Z Gastroenterol 2012; 50 - P2_10
DOI: 10.1055/s-0031-1295807

Bile acids downregulate the human hepatic organic anion transporter 7

C Jüngst 1, K Klein 2, J Eloranta 2, G Kullak-Ublick 2
  • 1Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg
  • 2Klinik für Klinische Pharmakologie und Toxikologie, Universitätsspital Zürich, Zürich, Schweiz

Organic anion transporters (OATs) play a major role for the uptake, distribution and elimination of a wide range of exogenous and endogenous compounds. The human organic anion transporter 7 (hOAT7, SLC22A9) has been characterized as the first liver-specific member of the OAT family and mediates exchange of sulfate-conjugates for small chain fatty acids across the sinusoidal membrane. Nuclear receptors and their ligands, such as bile acids, are key regulators of hepatic membrane transporters at the transcriptional level. Bile acids have been shown to decrease gene transcription via repression of the transcriptional activator hepatocyte nuclear factor–1α (HNF1α) involving a pathway dependent on the transcriptional repressor small heterodimer partner (SHP). Recently we have shown that OAT7 gene transcription is activated by HNF1α. Transport activity is likely to be affected by expression levels, hence it is our aim to study the expression and regulation of the hOAT7 gene in conditions of elevated intracellular bile acid levels which occur in cholestatic diseases. Treatment of human liver-derived Huh7 and HepG2 cells and of primary human hepatocytes with chenodeoxycholic acid (CDCA) resulted in a significant repression of hOAT7 mRNA as well as protein expression. Interestingly, HNF1α expression was also reduced after CDCA treatment, whereas SHP expression was increased. Overexpression of SHP by transient transfection of a SHP expression plasmid in Huh7 and HepG2 cells significantly decreased hOAT7 mRNA levels. hOAT7 promoter activity was reduced upon cotransfection of a luciferase-linked hOAT7 promoter fragment containing the HNF1α binding site with an SHP expression vector in HepG2 cells. These results show that bile acids negatively regulate hOAT7 gene expression by inducing SHP and thereby repressing the transcriptional activator HNF1α. Decreased OAT7 expression may lead to reduced OAT7-mediated substrate uptake into hepatocytes and sinusoidal export in cholestasis.