title: Hepatic expression of transcription factors affecting developmental regulation of UGT1A1 in the Han Chinese population.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology, First Affiliated Hospital, Zhengzhou University, No.1 East-Jian She Road, Zhengzhou, 45002, China.|Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Nie
authors.affiliation: Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China.
authors.forename: Hang
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Jiang-Feng
authors.initials: JF
authors.lastname: Li
authors.affiliation: Laboratory of Cardiovascular Disease and Drug Research, Zhengzhou No. 7 People's Hospital, Zhengzhou, China.
authors.forename: Xiang-Guang
authors.initials: XG
authors.lastname: Meng
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Shu-Jie
authors.initials: SJ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China.
authors.forename: Hong-Zheng
authors.initials: HZ
authors.lastname: Bi
authors.affiliation: Department of Pharmacology, School of Medicine, Zhengzhou University, 100 Science Road, Zhengzhou, 450001, China. zhanglirongzzu@126.com.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, First Affiliated Hospital, Zhengzhou University, No.1 East-Jian She Road, Zhengzhou, 45002, China. kanquancheng@126.com.
authors.forename: Quan-Cheng
authors.initials: QC
authors.lastname: Kan
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D005865:Gestational Age; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008099:Liver / Q000254:growth & development* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D012333:RNA, Messenger; D014157:Transcription Factors; D000099148:UGT1A1 Enzyme
keywords: Developmental regulation; Hepatic development; Neonatal jaundice; Transcription factors; UGT1A1