The Ileocyte Basolateral Organic Solute Transporter (OST -OST ) Complex: Finding The Missing Link in Enterohepatic Circulation

2005 ◽  
Vol 5 (1) ◽  
pp. 8-10 ◽  
Author(s):  
P. M. Gerk
Keyword(s):  
Enterohepatic Circulation ◽  
Missing Link ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Solute Transporter

scholarly journals A novel RARα/CAR-mediated mechanism for regulation of human organic solute transporter-β gene expression

2014 ◽  
Vol 306 (2) ◽  
pp. G154-G162 ◽  
Author(s):  
Shuhua Xu ◽  
An-Qiang Sun ◽  
Frederick J. Suchy
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Enterohepatic Circulation ◽  
Constitutive Androstane Receptor ◽  
Luciferase Reporter ◽  
Mobility Shift ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Maximal Induction ◽  
Solute Transporter

The organic solute transporter-α/β (OSTα/β) is a heteromeric transporter that is essential for bile acid and sterol disposition and for the enterohepatic circulation. To better understand the mechanism underlying OST gene regulation, the effects of retinoic acid (RA) on OSTα/β gene expression were investigated. The results show a dose-dependent induction of OSTβ but not OSTα expression in both Huh7 and HepG2 cells by RA treatment. A novel functional RA receptor response element (RARE; so-called DR5) in the promoter of OSTβ gene was identified. The interaction of RARα/RXRα with the RARE was verified by electrophoretic mobility shift and chromatin immunoprecipitation assays and its functional importance by hOSTβ promoter activation in luciferase reporter assays. The studies demonstrated that the RARE is also a constitutive androstane receptor (CAR) binding site for OSTβ gene regulation. These results suggest that OSTβ is a target of both FXR-mediated (by binding to IR-1 element) and RARα- and CAR-mediated (by binding to DR5 element) gene regulation pathways. In summary, this study has uncovered a novel RARE (DR5) element in the promoter of OSTβ that binds RARα or CAR heterodimerized with RXRα and appears to function synergistically with the IR-1 element to provide maximal induction of OSTβ in response to RA. These findings demonstrate a role for RARα and CAR in controlling OSTβ expression levels.

scholarly journals SLC51 family of steroid-derived molecule transporters (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database

2020 ◽  
Vol 2020 (4) ◽  
Author(s):  
Paul A. Dawson
Keyword(s):  
Enterohepatic Circulation ◽  
Chloride Ions ◽  
Dehydroepiandrosterone Sulphate ◽  
Sodium Potassium ◽  
Transporter Family ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Steroidogenic Cells ◽  
Inherited Mutations ◽  
The Brain

The SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the small intestine, bile duct, and liver, as part of the enterohepatic circulation [2, 4, 1]. OSTα/OSTβ is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [5]. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [4, 2]. OSTα/OSTβ heterodimers have been shown to transport [3H]taurocholic acid, [3H]dehydroepiandrosterone sulphate, [3H]estrone-3-sulphate, [3H]pregnenolone sulphate and [3H]dehydroepiandrosterone sulphate [2, 4, 5]. OSTα/OSTβ-mediated transport of bile salts is inhibited by clofazimine [9]. OSTα is suggested to be a seven TM protein, while OSTβ is a single TM 'ancillary' protein, both of which are thought to have intracellular C-termini [7]. Both proteins function in solute transport [7, 3]. Inherited mutations in OSTα and OSTβ are associated liver disease and congenital diarrhea in children [8, 6].

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.

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