OSTα-OSTβ: A major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia

Ballatori, Nazzareno; Christian, Whitney V.; Lee, Jin Young; Dawson, Paul A.; Soroka, Carol J.; Boyer, James L.; Madejczyk, Michael S.; Li, Na

doi:10.1002/hep.20961

Cited by 308 publications

(337 citation statements)

References 24 publications

(41 reference statements)

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“…As described elsewhere, bile acids are normally absent from the urine as a result of efficient hepatic clearance and reabsorption of bile acids in the proximal tubule by the apical sodiumdependent bile acid transporter Asbt (Slc10a2) 30 on the luminal membrane and the heterodimeric transporter Ost␣-Ost␤ 47-49 on the basolateral membrane. 16 The present study does not clarify the role of Mrp4 in the renal excretion of bile acids, because similar concentrations of bile acids were measured in urine in both groups after CBDL. Mrp4 is located on the apical membrane of the rat proximal tubule together with Mrp2.…”

Section: Discussionmentioning

confidence: 59%

“…16,17 However, the relative importance of these basolateral transporters and their own particular role in responding to cholestatic stress in the liver are not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…Antibodies to mouse Ost␣ and Ost␤ were kindly provided by Ned Ballatori. 16 All protein samples from livers and kidneys were analyzed as previously described. 16 All samples were run together on the same gel/blot using a triple-wide system from C.B.S.…”

Section: Methodsmentioning

confidence: 99%

“…Examples include Mrp3, which is primarily a bilirubin conjugate transporter and also a constitutive androstane receptor target, 15 and the recently described heterodimeric bile acid and organic solute transporter, Ost␣-Ost␤. 16,17 The relative contribution of Mrp4 in the protection against bile acid overload is unknown.…”

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confidence: 99%

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Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

et al. 2006

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Mrp4 is a member of the multidrug resistance-associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive upregulation in response to cholestatic injury or bile acid feeding. However, the relative importance of Mrp4 in a protective adaptive response to cholestatic injury is not known. To address this issue, common bile duct ligation (CBDL) was performed in wild-type and Mrp4؊/؊ mice and animals followed for 7 days. Histological analysis and serum aminotransferase levels revealed more severe liver injury in the absence of Mrp4 expression. Western analyses revealed that Mrp4, but not Mrp3, was significantly increased after CBDL in wild-type mice. Serum bile acid levels were significantly lower in Mrp4؊/؊ mice than in wild-type CBDL mice, whereas serum bilirubin levels were the same, suggesting that Mrp4 was required to effectively extrude bile acids from the cholestatic liver. Mrp3 and Ost␣-Ost␤ were upregulated in Mrp4؊/؊ mice but were unable to compensate for the loss of Mrp4. High-performance liquid chromatography analysis on liver extracts revealed that taurine tetrahydroxy bile acid/beta-muricholic acid ratios were increased twofold in Mrp4؊/؊ mice. In conclusion, hepatic Mrp4 plays a unique and essential protective role in the adaptive response to obstructive cholestatic liver injury. ( M ultidrug resistance-associated protein 4 (MRP4) (ABCC4) is an ATP-dependent organic anion transporter with broad substrate specificity. [1][2][3] It is a member of the ABC transporter superfamily 4 and is expressed in a variety of epithelia, including the basolateral and apical plasma membranes of the liver and kidneys, respectively. 5-7 However, this array of substrates and specific tissue localization have not provided insight into Mrp4 function in vivo.Mrp4 was first suggested to play a role in the adaptive response to the hepatic overload of bile acids following the genetic deletion of farnesoid X receptor (FXR), a bile acid sensor. 8,9 A subsequent study suggested that Mrp4 was not elevated upon feeding the hydrophobic bile acid, lithocholic acid. 10 Despite this finding, other studies have demonstrated that hepatic Mrp4 is upregulated in both rats and mice after bile duct ligation 6,11 and in pediatric patients with progressive familial intrahepatic cholestasis. 12 Recent studies demonstrate that MRP4 functions as an efflux pump for bile acids together with glutathione. 13 Further support for a role for MRP4 in hepatic bile acid overload is the recent demonstration that Mrp4 is upregulated by the constitutive androstane receptor. 14 Constitutive androstane receptor is a member of the nuclear hormone receptor superfamily that is required to elevate serum bile acids during cholestatic injury. 15 Cholestatic injury in mice, rats, and humans can also result in adaptive responses in other basolateral transporters. Examples include Mrp3, which is primarily a bilirubin conjugate transporter and also a constitutive androstane receptor target, 15 and the recently described heterodi...

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Section: Discussionmentioning

confidence: 59%

“…16,17 However, the relative importance of these basolateral transporters and their own particular role in responding to cholestatic stress in the liver are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

et al. 2006

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“…However, it is generally accepted that the absorptive transporters ASBT, MRP3, MCT1, OATP2B1 and OSTa/b have moderate to high intestinal expression levels. [12,[14][15][16]18,20,21,29,32,33,36,39,40] The three known intestinal exsorptive transporters for organic anions (BCRP, MRP2 and OSTa/b) all have relatively high expression levels -especially BCRP has a high intestinal expression compared with other tissues. [14,16,18,20,21,23,39] A high transporter expression level is likely indicative of an important role in the absorption or elimination of endogenous and exogenous substances.…”

Section: Intestinal Transporters For Organic Anions and Their Substramentioning

confidence: 99%

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

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Nfat5 is involved in the hyperosmotic regulation of Tmem184b: a putative modulator of ibuprofen transport in renal MDCK I cells

et al. 2019

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Nuclear factor of activated T cells 5 ( NFAT 5) is a transcription factor involved in the regulation of several genes involved in the response to extracellular hyperosmolality. Recently, the uptake of ibuprofen by an as yet unknown carrier was suggested in Madin‐Darby canine kidney ( MDCK ) I cells exposed to hyperosmolality. We therefore speculated that Nfat5 could be involved in the regulation of this ibuprofen carrier. Reverse transfection with si RNA against Nfat5 was used to knock down Nfat5 in MDCK I cells. The uptake of both radiolabelled taurine and ibuprofen was measured in MDCK I cells, first treated with si RNA against Nfat5 and afterwards cultivated with raffinose‐supplemented normal growth medium (500 mO sm) for 24 h. The si RNA transfection resulted in knockdown of Nfat5, and uptake of both taurine and ibuprofen was significantly decreased in transfected MDCK I cells. The decrease in ibuprofen uptake indicates that Nfat5 is involved in upregulation of the ibuprofen carrier. A transcriptome analysis of MDCK I cells treated with si RNA against Nfat5 revealed 989 genes upregulated by Nfat5 during hyperosmotic exposure. From these genes, the gene product transmembrane protein 184b was found to be regulated by Nfat5, and Tmem184b was the only potential gene product involved in the uptake of ibuprofen in MDCK I cells. Dataset The RNA sequencing dataset is available from the NCBI Gene Expression 452 Omnibus ( https://www.ncbi.nlm.nih.gov/geo/ ) with the accession number GSE122074 .

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OSTα-OSTβ: A major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia

Cited by 308 publications

References 24 publications

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Nfat5 is involved in the hyperosmotic regulation of Tmem184b: a putative modulator of ibuprofen transport in renal MDCK I cells

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