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DOI: 10.1055/s-0030-1253226
Organic Solute Transporter, OSTα-OSTβ: Its Role in Bile Acid Transport and Cholestasis
Publication History
Publication Date:
26 April 2010 (online)
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ABSTRACT
Organic solute transporter alpha-beta (OSTα-OSTβ) is a unique heteromeric transporter localized to the basolateral membrane of epithelial cells involved in sterol transport. It is believed to be the primary bile acid efflux transporter in the intestine of mammals and is therefore essential to bile acid homeostasis and the enterohepatic circulation. First described in the evolutionarily primitive small skate, Leucoraja erinacea, this facilitated transporter requires expression of both subunits for its function. It can transport a variety of bile acids, as well as estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, digoxin, and prostaglandin E2. Expression of both subunits is variable between species and tissues; in humans high expression is noted in the liver, small intestine, kidney, testis, and adrenal gland. OSTα-OSTβ is directly regulated by the bile acid sensing nuclear receptor, farnesoid X receptor (FXR). Furthermore, it is part of the complex regulatory pathway that controls bile acid synthesis and homeostasis. Hepatic OSTα-OSTβ is upregulated in cholestasis in both humans and rodents, where it appears to play a protective role. Additional studies are necessary to determine its role in liver injury, bile acid malabsorption, and lipid and glucose metabolism, as well as a potential protective role for kidney OSTα-OSTβ in cholestasis.
KEYWORDS
Bile acid homeostasis - ileal bile acid transporter - adaptive regulation - nuclear receptor
REFERENCES
- 1 Wong M H, Oelkers P, Craddock A L, Dawson P A. Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J Biol Chem. 1994; 269(2) 1340-1347
- 2 Wang W, Seward D J, Li L, Boyer J L, Ballatori N. 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) 9431-9436
- 3 Seward D J, Koh A S, Boyer J L, Ballatori N. Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta. J Biol Chem. 2003; 278(30) 27473-27482
- 4 Rao A, Haywood J, Craddock A L, Belinsky M G, Kruh G D, Dawson P A. The organic solute transporter α-β, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis. Proc Natl Acad Sci U S A. 2008; 105(10) 3891-3896
- 5 Soroka C J, Mennone A, Hagey L, Ballatori N, Boyer J L. Organic solute transporter α deficiency enhances renal excretion of bile acids and attenuates cholestasis. Hepatology. 2010; 51 181-190
- 6 Ballatori N, Christian W V, Lee J Y et al.. OSTalpha-OSTbeta: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology. 2005; 42(6) 1270-1279
- 7 Ballatori N, Li N, Fang F, Boyer J L, Christian W V, Hammond C L. OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids. Front Biosci. 2009; 14 2829-2844
- 8 Balesaria S, Pell R J, Abbott L J 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) 413-422
- 9 Lee H, Zhang Y, Lee F Y, Nelson S F, Gonzalez F J, Edwards P A. FXR regulates organic solute transporters α and β in the adrenal gland, kidney, and intestine. J Lipid Res. 2006; 47(1) 201-214
- 10 Dawson P A, Hubbert M, Haywood J et al.. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem. 2005; 280(8) 6960-6968
- 11 Soroka C J, Xu S, Mennone A, Lam P, Boyer J L. N-Glycosylation of the alpha subunit does not influence trafficking or functional activity of the human organic solute transporter alpha/beta. BMC Cell Biol. 2008; 9 57
- 12 Sun A-Q, Balasubramaniyan N, Xu K et al.. Protein-protein interactions and membrane localization of the human organic solute transporter. Am J Physiol Gastrointest Liver Physiol. 2007; 292(6) G1586-G1593
- 13 Li N, Cui Z, Fang F, Lee J Y, Ballatori N. Heterodimerization, trafficking and membrane topology of the two proteins, Ost α and Ost beta, that constitute the organic solute and steroid transporter. Biochem J. 2007; 407(3) 363-372
- 14 Boyer J L, Trauner M, Mennone A 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) G1124-G1130
- 15 Frankenberg T, Rao A, Chen F, Haywood J, Shneider B L, Dawson P A. Regulation of the mouse organic solute transporter α-β, Ostalpha-Ostbeta, by bile acids. Am J Physiol Gastrointest Liver Physiol. 2006; 290(5) G912-G922
- 16 Landrier J-F, Eloranta J J, Vavricka S R, Kullak-Ublick G A. The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-α and -β genes. Am J Physiol Gastrointest Liver Physiol. 2006; 290(3) G476-G485
- 17 Lu T T, Makishima M, Repa J J et al.. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000; 6(3) 507-515
- 18 Denson L A, Sturm E, Echevarria W et al.. The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology. 2001; 121(1) 140-147
- 19 Sinal C J, Tohkin M, Miyata M, Ward J M, Lambert G, Gonzalez F J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000; 102(6) 731-744
- 20 Grober J, Zaghini I, Fujii H et al.. Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J Biol Chem. 1999; 274(42) 29749-29754
- 21 Zollner G, Wagner M, Moustafa T et al.. 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. Am J Physiol Gastrointest Liver Physiol. 2006; 290(5) G923-G932
- 22 Ballatori N, Fang F, Christian W V, Li N, Hammond C L. 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) G179-G186
- 23 Inagaki T, Choi M, Moschetta A et al.. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005; 2(4) 217-225
- 24 Boyer J L. New perspectives for the treatment of cholestasis: lessons from basic science applied clinically. J Hepatol. 2007; 46(3) 365-371
- 25 Zollner G, Fickert P, Silbert D et al.. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol. 2003; 38(6) 717-727
- 26 Schaap F G, van der Gaag N A, Gouma D J, Jansen P LM. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology. 2009; 49(4) 1228-1235
- 27 Keitel V, Burdelski M, Warskulat U et al.. Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology. 2005; 41(5) 1160-1172
- 28 Chen J, Terada T, Ogasawara K, Katsura T, Inui K-i. Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis. Am J Physiol Renal Physiol. 2008; 295(1) F247-F252
- 29 Zollner G, Wagner M, Fickert P et al.. Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int. 2007; 27(7) 920-929
- 30 Hirohashi T, Suzuki H, Takikawa H, Sugiyama Y. ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3). J Biol Chem. 2000; 275(4) 2905-2910
- 31 Zamek-Gliszczynski M J, Nezasa K-i, Tian X et al.. Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3-/- and Abcc4-/- mice. J Pharmacol Exp Ther. 2006; 319(3) 1485-1491
- 32 Cui Y J, Aleksunes L M, Tanaka Y, Goedken M J, Klaassen C D. Compensatory induction of liver efflux transporters in response to ANIT-induced liver injury is impaired in FXR-null mice. Toxicol Sci. 2009; 110(1) 47-60
- 33 Donner M G, Keppler D. Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology. 2001; 34(2) 351-359
- 34 Ogawa K, Suzuki H, Hirohashi T et al.. Characterization of inducible nature of MRP3 in rat liver. Am J Physiol Gastrointest Liver Physiol. 2000; 278(3) G438-G446
- 35 Soroka C J, Lee J M, Azzaroli F, Boyer J L. Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology. 2001; 33(4) 783-791
- 36 Belinsky M G, Dawson P A, Shchaveleva I et al.. Analysis of the in vivo functions of Mrp3. Mol Pharmacol. 2005; 68(1) 160-168
- 37 Bohan A, Chen W-S, Denson L A, Held M A, Boyer J L. Tumor necrosis factor alpha-dependent up-regulation of Lrh-1 and Mrp3(Abcc3) reduces liver injury in obstructive cholestasis. J Biol Chem. 2003; 278(38) 36688-36698
- 38 Zelcer N, van de Wetering K, de Waart R et al.. Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides. J Hepatol. 2006; 44(4) 768-775
- 39 König J, Rost D, Cui Y, Keppler D. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology. 1999; 29(4) 1156-1163
- 40 Kruh G D, Belinsky M G, Gallo J M, Lee K. Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice. Cancer Metastasis Rev. 2007; 26(1) 5-14
- 41 Mennone A, Soroka C J, Cai S-Y et al.. Mrp4-/- mice have an impaired cytoprotective response in obstructive cholestasis. Hepatology. 2006; 43(5) 1013-1021
- 42 Assem M, Schuetz E G, Leggas M et al.. Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. J Biol Chem. 2004; 279(21) 22250-22257
- 43 Saini S PS, Sonoda J, Xu L et al.. A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification. Mol Pharmacol. 2004; 65(2) 292-300
- 44 Wagner M, Halilbasic E, Marschall H-U et al.. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology. 2005; 42(2) 420-430
- 45 Stedman C AM, Liddle C, Coulter S A et al.. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci U S A. 2005; 102(6) 2063-2068
- 46 Huang W, Zhang J, Moore D D. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest. 2004; 113(1) 137-143
- 47 Yin J, Wennberg R P, Xia Y C, Liu J W, Zhou H Z. Effect of a traditional Chinese medicine, yin zhi huang, on bilirubin clearance and conjugation. Dev Pharmacol Ther. 1991; 16(1) 59-64
- 48 Modica S, Bellafante E, Moschetta A. Master regulation of bile acid and xenobiotic metabolism via the FXR, PXR and CAR trio. Front Biosci. 2009; 14 4719-4745
- 49 Bloomer J R, Boyer J L. Phenobarbital effects in cholestatic liver diseases. Ann Intern Med. 1975; 82(3) 310-317
- 50 Khurana S, Singh P. Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver Int. 2006; 26(8) 943-948
- 51 Schlattjan J H, Winter C, Greven J. Regulation of renal tubular bile acid transport in the early phase of an obstructive cholestasis in the rat. Nephron Physiol. 2003; 95(3) 49-56
- 52 Stiehl A, Raedsch R, Rudolph G, Gundert-Remy U, Senn M. Biliary and urinary excretion of sulfated, glucuronidated and tetrahydroxylated bile acids in cirrhotic patients. Hepatology. 1985; 5(3) 492-495
- 53 Knisely A S, Strautnieks S S, Meier Y et al.. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology. 2006; 44(2) 478-486
- 54 Halpern M D, Dvorak B. Does abnormal bile acid metabolism contribute to NEC?. Semin Perinatol. 2008; 32(2) 114-121
- 55 Renner O, Harsch S, Strohmeyer A, Schimmel S, Stange E F. Reduced ileal expression of OSTalpha-OSTbeta in non-obese gallstone disease. J Lipid Res. 2008; 49(9) 2045-2054
- 56 Kakizaki S, Yamazaki Y, Takizawa D, Negishi M. New insights on the xenobiotic-sensing nuclear receptors in liver diseases—CAR and PXR—. Curr Drug Metab. 2008; 9(7) 614-621
- 57 Rezen T, Tamasi V, Lövgren-Sandblom A, Björkhem I, Meyer U A, Rozman D. Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers. BMC Genomics. 2009; 10 384
- 58 Stefano F, Sabrina C, Baldelli F, Mencarelli A. Bile acid-activated receptors in the treatment of dyslipidemia and related disorders. Prog Lipid Res. 2009; 49(2) 171-185
- 59 Lahtela J T, Arranto A J, Sotaniemi E A. Enzyme inducers improve insulin sensitivity in non-insulin-dependent diabetic subjects. Diabetes. 1985; 34(9) 911-916
- 60 Dong B, Saha P K, Huang W et al.. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci U S A. 2009; 106(44) 18831-18836
Carol J SorokaPh.D.
Department of Internal Medicine–Digestive, Yale University School of Medicine
333 Cedar Street/1080 LMP, P.O. Box 208019, New Haven, CT 06520-8019
Email: carol.soroka@yale.edu