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Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days

  • Molecular Toxicology
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Abstract

Perfluoroalkyl acids are widely used in numerous industrial and commercial applications due to their unique physical and chemical characteristics. Although perfluorooctanoic acid (PFOA) is associated with hepatomegaly through peroxisome proliferator-activated receptor α (PPARα) activation, liver fat accumulation and changes in gene expression related to fatty acid metabolism could still be found in PPARα-null mice exposed to PFOA. To explore the potential effects of PFOA on sterol regulatory element-binding proteins (SREBPs) activity, male mice were dosed with either Milli-Q water or PFOA at doses of 0.08, 0.31, 1.25, 5, and 20 mg/kg/day by gavage for 28 days. Liver total cholesterol concentrations and PFOA contents showed a dose-dependent decrease and increase, respectively. Transcriptional activity of PPARα and SREBPs was significantly enhanced in livers. Protein expression analyzed by Western blotting showed that PFOA exposure stimulated SREBP maturation. Furthermore, proteins blocked SREBP precursor transport, insulin-induced gene 1 (INSIG1) and INSIG2 proteins, as well as a protein-mediated nuclear SREBP proteolysis, F-box and WD-40 domain protein 7, decreased in mouse liver exposed to PFOA. The expression levels of the miR-183-96-182 cluster, which is possibly involved in a regulatory loop intermediated by SREBPs maturation, were also increased in the mouse liver after PFOA exposure. We also observed that PFOA induced lipid content and PPARα in Hepa 1-6 cells after exposure to PFOA for 72 h but SREBPs were not activated in vitro. These results demonstrated that SREBPs were maturated by activating the miR-183-96-182 cluster-SREBP regulatory loop in PFOA-exposed mouse liver.

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References

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bengoechea-Alonso MT, Ericsson J (2007) SREBP in signal transduction: cholesterol metabolism and beyond. Curr Opin Cell Biol 19(2):215–222

    Article  CAS  PubMed  Google Scholar 

  • Bjork JA, Butenhoff JL, Wallace KB (2011) Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes. Toxicology 288(1–3):8–17

    Article  CAS  PubMed  Google Scholar 

  • Dumortier O, Hinault C, Van Obberghen E (2013) MicroRNAs and metabolism crosstalk in energy homeostasis. Cell Metab 18(3):312–324

    Article  CAS  PubMed  Google Scholar 

  • Fang X, Zou S, Zhao Y et al (2012) Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor alpha expression by releasing cytokines. Arch Toxicol 86(10):1515–1525

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Alvarez A, Alvarez MS, Gonzalez R, Cucarella C, Muntane J, Casado M (2011) Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 286(24):21466–21477

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gao M, Bu L, Ma Y, Liu D (2013) Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice. PLoS ONE 8(6):e65641

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Haughom B, Spydevold O (1992) The mechanism underlying the hypolipemic effect of perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid. Biochim Biophys Acta 1128(1):65–72

    Article  CAS  PubMed  Google Scholar 

  • Horton JD (2002) Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem Soc T 30:1091–1095

    Article  CAS  Google Scholar 

  • Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109(9):1125–1131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jeon TI, Osborne TF (2012) SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol Metab 23(2):65–72

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jeon TI, Esquejo RM, Roqueta-Rivera M et al (2013) An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis. Cell Metab 18(1):51–61

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kennedy GL Jr, Butenhoff JL, Olsen GW et al (2004) The toxicology of perfluorooctanoate. Crit Rev Toxicol 34(4):351–384

    Article  CAS  PubMed  Google Scholar 

  • Kersten S, Desvergne B, Wahli W (2000) Roles of PPARs in health and disease. Nature 405(6785):421–424

    Article  CAS  PubMed  Google Scholar 

  • Knight BL, Hebbachi A, Hauton D et al (2005) A role for PPARalpha in the control of SREBP activity and lipid synthesis in the liver. Biochem J 389(Pt 2):413–421

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Konig B, Koch A, Spielmann J et al (2009) Activation of PPAR alpha and PPAR gamma reduces triacylglycerol synthesis in rat hepatoma cells by reduction of nuclear SREBP-1. Eur J Pharmacol 605(1–3):23–30

    Article  PubMed  Google Scholar 

  • Kudo N, Mizuguchi H, Yamamoto A, Kawashima Y (1999) Alterations by perfluorooctanoic acid of glycerolipid metabolism in rat liver. Chem Biol Interact 118(1):69–83

    Article  CAS  PubMed  Google Scholar 

  • Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J (2007) Perfluoroalkyl acids: a review of monitoring and toxicological findings. Toxicol Sci 99(2):366–394

    Article  CAS  PubMed  Google Scholar 

  • Matsuda M, Korn BS, Hammer RE et al (2001) SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Gene Dev 15(10):1206–1216

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Minata M, Harada KH, Karrman A et al (2010) Role of peroxisome proliferator-activated receptor-alpha in hepatobiliary injury induced by ammonium perfluorooctanoate in mouse liver. Ind Health 48(1):96–107

    Article  CAS  PubMed  Google Scholar 

  • Osborne TF (2001) CREating a SCAP-less liver keeps SREBPs pinned in the ER membrane and prevents increased lipid synthesis in response to low cholesterol and high insulin. Gene Dev 15(15):1873–1878

    Article  CAS  PubMed  Google Scholar 

  • Pyper SR, Viswakarma N, Yu S, Reddy JK (2010) PPARalpha: energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal 8:e002

    Article  PubMed Central  PubMed  Google Scholar 

  • Raghow R, Yellaturu C, Deng X, Park EA, Elam MB (2008) SREBPs: the crossroads of physiological and pathological lipid homeostasis. Trends Endocrinol Metab 19(2):65–73

    Article  CAS  PubMed  Google Scholar 

  • Rosen MB, Abbott BD, Wolf DC et al (2008a) Gene profiling in the livers of wild-type and PPARalpha-null mice exposed to perfluorooctanoic acid. Toxicol Pathol 36(4):592–607

    Article  CAS  PubMed  Google Scholar 

  • Rosen MB, Lee JS, Ren H et al (2008b) Toxicogenomic dissection of the perfluorooctanoic acid transcript profile in mouse liver: evidence for the involvement of nuclear receptors PPAR alpha and CAR. Toxicol Sci 103(1):46–56

    Article  CAS  PubMed  Google Scholar 

  • Rosen MB, Schmid JR, Corton JC, et al. (2010) Gene Expression Profiling in Wild-Type and PPARalpha-Null Mice Exposed to Perfluorooctane Sulfonate Reveals PPARalpha-Independent Effects. PPAR Res 2010, pii:794739

  • Scharmach E, Buhrke T, Lichtenstein D, Lampen A (2012) Perfluorooctanoic acid affects the activity of the hepatocyte nuclear factor 4 alpha (HNF4alpha). Toxicol Lett 212(2):106–112

    Article  CAS  PubMed  Google Scholar 

  • Shao W, Espenshade PJ (2012) Expanding roles for SREBP in metabolism. Cell Metab 16(4):414–419

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Takacs ML, Abbott BD (2007) Activation of mouse and human peroxisome proliferator-activated receptors (alpha, beta/delta, gamma) by perfluorooctanoic acid and perfluorooctane sulfonate. Toxicol Sci 95(1):108–117

    Article  CAS  PubMed  Google Scholar 

  • Tan X, Xie G, Sun X et al (2013) High fat diet feeding exaggerates perfluorooctanoic acid-induced liver injury in mice via modulating multiple metabolic pathways. PLoS ONE 8(4):e61409

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Varga T, Czimmerer Z, Nagy L (2011) PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 1812(8):1007–1022

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wan HT, Zhao YG, Wei X, Hui KY, Giesy JP, Wong CK (2012) PFOS-induced hepatic steatosis, the mechanistic actions on beta-oxidation and lipid transport. Biochim Biophys Acta 1820(7):1092–1101

    Article  CAS  PubMed  Google Scholar 

  • Wolf DC, Moore T, Abbott BD et al (2008) Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPAR-alpha knockout and wild-type mice. Toxicol Pathol 36(4):632–639

    Article  CAS  PubMed  Google Scholar 

  • Yan S, Wang J, Zhang W, Dai J (2014) Circulating MicroRNA profiles altered in mice after 28 days exposure to perfluorooctanoic acid. Toxicol Lett 224(1):24–31

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa T, Ide T, Shimano H et al (2003) Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Mol Endocrinol 17(7):1240–1254

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB14040202) and the National Natural Science Foundation of China (Grant 31320103915, 31025006 and 21277143).

Conflict of interest

The authors declare there are no conflicts of interest.

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Authors and Affiliations

  1. Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China

    Shengmin Yan, Jianshe Wang & Jiayin Dai

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  1. Shengmin Yan
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  2. Jianshe Wang
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  3. Jiayin Dai
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Correspondence to Jiayin Dai.

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Yan, S., Wang, J. & Dai, J. Activation of sterol regulatory element-binding proteins in mice exposed to perfluorooctanoic acid for 28 days. Arch Toxicol 89, 1569–1578 (2015). https://doi.org/10.1007/s00204-014-1322-7

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  • DOI: https://doi.org/10.1007/s00204-014-1322-7

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