Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTα-OSTβ in cholestasis in humans and rodents

Organic solute transporter (OST alpha-OST beta) is a novel heteromeric bile acid and sterol transporter expressed at the basolateral membranes of epithelium in the ileum, kidney, and liver. To determine whether OST alpha-OST beta undergoes farnesoid X receptor (FXR)-dependent adaptive regulation following cholestatic liver injury, mRNA and protein expression levels were analyzed in patients with primary biliary cirrhosis (PBC) and following common bile duct ligation (CBDL) in rats and Fxr null and wild-type mice. Hepatic OST alpha and OST beta mRNA increased 3- and 32- fold, respectively, in patients with PBC compared with controls, whereas expression of Ost alpha and Ost beta also increased in the liver of rats and mice following CBDL. In contrast, expression of Ost alpha and Ost beta mRNA was generally lower in Fxr null mice, and CBDL failed to enhance expression of Ost alpha and Ost beta compared with wild-type mice. HepG2 cells treated for 24 h with chenodeoxycholic acid, a selective FXR ligand, had higher levels of OST alpha and OST beta mRNA and protein. Increases in OST protein were visualized by confocal microscopy at the plasma membrane. These results indicate that expression of Ost alpha and Ost beta are highly regulated in response to cholestasis and that this response is dependent on the FXR bile acid receptor.