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

2018 ◽  
Vol 314 (5) ◽  
pp. G597-G609 ◽  
Author(s):  
Melina M. Malinen ◽  
Izna Ali ◽  
Jacqueline Bezençon ◽  
James J. Beaudoin ◽  
Kim L. R. Brouwer
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Tissue ◽  
Primary Biliary Cholangitis ◽  
Drug Induced ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Solute Transporter

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. OSTα/β expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OSTα/β-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 OSTα/β-mediated transport was evaluated. Expression of OSTα/β was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OSTα/β was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTα/β-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OSTα/β 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 OSTα/β-overexpressing cells. Our findings demonstrate that OSTα/β 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 OSTα/β is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OSTα/β substrates exhibit rapid, linear, and concentration-driven transport in an OSTα/β-overexpressing cell line. Drugs associated with hepatotoxicity modulate OSTα/β-mediated taurocholate transport. These data suggest that hepatic OSTα/β plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.

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.

Regulation of the mouse organic solute transporter α-β, Ostα-Ostβ, by bile acids

2006 ◽  
Vol 290 (5) ◽  
pp. G912-G922 ◽  
Author(s):  
Tamara Frankenberg ◽  
Anuradha Rao ◽  
Frank Chen ◽  
Jamie Haywood ◽  
Benjamin L. Shneider ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Promoter Activity ◽  
Colon Adenocarcinoma ◽  
Dominant Negative ◽  
Farnesoid X Receptor ◽  
Negative Feedback Regulation ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Solute Transporter

The mechanisms responsible for bile acid regulation of mouse intestinal organic solute transporter α-β (Ostα-Ostβ) expression were investigated. Expression of Ostα-Ostβ mRNA was increased in cecum and proximal colon of cholic acid-fed mice and in chenodeoxycholate-treated mouse CT26 colon adenocarcinoma cells. Sequence analysis revealed potential cis-acting elements for farnesoid X receptor (FXR) and liver receptor homolog-1 (LRH-1) in the mouse Ostα and Ostβ promoters and reporter constructs containing Ostα and Ostβ 5′-flanking sequences were positively regulated by bile acids. Expression of a dominant-negative FXR, reduction of FXR with interfering small RNA (siRNA), or mutation of the potential FXR elements decreased Ostα and Ostβ promoter activity and abolished the induction by chenodeoxycolic acid. Negative regulation of the Ostα and Ostβ promoters by bile acids was mediated through LRH-1 elements. Ostα and Ostβ promoter activities were increased by coexpression of LRH-1 and decreased by coexpression of SHP. Mutation of the potential LRH-1 elements and siRNA-mediated reduction of LRH-1 expression decreased basal promoter activity. As predicted from the promoter analyses, ileal Ostα and Ostβ mRNA expressions were increased in wild-type mice administered the FXR agonist GW4064 and decreased in FXR-null mice. Immunoblotting analysis revealed that Ostα and Ostβ intestinal protein expressions correlated with mRNA expression. The mouse Ostα and Ostβ promoters are unusual in that they contain functional FXR and LRH elements, which mediate, respectively, positive and negative feedback regulation by bile acids. Although the positive regulatory pathway appears to be dominant, this arrangement provides a mechanism to finely titrate Ostα-Ostβ expression to the bile acid flux.

scholarly journals Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Metabolites ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 282
Author(s):  
Cristina Gómez ◽  
Simon Stücheli ◽  
Denise V. Kratschmar ◽  
Jamal Bouitbir ◽  
Alex Odermatt
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Bile Acids ◽  
Liver Tissue ◽  
Bioactive Molecules ◽  
Rodent Species ◽  
Drug Induced ◽  
Tissue Samples ◽  
Drug Induced Liver Injury ◽  
Bile Acid Profiles

Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

scholarly journals Novel in Vitro Method Reveals Drugs That Inhibit Organic Solute Transporter Alpha/Beta (OSTα/β)

2018 ◽  
Vol 16 (1) ◽  
pp. 238-246 ◽  
Author(s):  
Melina M. Malinen ◽  
Antti Kauttonen ◽  
James J. Beaudoin ◽  
Noora Sjöstedt ◽  
Paavo Honkakoski ◽  
...  
Keyword(s):  
In Vitro Method ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Alpha Beta ◽  
Solute Transporter
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