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Hepatic expression of transcription factors affecting developmental regulation of UGT1A1 in the Han Chinese population

  • Pharmacogenetics
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Abstract

Purpose

Complete or partial inactivity of UGT1A1, the unique enzyme responsible for bilirubin glucuronidation, is commonly associated with hyperbilirubinemia. We investigated the dynamic expression of UGT1A1, and that of the transcription factors (TFs) involved in its developmental regulation, during human hepatic growth in Han Chinese individuals.

Methods

Eighty-eight prenatal, pediatric, and adult liver samples were obtained from Han Chinese individuals. Quantitative real-time polymerase chain reaction was used to evaluate mRNA expression of UGT1A1 and TFs including PXR, CAR, HNF1A, HNF4A, PPARA, etc. UGT1A1 protein levels and metabolic activity were determined by western blotting and high-performance liquid chromatography. Direct sequencing was employed to genotype UGT1A1*6 (211G˃A) and UGT1A1*28 (TA6˃TA7) polymorphisms.

Results

UGT1A1 expression was minimal in prenatal samples, but significantly elevated during pediatric and adult stages. mRNA and protein levels and metabolic activity were prominently increased (120-, 20-, and 10-fold, respectively) in pediatric and adult livers compared to prenatal samples. Furthermore, expression did not differ appreciably between pediatric and adult periods. Dynamic expression of TFs, including PXR, CAR, HNF1A, HNF4A, and PPARA, was consistent with UGT1A1 levels at each developmental stage. A pronounced correlation between expression of these TFs and that of UGT1A1 (P < 0.001) was observed. Moreover, UGT1A1*6 and UGT1A1*28 polymorphisms reduced levels of UGT1A1 by up to 40–60 %.

Conclusions

Hepatic expression of transcription factors is associated with developmental regulation of UGT1A1 in the Han Chinese population. Moreover, UGT1A1 polymorphisms are associated with reduced expression of UGT1A1 mRNA and protein, as well as enzyme activity.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant nos. 81173127 and 81273581).

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Authors and Affiliations

  1. Department of Gastroenterology, First Affiliated Hospital, Zhengzhou University, No.1 East-Jian She Road, Zhengzhou, 45002, China

    Ya-li Nie & Quan-cheng Kan

  2. Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China

    Ya-li Nie, Jiang-feng Li, Liang Yan, Pei Wang, Shu-jie Wang, Hong-zheng Bi & Li-rong Zhang

  3. Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China

    Hang He

  4. Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People’s Hospital, Zhengzhou, China

    Xiang-guang Meng

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  1. Ya-li Nie
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Correspondence to Li-rong Zhang or Quan-cheng Kan.

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Nie, Yl., He, H., Li, Jf. et al. Hepatic expression of transcription factors affecting developmental regulation of UGT1A1 in the Han Chinese population. Eur J Clin Pharmacol 73, 29–37 (2017). https://doi.org/10.1007/s00228-016-2137-7

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