Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: A novel mechanism involved in inflammation-associated hyperbilirubinaemia

Tzu-Yue Shiu, Tien-Yu Huang, Shih-Ming Huang, Yu-Lueng Shih, Heng-Cheng Chu, Wei-Kuo Chang, Tsai-Yuan Hsieh

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Jaundice or hyperbilirubinaemia is a common complication of sepsis. UGT1A1 (UDP-glucuronosyltransferase 1A1) is a critical gene for bilirubin metabolism and irinotecan detoxification. However, the molecular pathogenesis of hyperbilirubinaemia during inflammation needs to be further clarified. Human hepatic UGT1A1 expression was analysed by RT (reverse transcription)-PCR, qRT-PCR (quantitative real-time PCR) and Western blotting in response to LPS (lipopolysaccharide) stimulation. Transcription regulatory elements in the upstream promoter region of the human UGT1A1 gene were determined using EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation). The important role of the transcription regulatory element was examined using a luciferase assay, and was determined by qRT-PCR using a transcription factor activation inhibitor. LPS down-regulated the UGT1A1 mRNA expression in human hepatoma cell lines. A newly identified NF-κB (nuclear factor κB)-binding site was located on the upstream promoter region (-725/-716) of the human UGT1A1 gene. LPS-induced NF-κB activation and specific binding to the NF-κB-binding site can suppress human UGT1A1 promoter activity and human UGT1A1 expression. We demonstrated that LPS mediates the suppression of human UGT1A1 expression through specific binding of NF-κB to this newly identified NF-κB-binding site in the upstream promoter of the human UGT1A1 gene. The present study may partly explain the molecular pathogenesis of inflammation-associated hyperbilirubinaemia. © The Authors Journal compilation © 2013 Biochemical Society.
Original languageEnglish
Pages (from-to)761-770
Number of pages10
JournalBiochemical Journal
Volume449
Issue number3
DOIs
Publication statusPublished - 2013
Externally publishedYes

Fingerprint

Hyperbilirubinemia
Down-Regulation
Inflammation
Lipopolysaccharides
Transcription
Genes
irinotecan
Binding Sites
Genetic Promoter Regions
Real-Time Polymerase Chain Reaction
Assays
Chemical activation
UGT1A1 enzyme
Electrophoretic mobility
Detoxification
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
Jaundice
Luciferases
Bilirubin

Keywords

  • Hyperbilirubinaemia
  • Inhibitor
  • Lipopolysaccharide (LPS)
  • Nuclear factor κB (NF-κB)
  • Promoter
  • UDP-glucuronosyltransferase 1A1 (UGT1A1)
  • glucuronosyltransferase 1A1
  • immunoglobulin enhancer binding protein
  • lipopolysaccharide
  • animal experiment
  • article
  • binding site
  • cancer cell culture
  • chromatin immunoprecipitation
  • controlled study
  • disease association
  • down regulation
  • enzyme activation
  • gel mobility shift assay
  • human
  • human cell
  • hyperbilirubinemia
  • inflammation
  • mouse
  • nonhuman
  • pathogenesis
  • priority journal
  • protein expression
  • real time polymerase chain reaction
  • reverse transcription polymerase chain reaction
  • Western blotting
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line
  • DNA, Complementary
  • Down-Regulation
  • Glucuronosyltransferase
  • Hep G2 Cells
  • Humans
  • Hyperbilirubinemia
  • Inflammation
  • Lipopolysaccharides
  • Liver
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • NF-kappa B
  • Promoter Regions, Genetic
  • RNA, Messenger

Cite this

Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: A novel mechanism involved in inflammation-associated hyperbilirubinaemia. / Shiu, Tzu-Yue; Huang, Tien-Yu; Huang, Shih-Ming; Shih, Yu-Lueng; Chu, Heng-Cheng; Chang, Wei-Kuo; Hsieh, Tsai-Yuan.

In: Biochemical Journal, Vol. 449, No. 3, 2013, p. 761-770.

Research output: Contribution to journalArticle

Shiu, Tzu-Yue ; Huang, Tien-Yu ; Huang, Shih-Ming ; Shih, Yu-Lueng ; Chu, Heng-Cheng ; Chang, Wei-Kuo ; Hsieh, Tsai-Yuan. / Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: A novel mechanism involved in inflammation-associated hyperbilirubinaemia. In: Biochemical Journal. 2013 ; Vol. 449, No. 3. pp. 761-770.
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title = "Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: A novel mechanism involved in inflammation-associated hyperbilirubinaemia",
abstract = "Jaundice or hyperbilirubinaemia is a common complication of sepsis. UGT1A1 (UDP-glucuronosyltransferase 1A1) is a critical gene for bilirubin metabolism and irinotecan detoxification. However, the molecular pathogenesis of hyperbilirubinaemia during inflammation needs to be further clarified. Human hepatic UGT1A1 expression was analysed by RT (reverse transcription)-PCR, qRT-PCR (quantitative real-time PCR) and Western blotting in response to LPS (lipopolysaccharide) stimulation. Transcription regulatory elements in the upstream promoter region of the human UGT1A1 gene were determined using EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation). The important role of the transcription regulatory element was examined using a luciferase assay, and was determined by qRT-PCR using a transcription factor activation inhibitor. LPS down-regulated the UGT1A1 mRNA expression in human hepatoma cell lines. A newly identified NF-κB (nuclear factor κB)-binding site was located on the upstream promoter region (-725/-716) of the human UGT1A1 gene. LPS-induced NF-κB activation and specific binding to the NF-κB-binding site can suppress human UGT1A1 promoter activity and human UGT1A1 expression. We demonstrated that LPS mediates the suppression of human UGT1A1 expression through specific binding of NF-κB to this newly identified NF-κB-binding site in the upstream promoter of the human UGT1A1 gene. The present study may partly explain the molecular pathogenesis of inflammation-associated hyperbilirubinaemia. {\circledC} The Authors Journal compilation {\circledC} 2013 Biochemical Society.",
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author = "Tzu-Yue Shiu and Tien-Yu Huang and Shih-Ming Huang and Yu-Lueng Shih and Heng-Cheng Chu and Wei-Kuo Chang and Tsai-Yuan Hsieh",
note = "被引用次數:1 Export Date: 22 March 2016 CODEN: BIJOA 通訊地址: Shiu, T.-Y.; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; 電子郵件: tyh1216@ms46.hinet.net 化學物質/CAS: DNA, Complementary; Glucuronosyltransferase, 2.4.1.17; Lipopolysaccharides; NF-kappa B; RNA, Messenger; bilirubin uridine-diphosphoglucuronosyl transferase 1A1, 2.4.1.- 參考文獻: Tukey, R.H., Strassburg, C.P., Human UDP-glucuronosyltransferases: Metabolism, expression, and disease (2000) Annual Review of Pharmacology and Toxicology, 40, pp. 581-616. , DOI 10.1146/annurev.pharmtox.40.1.581; Van Es, H.H.G., Bout, A., Liu, J., Anderson, L., Duncan, A.M.V., Bosma, P., Oude, E.R., Schurr, E., Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37 (1993) Cytogenetics and Cell Genetics, 63 (2), pp. 114-116; Mackenzie, P.I., Bock, K.W., Burchell, B., Guillemette, C., Ikushiro, S.-I., Iyanagi, T., Miners, J.O., Nebert, D.W., Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily (2005) Pharmacogenetics and Genomics, 15 (10), pp. 677-685; Nakamura, A., Nakajima, M., Yamanaka, H., Fujiwara, R., Yokoi, T., Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines (2008) Drug Metab. Dispos., 36, pp. 1461-1464; Seppen, J., Bosma, P.J., Goldhoorn, B.G., Bakker, C.T.M., Chowdhury, J.R., Chowdhury, N.R., Jansen, P.L.M., Oude, E.R.P.J., Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase (1994) Journal of Clinical Investigation, 94 (6), pp. 2385-2391; Bosma, P.J., Chowdhury, J.R., Bakker, C., Gantla, S., De Boer, A., Oostra, B.A., Lindhout, D., Oude Elferink, R.P., The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome (1995) N. Engl. J. Med., 333, pp. 1171-1175; Raijmakers, M.T.M., Jansen, P.L.M., Steegers, E.A.P., Peters, W.H.M., Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene (2000) Journal of Hepatology, 33 (3), pp. 348-351. , DOI 10.1016/S0168-8278(00)80268-8; Hsieh, T.-Y., Shiu, T.-Y., Huang, S.-M., Lin, H.-H., Lee, T.-C., Chen, P.-J., Chu, H.-C., Chao, Y.-C., Molecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter (2007) Pharmacogenetics and Genomics, 17 (4), pp. 229-236. , DOI 10.1097/FPC.0b013e328012d0da, PII 0121301120070400000001; Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q.-H., Owens, I.S., Sueyoshi, T., The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR (2001) Hepatology, 33 (5), pp. 1232-1238. , DOI 10.1053/jhep.2001.24172; Sugatani, J., Yamakawa, K., Tonda, E., Nishitani, S., Yoshinari, K., Degawa, M., Abe, I., Miwa, M., The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics (2004) Biochemical Pharmacology, 67 (5), pp. 989-1000. , DOI 10.1016/j.bcp.2003.11.002; Sugatani, J., Nishitani, S., Yamakawa, K., Yoshinari, K., Sueyoshi, T., Negishi, M., Miwa, M., Transcriptional regulation of human UGT1A1 gene expression: Activated glucocorticoid receptor enhances constitutive androstane receptor/ pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1 (2005) Molecular Pharmacology, 67 (3), pp. 845-855. , DOI 10.1124/mol.104.007161; Sugatani, J., Yamakawa, K., Yoshinari, K., Machida, T., Takagi, H., Mori, M., Kakizaki, S., Miwa, M., Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia (2002) Biochemical and Biophysical Research Communications, 292 (2), pp. 492-497. , DOI 10.1006/bbrc.2002.6683; Whitehead, M.W., Hainsworth, I., Kingham, J.G.C., The causes of obvious jaundice in South West Wales: Perceptions versus reality (2001) Gut, 48 (3), pp. 409-413. , DOI 10.1136/gut.48.3.409; Zimmerman, H., Jaundice due to bacterial infection (1979) Gastroenterology, 77, pp. 362-374; Chand, N., Sanyal, A.J., Sepsis-induced cholestasis (2007) Hepatology, 45 (1), pp. 230-241. , DOI 10.1002/hep.21480; Trauner, M., Wagner, M., Fickert, P., Zollner, G., Molecular regulation of hepatobiliary transport systems: Clinical implications for understanding and treating cholestasis (2005) Journal of Clinical Gastroenterology, 39 (4 SUPPL.), pp. S111-S124; Zollner, G., Fickert, P., Zenz, R., Fuchsbichler, A., Stumptner, C., Kenner, L., Ferenci, P., Trauner, M., Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases (2001) Hepatology, 33 (3), pp. 633-646. , DOI 10.1053/jhep.2001.22646; Haga, Y., Tempero, M.A., Zetterman, R.K., Unconjugated bilirubin inhibits in vitro cytotoxic T lymphocyte activity of human lymphocytes (1996) Biochimica et Biophysica Acta - Molecular Basis of Disease, 1317 (1), pp. 65-70. , DOI 10.1016/0925-4439(96)00039-7; Fernandes, A., Silva, R.F.M., Falcao, A.S., Brito, M.A., Brites, D., Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS (2004) Journal of Neuroimmunology, 153 (1-2), pp. 64-75. , DOI 10.1016/j.jneuroim.2004.04.007, PII S016557280400147X; Rao, R., Endotoxemia and gut barrier dysfunction in alcoholic liver disease (2009) Hepatology, 50, pp. 638-644; Zhang, G., Ghosh, S., Toll-like receptor-mediated NF-κB activation: A phylogenetically conserved paradigm in innate immunity (2001) Journal of Clinical Investigation, 107 (1), pp. 13-19; Lenardo, M.J., Baltimore, D., NK-κB: A pleiotropic mediator of inducible and tissue-specific gene control (1989) Cell, 58 (2), pp. 227-229. , DOI 10.1016/0092-8674(89)90833-7; Verma, I.M., Stevenson, J., IκB kinase: Beginning, not the end (1997) Proc. 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Biol. Chem., 276, pp. 32008-32015",
year = "2013",
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language = "English",
volume = "449",
pages = "761--770",
journal = "Biochemical Journal",
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TY - JOUR

T1 - Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: A novel mechanism involved in inflammation-associated hyperbilirubinaemia

AU - Shiu, Tzu-Yue

AU - Huang, Tien-Yu

AU - Huang, Shih-Ming

AU - Shih, Yu-Lueng

AU - Chu, Heng-Cheng

AU - Chang, Wei-Kuo

AU - Hsieh, Tsai-Yuan

N1 - 被引用次數:1 Export Date: 22 March 2016 CODEN: BIJOA 通訊地址: Shiu, T.-Y.; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; 電子郵件: tyh1216@ms46.hinet.net 化學物質/CAS: DNA, Complementary; Glucuronosyltransferase, 2.4.1.17; Lipopolysaccharides; NF-kappa B; RNA, Messenger; bilirubin uridine-diphosphoglucuronosyl transferase 1A1, 2.4.1.- 參考文獻: Tukey, R.H., Strassburg, C.P., Human UDP-glucuronosyltransferases: Metabolism, expression, and disease (2000) Annual Review of Pharmacology and Toxicology, 40, pp. 581-616. , DOI 10.1146/annurev.pharmtox.40.1.581; Van Es, H.H.G., Bout, A., Liu, J., Anderson, L., Duncan, A.M.V., Bosma, P., Oude, E.R., Schurr, E., Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37 (1993) Cytogenetics and Cell Genetics, 63 (2), pp. 114-116; Mackenzie, P.I., Bock, K.W., Burchell, B., Guillemette, C., Ikushiro, S.-I., Iyanagi, T., Miners, J.O., Nebert, D.W., Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily (2005) Pharmacogenetics and Genomics, 15 (10), pp. 677-685; Nakamura, A., Nakajima, M., Yamanaka, H., Fujiwara, R., Yokoi, T., Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines (2008) Drug Metab. Dispos., 36, pp. 1461-1464; Seppen, J., Bosma, P.J., Goldhoorn, B.G., Bakker, C.T.M., Chowdhury, J.R., Chowdhury, N.R., Jansen, P.L.M., Oude, E.R.P.J., Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase (1994) Journal of Clinical Investigation, 94 (6), pp. 2385-2391; Bosma, P.J., Chowdhury, J.R., Bakker, C., Gantla, S., De Boer, A., Oostra, B.A., Lindhout, D., Oude Elferink, R.P., The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome (1995) N. Engl. J. Med., 333, pp. 1171-1175; Raijmakers, M.T.M., Jansen, P.L.M., Steegers, E.A.P., Peters, W.H.M., Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene (2000) Journal of Hepatology, 33 (3), pp. 348-351. , DOI 10.1016/S0168-8278(00)80268-8; Hsieh, T.-Y., Shiu, T.-Y., Huang, S.-M., Lin, H.-H., Lee, T.-C., Chen, P.-J., Chu, H.-C., Chao, Y.-C., Molecular pathogenesis of Gilbert's syndrome: Decreased TATA-binding protein binding affinity of UGT1A1 gene promoter (2007) Pharmacogenetics and Genomics, 17 (4), pp. 229-236. , DOI 10.1097/FPC.0b013e328012d0da, PII 0121301120070400000001; Sugatani, J., Kojima, H., Ueda, A., Kakizaki, S., Yoshinari, K., Gong, Q.-H., Owens, I.S., Sueyoshi, T., The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR (2001) Hepatology, 33 (5), pp. 1232-1238. , DOI 10.1053/jhep.2001.24172; Sugatani, J., Yamakawa, K., Tonda, E., Nishitani, S., Yoshinari, K., Degawa, M., Abe, I., Miwa, M., The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics (2004) Biochemical Pharmacology, 67 (5), pp. 989-1000. , DOI 10.1016/j.bcp.2003.11.002; Sugatani, J., Nishitani, S., Yamakawa, K., Yoshinari, K., Sueyoshi, T., Negishi, M., Miwa, M., Transcriptional regulation of human UGT1A1 gene expression: Activated glucocorticoid receptor enhances constitutive androstane receptor/ pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1 (2005) Molecular Pharmacology, 67 (3), pp. 845-855. , DOI 10.1124/mol.104.007161; Sugatani, J., Yamakawa, K., Yoshinari, K., Machida, T., Takagi, H., Mori, M., Kakizaki, S., Miwa, M., Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia (2002) Biochemical and Biophysical Research Communications, 292 (2), pp. 492-497. , DOI 10.1006/bbrc.2002.6683; Whitehead, M.W., Hainsworth, I., Kingham, J.G.C., The causes of obvious jaundice in South West Wales: Perceptions versus reality (2001) Gut, 48 (3), pp. 409-413. , DOI 10.1136/gut.48.3.409; Zimmerman, H., Jaundice due to bacterial infection (1979) Gastroenterology, 77, pp. 362-374; Chand, N., Sanyal, A.J., Sepsis-induced cholestasis (2007) Hepatology, 45 (1), pp. 230-241. , DOI 10.1002/hep.21480; Trauner, M., Wagner, M., Fickert, P., Zollner, G., Molecular regulation of hepatobiliary transport systems: Clinical implications for understanding and treating cholestasis (2005) Journal of Clinical Gastroenterology, 39 (4 SUPPL.), pp. S111-S124; Zollner, G., Fickert, P., Zenz, R., Fuchsbichler, A., Stumptner, C., Kenner, L., Ferenci, P., Trauner, M., Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases (2001) Hepatology, 33 (3), pp. 633-646. , DOI 10.1053/jhep.2001.22646; Haga, Y., Tempero, M.A., Zetterman, R.K., Unconjugated bilirubin inhibits in vitro cytotoxic T lymphocyte activity of human lymphocytes (1996) Biochimica et Biophysica Acta - Molecular Basis of Disease, 1317 (1), pp. 65-70. , DOI 10.1016/0925-4439(96)00039-7; Fernandes, A., Silva, R.F.M., Falcao, A.S., Brito, M.A., Brites, D., Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS (2004) Journal of Neuroimmunology, 153 (1-2), pp. 64-75. , DOI 10.1016/j.jneuroim.2004.04.007, PII S016557280400147X; Rao, R., Endotoxemia and gut barrier dysfunction in alcoholic liver disease (2009) Hepatology, 50, pp. 638-644; Zhang, G., Ghosh, S., Toll-like receptor-mediated NF-κB activation: A phylogenetically conserved paradigm in innate immunity (2001) Journal of Clinical Investigation, 107 (1), pp. 13-19; Lenardo, M.J., Baltimore, D., NK-κB: A pleiotropic mediator of inducible and tissue-specific gene control (1989) Cell, 58 (2), pp. 227-229. , DOI 10.1016/0092-8674(89)90833-7; Verma, I.M., Stevenson, J., IκB kinase: Beginning, not the end (1997) Proc. 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Biol. Chem., 276, pp. 32008-32015

PY - 2013

Y1 - 2013

N2 - Jaundice or hyperbilirubinaemia is a common complication of sepsis. UGT1A1 (UDP-glucuronosyltransferase 1A1) is a critical gene for bilirubin metabolism and irinotecan detoxification. However, the molecular pathogenesis of hyperbilirubinaemia during inflammation needs to be further clarified. Human hepatic UGT1A1 expression was analysed by RT (reverse transcription)-PCR, qRT-PCR (quantitative real-time PCR) and Western blotting in response to LPS (lipopolysaccharide) stimulation. Transcription regulatory elements in the upstream promoter region of the human UGT1A1 gene were determined using EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation). The important role of the transcription regulatory element was examined using a luciferase assay, and was determined by qRT-PCR using a transcription factor activation inhibitor. LPS down-regulated the UGT1A1 mRNA expression in human hepatoma cell lines. A newly identified NF-κB (nuclear factor κB)-binding site was located on the upstream promoter region (-725/-716) of the human UGT1A1 gene. LPS-induced NF-κB activation and specific binding to the NF-κB-binding site can suppress human UGT1A1 promoter activity and human UGT1A1 expression. We demonstrated that LPS mediates the suppression of human UGT1A1 expression through specific binding of NF-κB to this newly identified NF-κB-binding site in the upstream promoter of the human UGT1A1 gene. The present study may partly explain the molecular pathogenesis of inflammation-associated hyperbilirubinaemia. © The Authors Journal compilation © 2013 Biochemical Society.

AB - Jaundice or hyperbilirubinaemia is a common complication of sepsis. UGT1A1 (UDP-glucuronosyltransferase 1A1) is a critical gene for bilirubin metabolism and irinotecan detoxification. However, the molecular pathogenesis of hyperbilirubinaemia during inflammation needs to be further clarified. Human hepatic UGT1A1 expression was analysed by RT (reverse transcription)-PCR, qRT-PCR (quantitative real-time PCR) and Western blotting in response to LPS (lipopolysaccharide) stimulation. Transcription regulatory elements in the upstream promoter region of the human UGT1A1 gene were determined using EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation). The important role of the transcription regulatory element was examined using a luciferase assay, and was determined by qRT-PCR using a transcription factor activation inhibitor. LPS down-regulated the UGT1A1 mRNA expression in human hepatoma cell lines. A newly identified NF-κB (nuclear factor κB)-binding site was located on the upstream promoter region (-725/-716) of the human UGT1A1 gene. LPS-induced NF-κB activation and specific binding to the NF-κB-binding site can suppress human UGT1A1 promoter activity and human UGT1A1 expression. We demonstrated that LPS mediates the suppression of human UGT1A1 expression through specific binding of NF-κB to this newly identified NF-κB-binding site in the upstream promoter of the human UGT1A1 gene. The present study may partly explain the molecular pathogenesis of inflammation-associated hyperbilirubinaemia. © The Authors Journal compilation © 2013 Biochemical Society.

KW - Hyperbilirubinaemia

KW - Inhibitor

KW - Lipopolysaccharide (LPS)

KW - Nuclear factor κB (NF-κB)

KW - Promoter

KW - UDP-glucuronosyltransferase 1A1 (UGT1A1)

KW - glucuronosyltransferase 1A1

KW - immunoglobulin enhancer binding protein

KW - lipopolysaccharide

KW - animal experiment

KW - article

KW - binding site

KW - cancer cell culture

KW - chromatin immunoprecipitation

KW - controlled study

KW - disease association

KW - down regulation

KW - enzyme activation

KW - gel mobility shift assay

KW - human

KW - human cell

KW - hyperbilirubinemia

KW - inflammation

KW - mouse

KW - nonhuman

KW - pathogenesis

KW - priority journal

KW - protein expression

KW - real time polymerase chain reaction

KW - reverse transcription polymerase chain reaction

KW - Western blotting

KW - Animals

KW - Base Sequence

KW - Binding Sites

KW - Cell Line

KW - DNA, Complementary

KW - Down-Regulation

KW - Glucuronosyltransferase

KW - Hep G2 Cells

KW - Humans

KW - Hyperbilirubinemia

KW - Inflammation

KW - Lipopolysaccharides

KW - Liver

KW - Mice

KW - Mice, Inbred C57BL

KW - Models, Biological

KW - NF-kappa B

KW - Promoter Regions, Genetic

KW - RNA, Messenger

U2 - 10.1042/BJ20121055

DO - 10.1042/BJ20121055

M3 - Article

VL - 449

SP - 761

EP - 770

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 3

ER -