OATP1B3-1B7 a novel Organic Anion Transporting Polypeptide is modulated by FXR ligands and transports bile acids

OATP1B3-1B7 (LST-3TM12) is a member of the OATP1B (; SLCO1B; )-family. This transporter is not only functional, but also expressed in the membrane of the smooth endoplasmic reticulum of hepatocytes and enterocytes. OATP1B3-1B7 is a splice variant of; SLCO1B3; where the initial part is encoded by; SLCO1B3; , whereas the rest of the mRNA originates from the gene locus of; SLCO1B7; . In this study we not only showed that; SLCO1B3; and the mRNA encoding for OATP1B3-1B7 share the 5' untranslated region, but also that silencing of an initial; SLCO1B3; exon lowered the amount of; SLCO1B3; and of; SLCO1B7; mRNA in Huh-7 cells. To validate the assumption that both transcripts are regulated by the same promoter we tested the influence of the bile acid sensor farnesoid X receptor (FXR) on their transcription. Treatment of Huh-7 and HepaRG cells with activators of this known regulator of OATP1B3 not only increased; SLCO1B3,; but also OATP1B3-1B7 mRNA transcription. Applying a heterologous expression system we showed that several bile acids interact with OATP1B3-1B7 and that taurocholic acid and lithocholic acid are OATP1B3-1B7 substrates. As OATP1B3-1B7 is located in the smooth endoplasmic reticulum it may grant access to metabolizing enzymes. In accordance are our findings showing that the OATP1B3-1B7 inhibitor bromsulphthalein significantly reduced uptake of bile acids into human liver microsomes. Taken together we report that OATP1B3-1B7 transcription can be modulated with FXR agonists and antagonists and that OATP1B3-1B7 transports bile acids.