Regulation of OATP1B1 and OATP1B3 by HNF3α and/or c-Jun mediates rosuvastatin hepatic uptake

Organic anion transporting polypeptides 1B1 (OATP1B1, gene: SLCO1B1) and 1B3 (OATP1B3, gene: SLCO1B3), primarily expressed in the liver, mediate the hepatocellular uptake of various endogenous and exogenous compounds. While polymorphisms in their coding regions influence drug pharmacokinetics, the mechanisms regulating their transcription remain unclear. This study investigates the transcriptional regulation of SLCO1B1 and SLCO1B3 by identifying critical promoter regions and transcription factor binding sites. Luciferase reporter assays revealed key promoter regions: -52 to -208 nt for SLCO1B1 and -69 to -198 nt for SLCO1B3. Bioinformatics analysis predicted binding sites for HNF3α and c-Jun in the SLCO1B1 promoter, and a c-Jun binding site in the SLCO1B3 promoter. Mutagenesis and EMSA confirmed these sites' functional significance. Overexpression of HNF3α and c-Jun enhanced SLCO1B1 promoter activity and expression, while their knockdown had the opposite effect. Similarly, c-Jun overexpression upregulated SLCO1B3, and its knockdown reduced SLCO1B3 activity. Using rosuvastatin as a substrate, we found that overexpression of c-Jun and HNF3α, or increased phosphorylation of c-Jun, significantly increased hepatic uptake of rosuvastatin, while knockdown of HNF3α and c-Jun or inhibition of c-Jun phosphorylation decreased it. In conclusion, SLCO1B1 is co-regulated by HNF3α and c-Jun, while SLCO1B3 is primarily regulated by c-Jun. These findings highlight the role of HNF3α and/or c-Jun in regulating OATP1B1 and OATP1B3 expression and their impact on drug disposition.