Hepatocyte nuclear factor 1 alpha is a factor responsible for the interindividual variation of OATP1B1 mRNA levels in adult Japanese livers
Hepatocyte nuclear factor 1 alpha is a factor responsible for the interindividual variation of OATP1B1 mRNA levels in adult Japanese livers
复制标题
DOI：
10.1007/s11095-007-9458-2
复制
发表时间：
2007-12-01
影响因子：
3.7
通讯作者：
Chiba, Kan
中科院分区：
文献类型：
--
作者：
Furihata, Tomomi;Satoh, Tomomi;Chiba, Kan
目的.本研究的目的是阐明有机阴离子转运多肽（OATP，基因符号SLCO）1B 1 mRNA表达水平在人类肝脏中的个体差异的因素。在31份人肝脏样本中，通过实时PCR测定OATP 1B 1 mRNA表达水平。结果分析与位于启动子区的单核苷酸多态性（-11187G>A）和肝细胞核因子（HNF）1 α mRNA水平的关系。在分析的肝脏中，OATP 1B 1 mRNA表达水平的个体间变异性为4.9倍，与-11187G> A多态性无关。因此，-11187G> A多态性在荧光素酶测定中不改变SLCO 1B 1基因启动子活性。另一方面，OATP 1B 1 mRNA水平与HNF 1 α mRNA水平呈显著相关（r=0.83，P< 0.0001）。这种相关性与荧光素酶试验和染色质免疫沉淀试验的结果一致，表明HNF 1 α和SLCO 1B 1基因启动子之间存在功能性相互作用。我们的研究结果表明，HNF 1 α是OATP 1B 1 mRNA表达的重要调节因子，因此HNF 1 α的表达水平是OATP 1B 1 mRNA表达个体间差异的主要决定因素之一。
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) 1 alpha 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 HNF1 alpha 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 HNF1 alpha and SLCO1B1 gene promoter.Conclusions. Our results suggest that HNF1 alpha is an essential regulator of OATP1B1 mRNA expression and thus the level of HNF1 alpha expression is one of the major determinants of interindividual variability in OATP1B1 mRNA expression.