Hepatocyte nuclear factor 1 alpha is a factor responsible for the interindividual variation of OATP1B1 mRNA levels in adult Japanese livers

Pharm Res. 2007 Dec;24(12):2327-32. doi: 10.1007/s11095-007-9458-2. Epub 2007 Oct 12.

Abstract

Purpose: The aim of the present study was to clarify the factors responsible for interindividual variability of organic anion transporting polypeptide (OATP, gene symbol SLCO) 1B1 mRNA expression level in the human liver.

Materials and methods: OATP1B1 mRNA expression levels were determined by real-time PCR in 31 human liver samples. The results were analyzed in relation to a single nucleotide polymorphism (-11187G>A) located in the promoter region and levels of hepatocyte nuclear factor (HNF) 1alpha mRNA.

Results: There was a 4.9-fold interindividual variability of OATP1B1 mRNA expression level in the livers analyzed, which was not associated with -11187G>A polymorphism. Accordingly, the -11187G>A polymorphism did not alter the SLCO1B1 gene promoter activity in luciferase assays. On the other hand, OATP1B1 mRNA levels showed a significant correlation with HNF1alpha mRNA levels (r=0.83, P<0.0001). This correlation was consistent with the results of luciferase assays and chromatin immunoprecipitation assays showing functional interaction between HNF1alpha and SLCO1B1 gene promoter.

Conclusions: Our results suggest that HNF1alpha is an essential regulator of OATP1B1 mRNA expression and thus the level of HNF1alpha expression is one of the major determinants of interindividual variability in OATP1B1 mRNA expression.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Asian Continental Ancestry Group / genetics*
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Electrophoretic Mobility Shift Assay
  • Female
  • Genes, Reporter
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Humans
  • Japan
  • Liver / metabolism*
  • Liver-Specific Organic Anion Transporter 1
  • Luciferases / genetics
  • Male
  • Middle Aged
  • Organic Anion Transporters / genetics*
  • Organic Anion Transporters / metabolism
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic*
  • Protein Binding
  • RNA, Messenger / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection

Substances

  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • RNA, Messenger
  • SLCO1B1 protein, human
  • Luciferases