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Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor α expression by releasing cytokines

  • Molecular Toxicology
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Abstract

Kupffer cells (KCs) have been demonstrated to play a role in the regulation of intra-hepatic lipid metabolism through the synthesis and secretion of biologically active products. The involvement of KCs in the disturbance of lipid metabolism that induced by perfluorononanoic acid (PFNA), a known agonist of the peroxisome proliferator-activated receptor alpha (PPARα), was investigated in this study. Rats were exposed to PFNA or PFNA combined with gadolinium chloride, an inhibitor of KCs, for 14 days. PFNA exposure dose-dependently increased absolute and relative liver weights, induced triglyceride accumulation, up-regulated the expression of both SERBP-1c and PPARα, and stimulated the release of TNFα and IL-1β. Inactivation of KCs markedly lowered TNFα and IL-1β level, enhanced PFNA-induced expression of PPARα and its target genes, and reduced liver triglyceride levels. In vitro, PFNA-induced expression of PPARα in primary cultured hepatocytes was suppressed by recombinant rat TNFα and IL-1β. However, inhibition of the NF-κB pathway prevented this. Transient transfection and promoter analysis further revealed that these two cytokines and NF-κB were coordinately involved in the suppression of PPARα promoter activity. Our data demonstrate that TNFα and IL-1β released from KCs following PFNA exposure can suppress the expression of PPARα via NF-κB pathway, which partially contribute to the evident accumulation of triglycerides in rat liver.

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Abbreviations

PFC:

Perfluorinated compound

PFNA:

Perfluorononanoic acid

TG:

Triglyceride

TCHO:

Total cholesterol

LPS:

Lipopolysaccharide

IL-1β:

Interleukin-1 beta

IL-10:

Interleukin-10

IL-6:

Interleukin-6

TNFα:

Tumor necrosis factor-alphaNF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells

PPARs:

Peroxisome proliferator-activated receptors

References

  • Anderson SP, Yoon L, Richard EB, Dunn CS, Cattley RC, Corton JC (2002) Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice. Hepatology 36:544–554

    Article  PubMed  CAS  Google Scholar 

  • Babu AN, Damle SS, Moore EE, Ao L, Song Y, Johnson JL, Weyant M, Banerjee A, Meng X, Fullerton DA (2007) Hemoglobin-based oxygen carrier induces hepatic heme oxygenase 1 expression in Kupffer cells. Surgery 142:289–294

    Article  PubMed  Google Scholar 

  • Bartolome N, Arteta B, Martinez MJ, Chico Y, Ochoa B (2008) Kupffer cell products and interleukin 1beta directly promote VLDL secretion and apoB mRNA up-regulation in rodent hepatocytes. Innate Immun 14:255–266

    Article  PubMed  CAS  Google Scholar 

  • Bilzer M, Roggel F, Gerbes AL (2006) Role of KCs in host defense and liver disease. Liver Int 26:1175–1186

    Article  PubMed  CAS  Google Scholar 

  • Calafat AM, Wong LY, Kuklenyik Z, Reidy JA, Needham LL (2007) Polyfluoroalkyl chemicals in the US population: data from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 and comparisons with NHANES 1999–2000. Environ Health Perspect 115:1596–1602

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Hennig GE, Whiteley HE, Corton JC, Manautou JE (2000) Peroxisome proliferator-activated receptor alpha-null mice lack resistance to acetaminophen hepatotoxicity following clofibrate exposure. Toxicol Sci 57:338–344

    Article  PubMed  CAS  Google Scholar 

  • Giesy JP, Kannan K (2001) Global distribution of perfluorooctane sulfonate in wildlife. Environ Sci Technol 35:1339–1342

    Article  PubMed  CAS  Google Scholar 

  • Graham P, Brass NJ (1994) Multiple organ dysfunction: pathophysiology and therapeutic modalities. Crit Care Nurs Q 16:8–15

    PubMed  CAS  Google Scholar 

  • Hart K, Gill VA, Kannan K (2009) Temporal trends (1992–2007) of perfluorinated chemicals in Northern Sea Otters (Enhydra lutris kenyoni) from South-Central Alaska. Arch Environ Contam Toxicol 56:607–614

    Article  PubMed  CAS  Google Scholar 

  • Hong F, Radaeva S, Pan HN, Tian Z, Veech R, Gao B (2004) Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease. Hepatology 40:933–941

    PubMed  CAS  Google Scholar 

  • Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O’Doherty RM (2010) Inactivation of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59:347–357

    Article  PubMed  CAS  Google Scholar 

  • Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, Lee CH (2008) Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 7:485–495

    Article  PubMed  CAS  Google Scholar 

  • Kudo N, Kawashima Y (2003) Induction of triglyceride accumulation in the liver of rats by perfluorinated fatty acids with different carbon chain lengths: comparison with induction of peroxisomal β-oxidation. Biol Pharm Bull 26:47–51

    Article  PubMed  CAS  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 99:366–394

    Article  PubMed  CAS  Google Scholar 

  • Maher JM, Aleksunes LM, Dieter MZ, Tanaka Y, Peters JM, Manautou JE, Klaassen CD (2008) Nrf2- and PPAR alpha-mediated regulation of hepatic Mrp transporters after exposure to perfluorooctanoic acid and perfluorodecanoic acid. Toxicol Sci 106:319–328

    Article  PubMed  CAS  Google Scholar 

  • Marra F, Gastaldelli A, Svegliati Baroni G, Tell G, Tiribelli C (2008) Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med 14:72–81

    Article  PubMed  CAS  Google Scholar 

  • McMillian M, Nie AY, Parker JB, Leone A, Kemmerer M, Bryant S, Herlich J, Yieh L, Bittner A, Liu X, Wan J, Johnson MD (2004) Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver. Biochem Pharmacol 67:2141–2165

    Article  PubMed  CAS  Google Scholar 

  • Mehendale HM (2000) PPAR-α: a Key to the Mechanism of hepatoprotection by clofibrate. Toxicol Sci 57:187–190

    Article  PubMed  CAS  Google Scholar 

  • Minata M, Harada KH, Kärrman A, Hitomi T, Hirosawa M, Murata M, Gonzalez FJ, Koizumi A (2010) Role of peroxisome proliferator-activated receptor-alpha in hepatobiliary injury induced by ammonium perfluorooctanoate in mouse liver. Ind Health 48:96–107

    Article  PubMed  CAS  Google Scholar 

  • Nelson JW, Hatch EE, Webster TF (2010) Exposure to polyfluoroalkyl chemicals and cholesterol, body weight, and insulin resistance in the general US population. Environ Health Perspect 118:197–202

    Article  PubMed  CAS  Google Scholar 

  • Neyrinck AM, De Wispelaere LD, Vanhulle VP, Taper HS, Delzenne NM (2000) Are Kupffer cells involved in the metabolic adaptation of the liver to dietary carbohydrates given after fasting? Biochim Biophys Acta 1475:238–244

    Article  PubMed  CAS  Google Scholar 

  • Neyrinck AM, Taper HS, Gevers V, Declerck B, Delzenne NM (2002) Inhibition of Kupffer cell activity induces hepatic triglyceride synthesis in fasted rats, independent of lipopolysaccharide challenge. J Hepatol 36:466–473

    Article  PubMed  CAS  Google Scholar 

  • Odegaard JI, Ricardo-Gonzalez RR, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, Chawla A (2008) Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 7:496–507

    Article  PubMed  CAS  Google Scholar 

  • Rivera CA, Bradford BU, Hunt KJ, Adachi Y, Schrum LW, Koop DR, Burchardt ER, Rippe RA, Thurman RG (2001) Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol 281:G200–G207

    PubMed  CAS  Google Scholar 

  • Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M (2007) Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 47:571–579

    Article  PubMed  CAS  Google Scholar 

  • Rusyn I, Tsukamoto H, Thurman RG (1998) WY-14 643 rapidly activates nuclear factor kappaB in Kupffer cells before hepatocytes in vito. Carcinogenesis 19:1217–1222

    Article  PubMed  CAS  Google Scholar 

  • Smedsrød B, Pertoft H (1985) Preparation of pure hepatocytes and reticuloendothelial cells in high yield from a single rat liver by means of Percoll centrifugation and selective adherence. J Leukoc Biol 38:213–230

    PubMed  Google Scholar 

  • Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, Staels B, Kersten S, Müller M (2010) Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology 51:511–522

    Article  PubMed  CAS  Google Scholar 

  • Taniyasu S, Kannan K, Horii Y, Hanari N, Yamashita NA (2003) Survey of perfluorooctane sulfonate and related perfluorinated organic compounds in water, fish, birds, and humans from Japan. Environ Sci Technol 37:2634–2639

    Article  PubMed  CAS  Google Scholar 

  • Taniyasu S, Kannan K, So MK, Gulkowska A, Sinclair E, Okazawa T, Yamashita N (2005) Analysis of fluorotelomer alcohols, fluorotelomer acids, and short- and long-chain perfluorinated acids in water and biota. J Chromatogr A 1093:89–97

    Article  PubMed  CAS  Google Scholar 

  • Yeung LW, Yamashita N, Taniyasu S, Lam PK, Sinha RK, Borole DV, Kannan K (2009) A survey of perfluorinated compounds in surface water and biota including dolphins from the Ganges River and in other waterbodies in India. Chemosphere 76:55–62

    Article  PubMed  CAS  Google Scholar 

  • Youssef J, Badr M (1997) Activated Kupffer cells attenuate the liver response to the peroxisome proliferator perfluorooctanoic acid. Mol Cell Biochem 169:143–147

    Article  PubMed  CAS  Google Scholar 

  • Zhang H, Shi Z, Liu Y, Wei Y, Dai J (2008) Lipid homeostasis and oxidative stress in the liver of male rats exposed to perfluorododecanoic acid. Toxicol Appl Pharmacol 227:16–25

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grants 31025006, 20837004 and 21107078).

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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

    Xuemei Fang, Shanshan Zou, Ruina Cui, Wei Zhang, Jiayue Hu & Jiayin Dai

  2. Department of Chemistry and Life Science, Suzhou College, Suzhou, 234000, People’s Republic of China

    Xuemei Fang

  3. State Key Laboratory of Biomembrane and Membrane Biotechnology, Beijing, 100101, People’s Republic of China

    Yuanyuan Zhao

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  1. Xuemei Fang
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  2. Shanshan Zou
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  3. Yuanyuan Zhao
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  4. Ruina Cui
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  5. Wei Zhang
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  6. Jiayue Hu
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Correspondence to Jiayin Dai.

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Xuemei Fang and Shanshan Zou have contributed equally to this paper.

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Fang, X., Zou, S., Zhao, Y. et al. Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor α expression by releasing cytokines. Arch Toxicol 86, 1515–1525 (2012). https://doi.org/10.1007/s00204-012-0877-4

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