Cholestatic phenotype of a mouse model for organic solute transporter? (OST?/SLC51B) deficiency suggest a role of the beta subunit beyond an OST? chaperone

2020 ◽  
Vol 73 ◽  
pp. S546
Author(s):  
Sandra Van de Wiel ◽  
Vanesa Muncan ◽  
Ronald Oude-Elferink ◽  
Stan van de Graaf
Keyword(s):  
Mouse Model ◽  
Beta Subunit ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Solute Transporter

scholarly journals Role of Organic Solute Transporter Alpha/Beta in Hepatotoxic Bile Acid Transport and Drug Interactions

2020 ◽  
Vol 176 (1) ◽  
pp. 34-45 ◽  
Author(s):  
James J Beaudoin ◽  
Jacqueline Bezençon ◽  
Noora Sjöstedt ◽  
John K Fallon ◽  
Kim L R Brouwer
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Farnesoid X Receptor ◽  
Acid Transport ◽  
Bile Acid Transport ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
The Impact ◽  
Solute Transporter

Abstract Organic solute transporter (OST) α/β is a key bile acid transporter expressed in various organs, including the liver under cholestatic conditions. However, little is known about the involvement of OSTα/β in bile acid-mediated drug-induced liver injury (DILI), a major safety concern in drug development. This study investigated whether OSTα/β preferentially transports more hepatotoxic, conjugated, primary bile acids and to what extent xenobiotics inhibit this transport. Kinetic studies with OSTα/β-overexpressing cells revealed that OSTα/β preferentially transported bile acids in the following order: taurochenodeoxycholate > glycochenodeoxycholate > taurocholate > glycocholate. The apparent half-maximal inhibitory concentrations for OSTα/β-mediated bile acid (5 µM) transport inhibition by fidaxomicin, troglitazone sulfate, and ethinyl estradiol were: 210, 334, and 1050 µM, respectively, for taurochenodeoxycholate; 97.6, 333, and 337 µM, respectively, for glycochenodeoxycholate; 140, 265, and 527 µM, respectively, for taurocholate; 59.8, 102, and 117 µM, respectively, for glycocholate. The potential role of OSTα/β in hepatocellular glycine-conjugated bile acid accumulation and cholestatic DILI was evaluated using sandwich-cultured human hepatocytes (SCHH). Treatment of SCHH with the farnesoid X receptor agonist chenodeoxycholate (100 µM) resulted in substantial OSTα/β induction, among other proteomic alterations, reducing glycochenodeoxycholate and glycocholate accumulation in cells+bile 4.0- and 4.5-fold, respectively. Treatment of SCHH with troglitazone and fidaxomicin together under cholestatic conditions resulted in increased hepatocellular toxicity compared with either compound alone, suggesting that OSTα/β inhibition may accentuate DILI. In conclusion, this study provides insights into the role of OSTα/β in preferential disposition of bile acids associated with hepatotoxicity, the impact of xenobiotics on OSTα/β-mediated bile acid transport, and the role of this transporter in SCHH and cholestatic DILI.

Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-α/β in the adaptive response to bile acids

2006 ◽  
Vol 290 (5) ◽  
pp. G923-G932 ◽  
Author(s):  
Gernot Zollner ◽  
Martin Wagner ◽  
Tarek Moustafa ◽  
Peter Fickert ◽  
Dagmar Silbert ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Liver Toxicity ◽  
Farnesoid X Receptor ◽  
Multidrug Resistance Proteins ◽  
Organic Solute Transporter ◽  
Liver And Kidney ◽  
Organic Solute ◽  
Solute Transporter

The bile acid receptor farnesoid X receptor (FXR) is a key regulator of hepatic defense mechanisms against bile acids. A comprehensive study addressing the role of FXR in the coordinated regulation of adaptive mechanisms including biosynthesis, metabolism, and alternative export together with their functional significance is lacking. We therefore fed FXR knockout (FXR−/−) mice with cholic acid (CA) and ursodeoxycholic acid (UDCA). Bile acid synthesis and hydroxylation were assessed by real-time RT-PCR for cytochrome P-450 (Cyp)7a1, Cyp3a11, and Cyp2b10 and mass spectrometry-gas chromatography for determination of bile acid composition. Expression of the export systems multidrug resistance proteins (Mrp)4–6 in the liver and kidney and the recently identified basoalteral bile acid transporter, organic solute transporter (Ost-α/Ost-β), in the liver, kidney, and intestine was also investigated. CA and UDCA repressed Cyp7a1 in FXR+/+ mice and to lesser extents in FXR−/− mice and induced Cyp3a11 and Cyp2b10 independent of FXR. CA and UDCA were hydroxylated in both genotypes. CA induced Ost-α/Ost-β in the liver, kidney, and ileum in FXR+/+ but not FXR−/− mice, whereas UDCA had only minor effects. Mrp4 induction in the liver and kidney correlated with bile acid levels and was observed in UDCA-fed and CA-fed FXR−/− animals but not in CA-fed FXR+/+ animals. Mrp5/6 remained unaffected by bile acid treatment. In conclusion, we identified Ost-α/Ost-β as a novel FXR target. Absent Ost-α/Ost-β induction in CA-fed FXR−/− animals may contribute to increased liver injury in these animals. The induction of bile acid hydroxylation and Mrp4 was independent of FXR but could not counteract liver toxicity sufficiently. Limited effects of UDCA on Ost-α/Ost-β may jeopardize its therapeutic efficacy.

The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-α and -β genes

2006 ◽  
Vol 290 (3) ◽  
pp. G476-G485 ◽  
Author(s):  
Jean-François Landrier ◽  
Jyrki J. Eloranta ◽  
Stephan R. Vavricka ◽  
Gerd A. Kullak-Ublick
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cultured Cells ◽  
Farnesoid X Receptor ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Organic Solute Transporter ◽  
Genes Encoding ◽  
Organic Solute ◽  
Solute Transporter

Bile acids are synthesized from cholesterol in the liver and are excreted into bile via the hepatocyte canalicular bile salt export pump. After their passage into the intestine, bile acids are reabsorbed in the ileum by sodium-dependent uptake across the apical membrane of enterocytes. At the basolateral domain of ileal enterocytes, bile acids are extruded into portal blood by the heterodimeric organic solute transporter OSTα/OSTβ. Although the transport function of OSTα/OSTβ has been characterized, little is known about the regulation of its expression. We show here that human OSTα/OSTβ expression is induced by bile acids through ligand-dependent transactivation of both OST genes by the nuclear bile acid receptor/farnesoid X receptor (FXR). FXR agonists induced endogenous mRNA levels of OSTα and OSTβ in cultured cells, an effect that was not discernible upon inhibition of FXR expression by small interfering RNAs. Furthermore, OST mRNAs were induced in human ileal biopsies exposed to the bile acid chenodeoxycholic acid. Reporter constructs containing OSTα or OSTβ promoters were transactivated by FXR in the presence of its ligand. Two functional FXR binding motifs were identified in the OSTα gene and one in the OSTβ gene. Targeted mutation of these elements led to reduced inducibility of both OST promoters by FXR. In conclusion, the genes encoding the human OSTα/OSTβ complex are induced by bile acids and FXR. By coordinated control of OSTα/OSTβ expression, bile acids may adjust the rate of their own efflux from enterocytes in response to changes in intracellular bile acid levels.

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