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.
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Research Article|
January 09 2013
Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: a novel mechanism involved in inflammation-associated hyperbilirubinaemia
Tzu-Yue Shiu;
Tzu-Yue Shiu
*Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C.
†Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
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Tien-Yu Huang;
Tien-Yu Huang
†Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
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Shih-Ming Huang;
Shih-Ming Huang
‡Department of and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan, R.O.C.
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Yu-Lueng Shih;
Yu-Lueng Shih
†Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
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Heng-Cheng Chu;
Heng-Cheng Chu
†Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
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Wei-Kuo Chang;
Wei-Kuo Chang
†Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
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Tsai-Yuan Hsieh
Tsai-Yuan Hsieh
1
†Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
1To whom correspondence should be addressed (email tyh1216@ms46.hinet.net).
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Publisher: Portland Press Ltd
Received:
June 29 2012
Revision Received:
October 01 2012
Accepted:
November 06 2012
Accepted Manuscript online:
November 06 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 449 (3): 761–770.
Article history
Received:
June 29 2012
Revision Received:
October 01 2012
Accepted:
November 06 2012
Accepted Manuscript online:
November 06 2012
Citation
Tzu-Yue Shiu, Tien-Yu Huang, Shih-Ming Huang, Yu-Lueng Shih, Heng-Cheng Chu, Wei-Kuo Chang, Tsai-Yuan Hsieh; Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: a novel mechanism involved in inflammation-associated hyperbilirubinaemia. Biochem J 1 February 2013; 449 (3): 761–770. doi: https://doi.org/10.1042/BJ20121055
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