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Organic solute transporter OST?/? is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury.

ABSTRACT: The heteromeric steroid transporter organic solute transporter ?/? (OST?/?, 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 OST?/?. Based on observations first reported here that hepatic OST?/? is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OST?/? function and interaction with drugs and bile acids. OST?/? expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OST?/?-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?/?-mediated transport was evaluated. Expression of OST?/? was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OST?/? was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OST?/?-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OST?/? 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?/?-overexpressing cells. Our findings demonstrate that OST?/? 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?/? is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OST?/? substrates exhibit rapid, linear, and concentration-driven transport in an OST?/?-overexpressing cell line. Drugs associated with hepatotoxicity modulate OST?/?-mediated taurocholate transport. These data suggest that hepatic OST?/? plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.

SUBMITTER: Malinen MM

PROVIDER: S-EPMC6008059 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Malinen Melina M MM Ali Izna I Bezençon Jacqueline J Beaudoin James J JJ Brouwer Kim L R KLR

American journal of physiology. Gastrointestinal and liver physiology 20180208 5

The heteromeric steroid transporter organic solute transporter α/β (OSTα/β, 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 OSTα/β. Based on observations first reported here that hepatic OSTα/β is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OSTα/β function and interaction with drugs and bile acids. ...[more]

PMID: 29420067

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Project description:Co-immunoprecipitation studies using mouse ileal proteins and transfected HEK-293 (human embryonic kidney-293) cells revealed that the two proteins, Ostalpha and Ostbeta, which generate the organic-solute transporter are able to immunoprecipitate each other, indicating a heteromeric complex. Mouse ileal Ostalpha protein appeared on Western blots largely as bands of 40 and 80 kDa, the latter band consistent with an Ostalpha homodimer, and both of these bands were sensitive to digestion by the glycosidase PNGase F (peptide:N-glycosidase F). Ostbeta appeared as bands of 17 and 19 kDa, and these bands were not sensitive to PNGase F. Both the 40 and 80 kDa forms of Ostalpha, and only the 19 kDa form of Ostbeta, were detected among the immunoprecipitated proteins, indicating that the interaction between Ostalpha and Ostbeta is associated with specific post-translational processing. Additional evidence for homodimerization of Ostalpha and for a direct interaction between Ostalpha and Ostbeta was provided by BiFC (bimolecular fluorescence complementation) analysis of HEK-293 cells transfected with Ostalpha and Ostbeta tagged with yellow-fluorescent-protein fragments. BiFC analysis and surface immunolabelling of transfected HEK-293 cells also indicated that the C-termini of both Ostalpha and Ostbeta are facing the intracellular space. The interaction between Ostalpha and Ostbeta was required not only for delivery of the proteins to the plasma membrane, but it increased their stability, as noted in transfected HEK-293 cells and in tissues from Ostalpha-deficient (Ostalpha-/-) mice. In Ostalpha-/- mice, Ostbeta mRNA levels were maintained, yet Ostbeta protein was not detectable, indicating that Ostbeta protein is not stable in the absence of Ostalpha. Overall, these findings identify the membrane topology of Ostalpha and Ostbeta, demonstrate that these proteins are present as heterodimers and/or heteromultimers, and indicate that the interaction between Ostalpha and Ostbeta increases the stability of the proteins and is required for delivery of the heteromeric complex to the plasma membrane.

Dataset Information

Organic solute transporter OST?/? is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury.

Publications

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

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