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) 1α 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 HNF1α 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 HNF1α and SLCO1B1 gene promoter.
Conclusions
Our results suggest that HNF1α is an essential regulator of OATP1B1 mRNA expression and thus the level of HNF1α expression is one of the major determinants of interindividual variability in OATP1B1 mRNA expression.
Abbreviations
- HNF:
-
Hepatocyte nuclear factor
- MODY:
-
Maturity-onset diabetes of the young
- OATP:
-
Organic anion transporting polypeptide
- PCR:
-
Polymerase chain reaction
- SLCO:
-
Solute carrier organic anion transporter
- SNP:
-
Single nucleotide polymorphism
References
B. Hagenbuch, and P. J. Meier. The superfamily of organic anion transporting polypeptides. Biochim. Biophys. Acta 1609:1–18 (2003).
G. A. Kullak-Ublick, B. Stieger, and P. J. Meier. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126:322–342 (2004).
Y. Kameyama, K. Yamashita, K. Kobayashi, M. Hosokawa, and K. Chiba. Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet. Genomics 15:513–522 (2005).
M. Niemi, E. Schaeffeler, T. Lang, M. F. Fromm, M. Neuvonen, C. Kyrklund, J. T. Backman, R. Kerb, M. Schwab, P. J. Neuvonen, M. Eichelbaum, and K. T. Kivisto. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14:429–440 (2004).
Y. Nishizato, I. Ieiri, H. Suzuki, M. Kimura, K. Kawabata, T. Hirota, H. Takane, S. Irie, H. Kusuhara, Y. Urasaki, A. Urae, S. Higuchi, K. Otsubo, and Y. Sugiyama. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin. Pharmacol. Ther. 73:554–565 (2003).
C. S. Huang, M. J. Huang, M. S. Lin, S. S. Yang, H. C. Teng, and K. S. Tang. Genetic factors related to unconjugated hyperbilirubinemia amongst adults. Pharmacogenet. Genomics 15:43–50 (2005).
Y. Cui, J. Konig, A. T. Nies, M. Pfannschmidt, M. Hergt, W. W. Franke, W. Alt, R. Moll, and D. Keppler. Detection of the human organic anion transporters SLC21A6 (OATP2) and SLC21A8 (OATP8) in liver and hepatocellular carcinoma. Lab. Invest. 83:527–538 (2003).
M. Oswald, G. A. Kullak-Ublick, G. Paumgartner, and U. Beuers. Expression of hepatic transporters OATP-C and MRP2 in primary sclerosing cholangitis. Liver. 21:247–253 (2001).
M. Kinoshita, and M. Miyata. Underexpression of mRNA in human hepatocellular carcinoma focusing on eight loci. Hepatology 36:433–438 (2002).
G. Zollner, M. Wagner, P. Fickert, D. Silbert, A. Fuchsbichler, K. Zatloukal, H. Denk, and M. Trauner. Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int. 25:367–379 (2005).
R. H. Ho, R. G. Tirona, B. F. Leake, H. Glaeser, W. Lee, C. J. Lemke, Y. Wang, and R. B. Kim. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130:1793–1806 (2006).
D. Jung, B. Hagenbuch, L. Gresh, M. Pontoglio, P. J. Meier, and G. A. Kullak-Ublick. Characterization of the human OATP-C (SLC21A6) gene promoter and regulation of liver-specific OATP genes by hepatocyte nuclear factor 1 alpha. J. Biol. Chem. 276:37206–37214 (2001).
M. Niemi, J. T. Backman, L. I. Kajosaari, J. B. Leathart, M. Neuvonen, A. K. Daly, M. Eichelbaum, K. T. Kivisto, and P. J. Neuvonen. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin. Pharmacol. Ther. 77:468–478 (2005).
T. Furihata, M. Hosokawa, M. Masuda, T. Satoh, and K. Chiba. Hepatocyte nuclear factor-4alpha plays pivotal roles in the regulation of mouse carboxylesterase 2 gene transcription in mouse liver. Arch. Biochem. Biophys. 447:107–117 (2006).
J. B. de Kok, R. W. Roelofs, B. A. Giesendorf, J. L. Pennings, E. T. Waas, T. Feuth, D. W. Swinkels, and P. N. Span. Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes. Lab. Invest. 85:154–159 (2005).
J. Antonov, D. R. Goldstein, A. Oberli, A. Baltzer, M. Pirotta, A. Fleischmann, H. J. Altermatt, and R. Jaggi. Reliable gene expression measurements from degraded RNA by quantitative real-time PCR depend on short amplicons and a proper normalization. Lab. Invest. 85:1040–1050 (2005).
J. Vandesompele, K. De Preter, F. Pattyn, B. Poppe, N. Van Roy, A. De Paepe, and F. Speleman. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3:RESEARCH0034 (2002).
T. Furihata, M. Hosokawa, F. Nakata, T. Satoh, and K. Chiba. Purification, molecular cloning, and functional expression of inducible liver acylcarnitine hydrolase in C57BL/6 mouse, belonging to the carboxylesterase multigene family. Arch. Biochem. Biophys. 416:101–109 (2003).
T. Furihata, M. Hosokawa, T. Satoh, and K. Chiba. Synergistic role of specificity proteins and upstream stimulatory factor 1 in transactivation of the mouse carboxylesterase 2/microsomal acylcarnitine hydrolase gene promoter. Biochem. J. 384:101–110 (2004).
K. Kobayashi, S. Yamagami, T. Higuchi, M. Hosokawa, and K. Chiba. Key structural features of ligands for activation of human pregnane X receptor. Drug. Metab. Dispos. 32:468–472 (2004).
A. del Castillo-Olivares, J. A. Campos, W. M. Pandak, and G. Gil. The role of alpha1-fetoprotein transcription factor/LRH-1 in bile acid biosynthesis: a known nuclear receptor activator that can act as a suppressor of bile acid biosynthesis. J. Biol. Chem. 279:16813–16821 (2004).
F. M. Giuffrida, and A. F. Reis. Genetic and clinical characteristics of maturity-onset diabetes of the young. Diabetes Obes. Metab. 7:318–326 (2005).
S. Ellard. Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. Hum. Mutat. 16:377–385 (2000).
P. Boileau, C. Wolfrum, D. Q. Shih, T. A. Yang, A. W. Wolkoff, and M. Stoffel. Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1alpha-deficient mice: a mechanism for hypersensitivity to sulfonylurea therapy in patients with maturity-onset diabetes of the young, type 3 (MODY3). Diabetes 51:S343–S348 (2002).
J. M. Maher, A. L. Slitt, T. N. Callaghan, X. Cheng, C. Cheung, F. J. Gonzalez, and C. D. Klaassen. Alterations in transporter expression in liver, kidney, and duodenum after targeted disruption of the transcription factor HNF1alpha. Biochem. Pharmacol. 72:512–522 (2006).
D. Q. Shih, M. Bussen, E. Sehayek, M. Ananthanarayanan, B. L. Shneider, F. J. Suchy, S. Shefer, J. S. Bollileni, F. J. Gonzalez, J. L. Breslow, and M. Stoffel. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat. Genet. 27:375–382 (2001).
Acknowledgements
We would like to thank Dr. Masayoshi Tani, Dr. Hironobu Minami, Dr. Yasutsuna Sasaki and Dr. Satoshi Suzuki for their cooperation. We thank Dr. Ryuichirou Satoh (Lab. of Food Biochemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo) for providing HNF1α expression plasmid. We would also like to thank Dr. Masakiyo Hosokawa, Dr. Kaori Morimoto, Sasitorn Aueviriyavit, MS and other laboratory members for their technical assistance.
This work was supported by a grant (18890044) from the Ministry of Education, Sciences, Sports and Culture of Japan and by grants-in-aid from the Ministry of Health, Labor and Welfare of Japan (Health and Labor Sciences Research Grants, Risk Analysis Research on Food and Pharmaceuticals).
Author information
Authors and Affiliations
Corresponding author
Additional information
Tomomi Satoh and Naoko Yamamoto equally contributed to this work.
Rights and permissions
About this article
Cite this article
Furihata, T., Satoh, T., Yamamoto, N. et al. Hepatocyte Nuclear Factor 1 Alpha is a Factor Responsible for the Interindividual Variation of OATP1B1 mRNA Levels in Adult Japanese Livers. Pharm Res 24, 2327–2332 (2007). https://doi.org/10.1007/s11095-007-9458-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-007-9458-2