Organic solute transporter OSTα/β is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury

The heteromeric steroid transporter organic solute transporter alpha/beta (OST alpha/beta, SLCSIA/B) was discovered over a decade ago, but its physiological significance in the liver remains uncertain. A major challenge has been the lack of suitable models expressing OST alpha/beta. Based on observations first reported here that hepatic OST alpha/beta is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OST alpha/beta function and interaction with drugs and bile acids. OST alpha/beta expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OST alpha/beta-mediated transport in the established in vitro model. The effect of bile acids and drugs, including those associated with cholestatic drug-induced liver injury, on OST alpha/beta-mediated transport was evaluated. Expression of OST alpha/beta was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis. whereas hepatocyte expression of OST alpha/beta was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTa/B-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OST alpha/beta inhibitors: a biomarker for cholestasis, glycochenodeoxycholic acid; the major metabolite of troglitazone, troglitazone sulfate; and a macrocyclic antibiotic. fidaxomicin. Additionally, some drugs (e.g.. digoxin) consistently stimulated taurocholate uptake in OST alpha/beta-overexpressing cells. Our findings demonstrate that OST alpha/beta is an important transporter in liver disease and imply a role for this transporter in bile acid-bile acid and drug-bile acid interactions, as well as cholestatic drug-induced liver injury. NEW & NOTEWORTHY The organic solute transporter OST alpha/beta is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OST alpha/beta substrates exhibit rapid, linear, and concentration-driven transport in an OST alpha/beta-overexpressing cell line. Drugs associated with hepatotoxicity modulate OST alpha/beta-mediated taurocholate transport. These data suggest that hepatic OST alpha/beta plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.