Human Transporters

OST α and β

OST α and β (Organic Solute Transporter α and β)

Gene names:  SLC51A and SLC51B


OSTα / β (SLC51A and B) is a facilitative, sodium-independent bile acid transporter originally cloned from the little skate (Leucoraja erinacea) by Wang et al [1]. Human and mouse orthologues were subsequently cloned by the same group [2]. Uniquely among organic anion transporters, OSTα / β is generated by co-expression of two distinct gene products, OOSTα / β. OOSTα / β is expressed at highest levels in organs of the enterohepatic bile acid circulation: the small intestine, liver and kidney. OSTα / β is localized to the basolateral membrane of epithelial cells where it transports bile acids, conjugated steroids and structurally related molecules. It acts in concert with ASBT in enterocytes in the transport of bile acids from the lumen to the blood. It seems to play a protective role in the cholestatic liver by extruding bile acids from hepatocytes to the blood, thereby reducing intracellular bile acid concentration. OSTα / β also works in conjunction with ASBT in the proximal tubule cells as a salvage mechanism to conserve bile acids. In addition, it is expressed in the adrenal gland where its proposed role involves the transport of conjugated steroids. Similar to other bile acid transporters, OSTα / β expression is regulated by bile acid levels though FXR-mediated mechanisms in response to cholestatic conditions both in enterocytes and hepatocytes. Through this adaptive regulation OSTα / β plays a protective role in liver cholestasis. 


Expression of OSTα / β subunits is closely coordinated, with high levels in the small intestine, kidney, liver, testis, lower level in the colon, ovary and adrenal gland. Lower levels of OST mRNA can be measured in the heart, lung, brain, pituitary, thyroid gland, uterus, mammary gland and fat [2]. Human OSTα / β are localized to the basolateral membrane of important epithelial cells such as enterocytes, renal tubular cells, cholangiocytes and hepatocytes [3]. 

Function, physiology, and clinically significant polymorphisms

The two subunits are encoded on different chromosomes, with the respective genes located at 3q29 and 15q22. The  α subunit is a 340-amino acid protein of 40 kDa, containing seven transmembrane domains, whereas the β subunit is a smaller, 17kDa, single transmembrane domain protein of 128 amino acids [2]. Early studies in oocytes demonstrated that both subunits are needed for proper transport of taurocholate (TC) [2]. These results were confirmed in HEK293 and MDCKII cells overexpressing OSTα / β subunits [4]. Ostβ expression is required for N-glycosylation of the β subunit and subsequent translocation of the mature protein to the plasma membrane [4]. Two-hybrid, co-immunoprecipitation and bimolecular fluorescence complementation studies confirmed physical interaction between human OSTα / β subunits [5, 6], and data with truncated mutants suggested that the formation of the protein complex occurs intracellularly and the established dimer moves to the plasma membrane [5, 6]. In Ostα knockout mice, Ostβ mRNA levels were maintained in all tissues examined, yet Ostβ protein was not detected, suggesting that the subunits are not stable without heterodimerization [5].
Transcellular transport of TC in MDCKII cells expressing both ASBT and OSTα / β subunits grown on transwell plates confirms that ASBT and OSTα / β cooperate in bile acid transport [4].
OSTα / β-mediated bile acid transport is sodium-independent, saturable, and can be inhibited by organic anions and steroids. OST α/ β transports bile acids, conjugated steroids and structurally related molecules, including estrone 3-sulfate (E3S), pregnenolone sulfate (PREGS), dehydroepiandrosterone-sulfate (DHEAS), taurocholate, prostaglandin E2 and digoxin [2, 7-9]. Transport of E3S can be inhibited by litocholic acid, glycolithocholic acid, TC and their sulfated versions. Digoxin, spironolactone, probenecid, indomethacin and sulfobromophthalein also effectively inhibited OSTα/β-mediated E3S transport [2]. In OSTα/β-expressing HEK293 cells, troglitazone sulfate, estrone 3-sulfate, indomethacin, spironolactone, GCDC and TLCAS suppressed TC uptake when applied for 10 minutes as a preincubation but not during the uptake phase, while fidaxomicin inhibited only when co-administered with TC in the uptake phase [10].
In the ileum, OSTα / β cooperates with ASBT in the transport of bile acids across enterocytes. However, in the proximal small intestine, colon, and cecum, it may function to efflux bile acids that enter the enterocytes via nonionic diffusion or facilitative transport [11].
In Ost-deficient mice, serum bile acid levels were decreased by 60%, and the total bile acid pool was also significantly depleted, suggesting a crucial role of OSTα / β in intestinal bile acid uptake. Ileal absorption of TC was also markedly reduced in knock-out mice. As a consequence, serum cholesterol and triglyceride levels were moderately lowered, since bile acids are required for lipid absorption. To compensate for the loss of Ost function, expression of other bile acid transporters was altered in the small intestine, liver and kidney through FXR- and Fgf15-mediated responses. Expression of Asbt and the basolateral bile acid pump Mrp3 was upregulated in all three organs, providing a compensatory mechanism to maintain bile acid homeostasis. Bsep, Mrp2 and Ntcp mRNA levels were increased in the liver only. In contrast, the rate-limiting enzyme of bile acid synthesis, Cyp7a1, was downregulated in the liver. Considering these data, OSTα / β is a major basolateral export pump of bile acids in the small intestine, liver and kidney [12]. 
Adaptive regulation of bile acid transporters in the cholestatic liver to prevent liver injury caused by the accumulation of bile acids has been demonstrated previously [13, 14]. This response is either directly or indirectly mediated by FXR [13, 15], and regulation of OSTα / β expression by bile acids is subject to intensive examination. OST  and  are upregulated in the liver of patients with primary biliary cirrhosis, nonalcoholic steatohepatitis, obstructive cholestasis and primary biliary cholangitis; in rats and mice following common bile duct ligation, and also in Fxr knock-out mice. Ost upregulation was confirmed at both mRNA and protein level, and the role of Fxr was also demonstrated. Upregulation of OST subunits following chenodeoxycholic acid (CDCA) treatment was reproduced in HepG2 cells [16][10, 17]. 
OST  α / β mRNA levels also increased in response to CDCA treatment via an FXR-dependent mechanism both in human hepatoma cell lines and human ileal tissue [18]. Via bile acid-dependent and FXR-mediated regulation of OST and ASBT expression levels, enterocytes seem to be coordinating the rate of bile acid efflux and uptake in response to changes in luminal bile acid load. Recent studies on sandwich-cultured human hepatocytes revealed a significant preventive role of OSTα / β in cholestatic conditions through the adaptive response of hepatocytes, regulated through FXR [7, 19, 20]. BSEP inhibition leads to the same gene expression activation as CDCA treatment via increasing the intracellular bile acid concentration. However, coadministration of the BSEP inhibitor troglitazone with CDCA prevented the elevation of OSTα / β, as troglitazone shows FXR antagonist properties [21].
In summary, bile acids can regulate their own uptake and efflux from both enterocytes and hepatocytes via induction or repression of the respective uptake and efflux pumps. The protective role of OSTα / β in cholestatic conditions has also been suggested based on data with Ost α knock-out mice, where the loss of Ostα function protected from liver injury during oral bile acid feeding. In cholestasis, upregulation of Ostα mediates the transport of bile salts from hepatocytes into the sinusoidal compartment, which may protect from liver injury [22]. 
Altered disposition of labeled E3S and DHEAS in Ostα knock-out mice indicated the role of Ostα / β in bile acid and conjugated steroid reabsorption in the kidney, where it acts in concert with ASBT as a salvage mechanism to conserve bile acids [12].
In addition to its role in bile acid circulation, OST α / β is also expressed in the adrenal gland where it has been proposed to participate in the secretion of conjugated steroid intermediates such as E3S and DHEAS [3, 23]. OST expression is regulated by FXR in this tissue as well [23].
Although several genetic variants with single amino acid changes have been reported for human OSTα , to date there is no clinical data available on their relevance, meaning that there is no clinically significant polymorphism reported for this gene. 

Clinical significance

Currently there is no human disease associated with dysfunction of Ost α / β; however, altered expression of the transporter has been reported in cases of bile acid malabsorption and gallstone formation [24, 25].

Rodent orthologues

Just like in humans, the two subunits are encoded on different chromosomes in mice (positions 16B3 and 9C for mOst α and mOst β, respectively). Human and rat orthologues were cloned by the same group, and although there is only 25-41% amino acid identity between the mammalian and skate proteins, thanks to many conserved amino acid substitutions the amino acid similarity is around 62-70% [2]. Putative OSTα orthologues have been identified in invertebrates, although bile acids have not been detected in these species, suggesting an original physiological function of OST other than bile acid transport, most likely transport of steroid hormones and eicosanoids [26].
The mouse orthologue of OSTα shares 83% amino acid homology with the human protein. For OSTβ, the homology is 63% between mice and humans [1, 2]. Both human and mouse transporters have overlapping substrate profiles with skate OSTα / β [2]. 
While human OST is expressed in hepatocytes and cholangiocytes, mouse and rat hepatocytes have no detectable levels of Ost mRNA, and cholangiocytes produce only moderate levels of Ost mRNA under non-cholestatic conditions [3, 16]. However, Ost mRNA expression increases significantly in extrahepatic cholestasis [16, 27]. Otherwise, mouse Ost expression pattern is in good correlation with that of the intestinal bile acid transporter Asbt, with mRNA levels increasing proximodistally from the duodenum to the ileum, further confirming the crucial role of Ostα / β in intestinal bile acid reabsorption, as well as protecting the enterocytes from bile acid accumulation [28]. This species-specific difference in the localization of bile acid transporters may reflect differences in cholesterol and bile acid metabolism between rodents and humans, notably the higher level of intestinal sterol absorption and hepatic cholesterol synthesis in rodents [3]. 
Immunostaining of mouse and rat epithelial cells confirmed the basolateral localization of the heterodimer in enterocytes and proximal tubule cells [3, 4]. 
There is no significant difference in substrate specificity between the human and mouse orthologues [2]. 

Regulatory requirements

Due to the lack of reported DDI’s or food-drug interactions associated with OSTα / β, no recommendations for OSTα / β transporter investigation exist in either the FDA or EMA guidelines.

Location Endogenous substrates In vitro substrates used experimentally Substrate drugs Inhibitors
small intestine, kidney, liver, testes, colon, ovary, adrenal gland bile acids, prostaglandin-E2, DHEAS taurocholate, estrone-3-sulfate digoxin spironolactone, probenecid, indomethacin, bromosulfophthalein, fidaxomicin, troglitazone sulfate, ethinyl estradiol



1.    Wang, W., et al., Expression cloning of two genes that together mediate organic solute and steroid transport in the liver of a marine vertebrate. Proc Natl Acad Sci U S A, 2001. 98(16): p. 9431-6.
2.    Seward, D.J., et al., Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta. J Biol Chem, 2003. 278(30): p. 27473-82.
3.    Ballatori, N., et al., OSTalpha-OSTbeta: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology, 2005. 42(6): p. 1270-9.
4.    Dawson, P.A., et al., The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem, 2005. 280(8): p. 6960-8.
5.    Li, N., et al., Heterodimerization, trafficking and membrane topology of the two proteins, Ost alpha and Ost beta, that constitute the organic solute and steroid transporter. Biochem J, 2007. 407(3): p. 363-72.
6.    Sun, A.Q., et al., Protein-protein interactions and membrane localization of the human organic solute transporter. Am J Physiol Gastrointest Liver Physiol, 2007. 292(6): p. G1586-93.
7.    Beaudoin, J.J., et al., Role of Organic Solute Transporter Alpha/Beta in Hepatotoxic Bile Acid Transport and Drug Interactions. Toxicol Sci, 2020. 176(1): p. 34-35.
8.    Suga, T., et al., Characterization of conjugated and unconjugated bile acid transport via human organic solute transporter alpha/beta. Biochim Biophys Acta Biomembr, 2019. 1861(5): p. 1023-1029.
9.    Fang, F., et al., Neurosteroid transport by the organic solute transporter OSTalpha-OSTbeta. J Neurochem, 2010. 115(1): p. 220-33.
10.    Malinen, M.M., et al., Organic solute transporter OSTalpha/beta is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury. Am J Physiol Gastrointest Liver Physiol, 2018. 314(5): p. G597-G609.
11.    Dawson, P.A., M.L. Hubbert, and A. Rao, Getting the mOST from OST: Role of organic solute transporter, OSTalpha-OSTbeta, in bile acid and steroid metabolism. Biochim Biophys Acta, 2010. 1801(9): p. 994-1004.
12.    Ballatori, N., et al., Ostalpha-Ostbeta is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver. Am J Physiol Gastrointest Liver Physiol, 2008. 295(1): p. G179-G186.
13.    Wagner, M., et al., Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology, 2003. 125(3): p. 825-38.
14.    Trauner, M. and J.L. Boyer, Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev, 2003. 83(2): p. 633-71.
15.    Boyer, J.L., Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease? Gastroenterology, 2005. 129(2): p. 735-40.
16.    Boyer, J.L., et al., Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol, 2006. 290(6): p. G1124-30.
17.    Chai, J., et al., Hepatic expression of detoxification enzymes is decreased in human obstructive cholestasis due to gallstone biliary obstruction. PLoS One, 2015. 10(3): p. e0120055.
18.    Landrier, J.F., et al., The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Am J Physiol Gastrointest Liver Physiol, 2006. 290(3): p. G476-85.
19.    Jonathan P. Jackson, K.M.F., Weslyn W. Friley, Robert L. St. Claire III, Chris Black, and Kenneth R. Brouwer, Basolateral Efflux Transporters: A Potentially Important Pathway for the Prevention of Cholestatic Hepatotoxicity. APPLIED IN VITRO TOXICOLOGY, 2016. Volume 2(Number 4).
20.    Guo, C., et al., Farnesoid X Receptor Agonists Obeticholic Acid and Chenodeoxycholic Acid Increase Bile Acid Efflux in Sandwich-Cultured Human Hepatocytes: Functional Evidence and Mechanisms. J Pharmacol Exp Ther, 2018. 365(2): p. 413-421.
21.    Jackson, J.P., et al., Cholestatic Drug Induced Liver Injury: A Function of Bile Salt Export Pump Inhibition and Farnesoid X Receptor Antagonism. Applied In Vitro Toxicology, 2018. 4(3): p. 265-79.
22.    Soroka, C.J., et al., Mouse organic solute transporter alpha deficiency enhances renal excretion of bile acids and attenuates cholestasis. Hepatology, 2010. 51(1): p. 181-90.
23.    Lee, H., et al., FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine. J Lipid Res, 2006. 47(1): p. 201-14.
24.    Balesaria, S., et al., Exploring possible mechanisms for primary bile acid malabsorption: evidence for different regulation of ileal bile acid transporter transcripts in chronic diarrhoea. Eur J Gastroenterol Hepatol, 2008. 20(5): p. 413-22.
25.    Renner, O., et al., Reduced ileal expression of OSTalpha-OSTbeta in non-obese gallstone disease. J Lipid Res, 2008. 49(9): p. 2045-54.
26.    Hofmann, A.F., L.R. Hagey, and M.D. Krasowski, Bile salts of vertebrates: structural variation and possible evolutionary significance. J Lipid Res, 2010. 51(2): p. 226-46.
27.    Zollner, G., et al., Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids. Am J Physiol Gastrointest Liver Physiol, 2006. 290(5): p. G923-32.
28.    Ferrebee, C.B., et al., Organic Solute Transporter alpha-beta Protects Ileal Enterocytes From Bile Acid-Induced Injury. Cell Mol Gastroenterol Hepatol, 2018. 5(4): p. 499-522.

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