Organic solute transporter OSTalpha/beta is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury.
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Malinen MM, Ali I, Bezencon J, Beaudoin JJ, Brouwer KLR
Organic solute transporter OSTalpha/beta is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury.
Am J Physiol Gastrointest Liver Physiol. 2018 May 1;314(5):G597-G609. doi: 10.1152/ajpgi.00310.2017. Epub 2018 Feb 8.
- PubMed ID
- 29420067 [ View in PubMed]
- Abstract
The heteromeric steroid transporter organic solute transporter alpha/beta (OSTalpha/beta, SLC51A/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 OSTalpha/beta. Based on observations first reported here that hepatic OSTalpha/beta is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OSTalpha/beta function and interaction with drugs and bile acids. OSTalpha/beta expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OSTalpha/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 OSTalpha/beta-mediated transport was evaluated. Expression of OSTalpha/beta was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OSTalpha/beta was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTalpha/beta-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OSTalpha/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 OSTalpha/beta-overexpressing cells. Our findings demonstrate that OSTalpha/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 OSTalpha/beta is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OSTalpha/beta substrates exhibit rapid, linear, and concentration-driven transport in an OSTalpha/beta-overexpressing cell line. Drugs associated with hepatotoxicity modulate OSTalpha/beta-mediated taurocholate transport. These data suggest that hepatic OSTalpha/beta plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Digoxin Organic solute transporter subunit alpha Protein Humans UnknownSubstrateDetails Digoxin Organic solute transporter subunit beta Protein Humans UnknownSubstrateDetails