, including nephrotoxicity, hepatotoxicity, and disruption of the intestinal barrier. However, mechanisms associated with FB1 toxicity are still unclear. Preliminary studies have highlighted the role of liver X receptors (LXRs) during FB1 exposure. LXRs belong to the nuclear receptor family and control the expression of genes involved in cholesterol and lipid homeostasis. In this context, the toxicity of FB1 was compared in female wild-type (LXR+/+) and LXRα,β double knockout (LXR−/−) mice in the absence or presence of FB1 (10 mg/kg body weight/day) for 28 days. Exposure to FB1 supplemented in the mice’s drinking water resulted in more pronounced hepatotoxicity in LXR−/− mice compared to LXR+/+ mice, as indicated by hepatic transaminase levels (ALT, AST) and hepatic inflammatory and fibrotic lesions. Next, the effect of FB1 exposure on the liver transcriptome was investigated. FB1 exposure led to a specific transcriptional response in LXR−/− mice that included altered cholesterol and bile acid homeostasis. ELISA showed that these effects were associated with an elevated FB1 concentration in the plasma of LXR−/− mice, suggesting that LXRs participate in intestinal absorption and/or clearance of the toxin. In summary, this study demonstrates an important role of LXRs in protecting the liver against FB1-induced toxicity, suggesting an alternative mechanism not related to the inhibition of sphingolipid synthesis for mycotoxin toxicity.

Keywords

Fumonisin Ceramide Liver LXR Hepatotoxicity 

Notes

Acknowledgements

MR was supported by a Fellowship from the Ministère de l’Education Nationale, de la Recherche et de la Technologie. This study was supported by the ANR Fumolip (ANR-16-CE21-0003) and ANR LipoReg (ANR-15-Carn0016), France. We thank Dr. David J. Mangelsdorf (Howard Hughes Medical Institute, Dallas, TX) for providing us with the LXR-deficient mice and for constructive discussions. We thank all members of the EZOP staff. We thank Aurore Laurent Monbrun for his excellent work on plasma biochemistry. We also thank the staff from the Genotoul: Anexplo, GeT-TriX, and Metatoul-Lipidomic facilities.

Compliance with ethicalstandards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2018_2345_MOESM1_ESM.docx (28 kb)
Supplementary material 1 (DOCX 27 KB)

References

  1. Asselah T, Bièche I, Laurendeau I et al (2005) Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C. Gastroenterology 129:2064–2075.  https://doi.org/10.1053/j.gastro.2005.09.010 CrossRefGoogle Scholar
  2. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 57:289–300Google Scholar
  3. Benlasher E, Geng X, Xuan Nguyen NT et al (2012) Comparative effects of fumonisins on sphingolipid metabolism and toxicity in ducks and Turkeys. Avian Dis 56:120–127.  https://doi.org/10.1637/9853-071911-Reg.1 CrossRefGoogle Scholar
  4. Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917.  https://doi.org/10.1139/o59-099 CrossRefGoogle Scholar
  5. Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19:185–193CrossRefGoogle Scholar
  6. Bondy GS, Suzuki CAM, Fernie SM et al (1997) Toxicity of fumonisin B1to B6C3F1mice: A 14-day gavage study. Food Chem Toxicol 35:981–989.  https://doi.org/10.1016/S0278-6915(97)87267-5 CrossRefGoogle Scholar
  7. Bonzón-Kulichenko E, Schwudke D, Gallardo N et al (2009) Central leptin regulates total ceramide content and sterol regulatory element binding protein-1C proteolytic maturation in rat white adipose tissue. Endocrinology 150:169–178.  https://doi.org/10.1210/en.2008-0505 CrossRefGoogle Scholar
  8. Burel C, Tanguy M, Guerre P et al (2013) Effect of low dose of fumonisins on pig health: immune status, intestinal microbiota and sensitivity to Salmonella. Toxins (Basel) 5:841–864.  https://doi.org/10.3390/toxins5040841 CrossRefGoogle Scholar
  9. Devriendt B, Gallois M, Verdonck F et al (2009) The food contaminant fumonisin B(1) reduces the maturation of porcine CD11R1(+) intestinal antigen presenting cells and antigen-specific immune responses, leading to a prolonged intestinal ETEC infection. Vet Res 40:40.  https://doi.org/10.1051/vetres/2009023 CrossRefGoogle Scholar
  10. Ducheix S, Montagner A, Theodorou V et al (2013) The liver X receptor: a master regulator of the gut–liver axis and a target for non alcoholic fatty liver disease. Biochem Pharmacol 86:96–105.  https://doi.org/10.1016/j.bcp.2013.03.016 CrossRefGoogle Scholar
  11. (Ec) No 1126/2007 Commission Regulation (2007) COMMISSION REGULATION (EC) No 1126/2007Google Scholar
  12. (Ec) No 576/2006 Commission Recommendation (2006) COMMISSION RECOMMENDATION (EC) No 576/2006Google Scholar
  13. Edgar R, Domrachev M, Lash AE (2002) Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30:207–210CrossRefGoogle Scholar
  14. Gentleman RC, Carey VJ, Bates DM et al (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:R80.  https://doi.org/10.1186/gb-2004-5-10-r80 CrossRefGoogle Scholar
  15. Grenier B, Bracarense A-PFL, Schwartz HE et al (2012) The low intestinal and hepatic toxicity of hydrolyzed fumonisin B1 correlates with its inability to alter the metabolism of sphingolipids. Biochem Pharmacol 83:1465–1473.  https://doi.org/10.1016/j.bcp.2012.02.007 CrossRefGoogle Scholar
  16. Gronemeyer H, Gustafsson J-Å, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3:950–964.  https://doi.org/10.1038/nrd1551 CrossRefGoogle Scholar
  17. Haschek WM, Gumprecht LA, Smith G et al (2001) Fumonisin toxicosis in swine: an overview of porcine pulmonary edema and current perspectives. Environ Health Perspect 109 Suppl:251–257Google Scholar
  18. Holland WL, Bikman BT, Wang L-P et al (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice. J Clin Invest 121:1858–1870.  https://doi.org/10.1172/JCI43378 CrossRefGoogle Scholar
  19. Howard PC, Eppley RM, Stack ME et al (2001) Fumonisin b1 carcinogenicity in a two-year feeding study using F344 rats and B6C3F1 mice. Environ Health Perspect 109:277–282.  https://doi.org/10.1289/ehp.01109s2277 Google Scholar
  20. Howard PC, Couch LH, Patton RE et al (2002) Comparison of the toxicity of several fumonisin derivatives in a 28-day feeding study with female B6C3F(1) mice. Toxicol Appl Pharmacol 185:153–165CrossRefGoogle Scholar
  21. Humphreys SH, Carrington C, Bolger M (2001) A quantitative risk assessment for fumonisins B1 and B2 in US corn. Food Addit Contam 18:211–220.  https://doi.org/10.1080/02652030010021486 CrossRefGoogle Scholar
  22. JECFA (2001) Safety Evaluation of Certain Mycotoxins in Food (WHO Food Additives Series No. 47:150–161). 56th Meeting of the JECFA, Geneva, International Programme on Chemical Safety, WHOGoogle Scholar
  23. Johnson V, Sharma R (2001) Gender-dependent immunosuppression following subacute exposure to fumonisin B1. Int Immunopharmacol 1:2023–2034.  https://doi.org/10.1016/S1567-5769(01)00131-X CrossRefGoogle Scholar
  24. Loiseau N, Debrauwer L, Sambou T et al (2007) Fumonisin B1 exposure and its selective effect on porcine jejunal segment: Sphingolipids, glycolipids and trans-epithelial passage disturbance. Biochem Pharmacol.  https://doi.org/10.1016/j.bcp.2007.03.031 Google Scholar
  25. Loiseau N, Polizzi A, Dupuy A et al (2015) New insights into the organ-specific adverse effects of fumonisin B1: comparison between lung and liver. Arch Toxicol 89:1619–1629.  https://doi.org/10.1007/s00204-014-1323-6 CrossRefGoogle Scholar
  26. Marasas WFO, Riley RT, Hendricks KA et al (2004) Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize. J Nutr 134:711–716.  https://doi.org/10.1093/jn/134.4.711 CrossRefGoogle Scholar
  27. Marin DE, Taranu I, Pascale F et al (2006) Sex-related differences in the immune response of weanling piglets exposed to low doses of fumonisin extract. Br J Nutr 95:1185–1192CrossRefGoogle Scholar
  28. Masching S, Naehrer K, Schwartz-Zimmermann H-E et al (2016) Gastrointestinal degradation of fumonisin b1 by carboxylesterase FumD prevents fumonisin induced alteration of sphingolipid metabolism in Turkey and swine. Toxins (Basel) 8:84.  https://doi.org/10.3390/toxins8030084 CrossRefGoogle Scholar
  29. Merrill AH, Wang E, Vales TR et al (1996) Fumonisin toxicity and sphingolipid biosynthesis. Adv Exp Med Biol 392:297–306CrossRefGoogle Scholar
  30. National Toxicology Program (2001) Toxicology and carcinogenesis studies of fumonisin B1 (cas no. 116355-83-0) in F344/N rats and B6C3F1 mice (feed studies). Natl Toxicol Program Tech Rep Ser (496):1–352Google Scholar
  31. Ohno Y, Suto S, Yamanaka M et al (2010) ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. Proc Natl Acad Sci USA 107:18439–18444.  https://doi.org/10.1073/pnas.1005572107 CrossRefGoogle Scholar
  32. Peet DJ, Turley SD, Ma W et al (1998) Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93:693–704CrossRefGoogle Scholar
  33. R Core Team (2008) R: a language and environment for statistical computingGoogle Scholar
  34. Raichur S, Wang ST, Chan PW et al (2014) CerS2 Haploinsufficiency Inhibits β-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance. Cell Metab 20:687–695.  https://doi.org/10.1016/j.cmet.2014.09.015 CrossRefGoogle Scholar
  35. Régnier M, Gourbeyre P, Pinton P et al (2017a) Identification of signaling pathways targeted by the food contaminant FB1: transcriptome and kinome analysis of samples from pig liver and intestine. Mol Nutr Food Res 61:1700433.  https://doi.org/10.1002/mnfr.201700433 CrossRefGoogle Scholar
  36. Régnier M, Polizzi A, Lippi Y et al (2017b) Insights into the role of hepatocyte PPARα activity in response to fasting. Mol Cell Endocrinol.  https://doi.org/10.1016/j.mce.2017.07.035 Google Scholar
  37. Riedel S, Abel S, Burger H-M et al (2016) Differential modulation of the lipid metabolism as a model for cellular resistance to fumonisin B1—induced cytotoxic effects in vitro. Prostaglandins Leukot Essent Fat Acids 109:39–51.  https://doi.org/10.1016/j.plefa.2016.04.006 CrossRefGoogle Scholar
  38. Riley RT, Enongene E, Voss KA et al (2001) Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environ Health Perspect 109(Suppl 2):301–308CrossRefGoogle Scholar
  39. Rong X, Albert CJ, Hong C et al (2013) LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab 18:685–697.  https://doi.org/10.1016/j.cmet.2013.10.002 CrossRefGoogle Scholar
  40. Rosenthal EA, Ronald J, Rothstein J et al (2011) Linkage and association of phospholipid transfer protein activity to LASS4. J Lipid Res 52:1837–1846.  https://doi.org/10.1194/jlr.P016576 CrossRefGoogle Scholar
  41. Scheek S, Brown MS, Goldstein JL (1997) Sphingomyelin depletion in cultured cells blocks proteolysis of sterol regulatory element binding proteins at site 1. Proc Natl Acad Sci USA 94:11179–11183CrossRefGoogle Scholar
  42. Scheig R (1996) Evaluation of tests used to screen patients with liver disorders. Prim Care 23:551–560CrossRefGoogle Scholar
  43. Schmidt E, Schmidt FW (1993) Enzyme diagnosis of liver diseases. Clin Biochem 26:241–251CrossRefGoogle Scholar
  44. Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:1–25.  https://doi.org/10.2202/1544-6115.1027 CrossRefGoogle Scholar
  45. Stratford S, DeWald DB, Summers SA (2001) Ceramide dissociates 3′-phosphoinositide production from pleckstrin homology domain translocation. Biochem J 354:359–368CrossRefGoogle Scholar
  46. Szklarczyk D, Franceschini A, Wyder S et al (2015) STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–D452.  https://doi.org/10.1093/nar/gku1003 CrossRefGoogle Scholar
  47. Teboul M, Enmark E, Li Q et al (1995) OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. Proc Natl Acad Sci USA 92:2096–2100CrossRefGoogle Scholar
  48. Turpin SM, Nicholls HT, Willmes DM et al (2014) Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab 20:678–686.  https://doi.org/10.1016/j.cmet.2014.08.002 CrossRefGoogle Scholar
  49. Voss KA, Chamberlain WJ, Bacon CW et al (1995) Subchronic feeding study of the mycotoxin fumonisin B1 in B6C3F1 mice and Fischer 344 rats. Fundam Appl Toxicol 24:102–110.  https://doi.org/10.1006/FAAT.1995.1012 CrossRefGoogle Scholar
  50. Wan Norhas WM, Abdulamir AS, Abu Bakar F et al (2009) The health and toxic adverse effects of fusarium fungal mycotoxin, fumonisins, on human population. Am J Infect Dis 5:273–281.  https://doi.org/10.3844/ajidsp.2009.273.281 CrossRefGoogle Scholar
  51. Wang E, Norred WP, Bacon CW et al (1991) Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme. J Biol Chem 266:14486–14490Google Scholar
  52. Wang B, Rong X, Duerr MA et al (2016) Intestinal phospholipid remodeling is required for dietary-lipid uptake and survival on a high-fat diet. Cell Metab 23:492–504.  https://doi.org/10.1016/j.cmet.2016.01.001 CrossRefGoogle Scholar
  53. Yang M, Wang C, Li S et al (2017) Annexin A2 promotes liver fibrosis by mediating von Willebrand factor secretion. Dig Liver Dis 49:780–788.  https://doi.org/10.1016/j.dld.2017.02.013 CrossRefGoogle Scholar
  54. Yu L, York J, von Bergmann K et al (2003) Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8. J Biol Chem 278:15565–15570.  https://doi.org/10.1074/jbc.M301311200 CrossRefGoogle Scholar
  55. Yu L, Gupta S, Xu F et al (2005) Expression of ABCG5 and ABCG8 Is required for regulation of biliary cholesterol secretion. J Biol Chem 280:8742–8747.  https://doi.org/10.1074/jbc.M411080200 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Marion Régnier
    • 1
  • Arnaud Polizzi
    • 1
  • Céline Lukowicz
    • 1
  • Sarra Smati
    • 1
    • 2
  • Frédéric Lasserre
    • 1
  • Yannick Lippi
    • 1
  • Claire Naylies
    • 1
  • Joelle Laffitte
    • 1
  • Colette Bétoulières
    • 1
  • Alexandra Montagner
    • 1
  • Simon Ducheix
    • 1
  • Pascal Gourbeyre
    • 1
  • Sandrine Ellero-Simatos
    • 1
  • Sandrine Menard
    • 1
  • Justine Bertrand-Michel
    • 3
  • Talal Al Saati
    • 4
  • Jean-Marc Lobaccaro
    • 5
  • Hester M. Burger
    • 6
  • Wentzel C. Gelderblom
    • 6
    • 7
  • Hervé Guillou
    • 1
  • Isabelle P. Oswald
    • 1
    Email author
  • Nicolas Loiseau
    • 1
    Email author
  1. 1.Toxalim (Research Centre in Food Toxicology)Université de Toulouse, UMR1331 INRA, ENVT, INP-Purpan, UPSToulouseFrance
  2. 2.I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM)-U 1048Université de Toulouse CHU de ToulouseToulouseFrance
  3. 3.MetaToul-Lipidomic Facility-MetaboHUB, INSERM UMR1048, Institute of Cardiovascular and Metabolic DiseasesUniversité Paul Sabatier-Toulouse IIIToulouseFrance
  4. 4.Histopathology facilityINSERM/UPS/ENVT, US006/CREFREToulouseFrance
  5. 5.GReDUniversité de Clermont Auvergne, CNRS, INSERMClermont-FerrandFrance
  6. 6.Institute of Biomedical and Microbial BiotechnologyCape Peninsula University of TechnologyBellvilleSouth Africa
  7. 7.Department of BiochemistryUniversity of StellenboschMatielandSouth Africa

Personalised recommendations