Abstract��Bile acids participated in regulation of many physiological functions in the human body. Transporters in liver and intestinal play an important role in maintaining the enterohepatic circulation and bile acid homeostasis. With the rapid development of molecular biology in recent years, there has been great progress toward cloning and identifying the individual bile acid transporters and explaining their complex regulation. Bile acid transporters were regulated by various factors including bile acids, nuclear receptors, transcription factors, hormones, etc., which influence their protein expression, cell location and transport activities. This article reviews the research progress of bile acid transporters for the purpose of providing references for the mechanism research of bile acid transporter related disorders and drug development .
SONG Y, XU C, SHAO S, et al. Thyroid-stimulating hormone regulates hepatic bile acid homeostasis via SREBP-2/HNF-4alpha/CYP7A1 axis[J]. J Hepatol, 2015, 62(5):1171-1179.
[2]
DORING B, LUTTEKE T, GEYER J, et al. The SLC10 carrier family:transport functions and molecular structure[J]. Curr Top Membr, 2012, 70:105-168.
[3]
AN H, DOUILLARD F P, WANG G, et al. Integrated transcriptomic and proteomic analysis of the bile stress response in a centenarian-originated probiotic Bifidobacterium longum BBMN68[J]. Mol Cell Proteomics, 2014, 13(10):2558-2572.
[4]
FERREBEE C B, DAWSON P A. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids[J]. Acta Pharm Sin B, 2015, 5(2):129-134.
[5]
SCHADT H S, WOLF A, POGNAN F, et al. Bile acids in drug induced liver injury:key players and surrogate markers[J]. Clin Res Hepatol Gastroenterol, 2016, 40(3):257-266.
[6]
STALEY C, WEINGARDEN A R, KHORUTS A, et al. Interaction of gut microbiota with bile acid metabolism and its influence on disease states[J]. Appl Microbiol Biot, 2016, 5(2):129-134.
[7]
FERREBEE C B, DAWSON P A. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids[J]. Acta Pharm Sin B(ҩѧѧ�� Ӣ�İ�), 2015, 5(2):129-134.
[8]
STAUDINGER J L, WOODY S, SUN M, et al. Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver[J]. Drug Metab Rev, 2013, 45(1):48-59.
[9]
ALREFAI W A, GILL R K. Bile acid transporters:structure, function, regulation and pathophysiological implications[J]. Pharm Res, 2007, 24(10):1803-1823.
[10]
ANWER M S, STIEGER B. Sodium-dependent bile salt transporters of the SLC10A transporter family:more than solute transporters[J]. Pflugers Arch, 2014, 466(1):77-89.
[11]
GREUPINK R, NABUURS S B, ZARZYCKA B, et al. In silico identification of potential cholestasis-inducing agents via modeling of Na(+)-dependent taurocholate cotransporting polypeptide substrate specificity[J]. Toxicol Sci, 2012, 129(1):35-48.
[12]
DONG Z, EKINS S, POLLI J E. Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP)[J]. Mol Pharm, 2013, 10(3):1008-1019.
[13]
KOSTERS A, KARPEN S J. Bile acid transporters in health and disease[J]. Xenobiotica, 2008, 38(7-8):1043-1071.
[14]
DAWSON P A, LAN T, RAO A. Bile acid transporters[J]. J Lipid Res, 2009, 50(12):2340-2357.
[15]
JUNG D, HAGENBUCH B, FRIED M, et al. Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene[J]. Am J Physiol Gastrointest Liver Physiol, 2004, 286(5):752-761.
[16]
LI D, ZIMMERMAN T L, THEVANANTHER S, et al. Interleukin-1 beta-mediated suppression of RXR:RAR transactivation of the Ntcp promoter is JNK-dependent[J]. J Biol Chem, 2002, 277(35):31416-31422.
[17]
HOFMANN A F, HAGEY L R. Bile acids:chemistry, pathochemistry, biology, pathobiology, and therapeutics[J]. Cell Mol Life Sci, 2008, 65(16):2461-2483.
[18]
LI H, CHEN F, SHANG Q, et al. FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade[J]. Am J Physiol Gastrointest Liver Physiol, 2005, 288(1):60-66.
[19]
MATSUBARA T, LI F, GONZALEZ F J. FXR signaling in the enterohepatic system[J]. Mol Cell Endocrinol, 2013, 368(1-2):17-29.
[20]
SINHA J, CHEN F, MILOH T, et al. beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes[J]. Am J Physiol Gastrointest Liver Physiol, 2008, 295(5):996-1003.
[21]
ARRESE M, TRAUNER M, SACCHIERO R J, et al. Neither intestinal sequestration of bile acids nor common bile duct ligation modulate the expression and function of the rat ileal bile acid transporter[J]. Hepatology, 1998, 28(4):1081-1087.
[22]
KAZGAN N, METUKURI M R, PURUSHOTHAM A, et al. Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1alpha-FXR signaling and alters systemic bile acid homeostasis[J]. Gastroenterology, 2014, 146(4):1006-1016.
[23]
PARKER R A, GARCIA R, RYAN C S, et al. Bile acid and sterol metabolism with combined HMG-CoA reductase and PCSK9 suppression[J]. J Lipid Res, 2013, 54(9):2400-2409.
[24]
NEIMARK E, CHEN F, LI X, et al. c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter[J]. Gastroenterology, 2006, 131(2):554-567.
[25]
POUPON R. ASBT inhibitors in cholangiopathies-Good for mice, good for men?[J]. J Hepatol, 2016, 64(3):537-538.
[26]
IUSUF D, VAN DE STEEG E, SCHINKEL A H. Functions of OATP1A and 1B transporters in vivo:insights from mouse models[J]. Trends Pharmacol Sci, 2012, 33(2):100-108.
[27]
DAWSON P A, KARPEN S J. Intestinal transport and metabolism of bile acids[J]. J Lipid Res, 2015, 56(6):1085-1099.
[28]
MEYER Z S H, KIM R B. Hepatic OATP1B transporters and nuclear receptors PXR and CAR:interplay, regulation of drug disposition genes, and single nucleotide polymorphisms[J]. Mol Pharm, 2009, 6(6):1644-1661.
[29]
VAN DE STEEG E, STRANECKY V, HARTMANNOVA H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver[J]. J Clin Invest, 2012, 122(2):519-528.
[30]
SVOBODA M, RIHA J, WLCEK K, et al. Organic anion transporting polypeptides (OATPs):regulation of expression and function[J]. Curr Drug Metab, 2011, 12(2):139-153.
[31]
HAYASHI H, TAKADA T, SUZUKI H, et al. Transport by vesicles of glycine- and taurine-conjugated bile salts and taurolithocholate 3-sulfate:a comparison of human BSEP with rat Bsep[J]. Biochim Biophys Acta, 2005, 1738(1-3):54-62.
[32]
HIRANO M, MAEDA K, HAYASHI H, et al. Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin[J]. J Pharmacol Exp Ther, 2005, 314(2):876-882.
[33]
TELBISZ A, HOMOLYA L. Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function[J]. Expert Opin Ther Targets, 2016, 20(4):501-514.
[34]
WOODS A, HESLEGRAVE A J, MUCKETT P J, et al. LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice[J]. Biochem J, 2011, 434(1):49-60.
[35]
HOEKE M O, PLASS J R, HEEGSMA J, et al. Low retinol levels differentially modulate bile salt-induced expression of human and mouse hepatic bile salt transporters[J]. Hepatology, 2009, 49(1):151-159.
[36]
ANANTHANARAYANAN M, LI Y. PFIC2 and ethnicity-specific bile salt export pump (BSEP, ABCB11) mutations:where do we go from here?[J]. Liver Int, 2010, 30(6):777-779.
[37]
STINDT J, KLUGE S, DROGE C, et al. Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency[J]. Hepatology, 2016, 63(2):524-537.
[38]
WOODHEAD J L, YANG K, SILER S Q, et al. Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury[J]. Front Pharmacol, 2014, 5:240.
[39]
CHAI J, HE Y, CAI S Y, et al. Elevated hepatic multidrug resistance-associated protein 3/ATP-binding cassette subfamily C 3 expression in human obstructive cholestasis is mediated through tumor necrosis factor alpha and c-Jun NH2-terminal kinase/stress-activated protein kinase-signaling pathway[J]. Hepatology, 2012, 55(5):1485-1494.
[40]
MENNONE A, SOROKA C J, CAI S Y, et al. Mrp4-/- mice have an impaired cytoprotective response in obstructive cholestasis[J]. Hepatology, 2006, 43(5):1013-1021.
[41]
KOCK K, FERSLEW B C, NETTERBERG I, et al. Risk factors for development of cholestatic drug-induced liver injury:inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4[J]. Drug Metab Dispos, 2014, 42(4):665-674.
[42]
SOROKA C J, BALLATORI N, BOYER J L. Organic solute transporter, OSTalpha-OSTbeta:its role in bile acid transport and cholestasis[J]. Semin Liver Dis, 2010, 30(2):178-185.
[43]
BAGHDASARYAN A, CHIBA P, TRAUNER M. Clinical application of transcriptional activators of bile salt transporters[J]. Mol Aspects Med, 2014, 37:57-76.
[44]
BALLATORI N, CHRISTIAN W V, WHEELER S G, et al. The heteromeric organic solute transporter, OSTalpha-OSTbeta/SLC51:a transporter for steroid-derived molecules[J]. Mol Aspects Med, 2013, 34(2-3):683-692.
[45]
LEE Y K, SCHMIDT D R, CUMMINS C L, et al. Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis[J]. Mol Endocrinol, 2008, 22(6):1345-1356.
[46]
KHAN A A, CHOW E C, PORTE R J, et al. Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver[J]. Biopharm Drug Dispos, 2009, 30(5):241-258.
[47]
DING L, YANG L, WANG Z, et al. Bile acid nuclear receptor FXR and digestive system diseases[J]. Acta Pharm Sin B(ҩѧѧ�� Ӣ�İ�), 2015, 5(2):135-144.
[48]
ARAB J P, KARPEN S J, DAWSON P A, et al. Bile acids and nonalcoholic fatty liver disease:molecular insights and therapeutic perspectives[J]. Hepatology, 2016, 65(1):350-362.
[49]
PADDA M S, SANCHEZ M, AKHTAR A J, et al. Drug-induced cholestasis[J]. Hepatology, 2011, 53(4):1377-1387.
[50]
YANG D, BI-KUI Z, XIN-RONG F, et al. Evaluation on hepatoprotection in Nrf2/ARE oxidation/chemical stress defense pathway caused by isoliquiritigenin based on analysis of bile acids[J]. Chin Pharm J(�й�ҩѧ��־), 2015, 50(21):1905-1911.
2017, Vol. 52 
