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Semin Liver Dis 2010; 30(2): 160-177
DOI: 10.1055/s-0030-1253225
© Thieme Medical Publishers

Nuclear Receptor Regulation of the Adaptive Response of Bile Acid Transporters in Cholestasis

Martin Wagner1 , Gernot Zollner1 , Michael Trauner1
  • 1Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Publication History

Publication Date:
26 April 2010 (online)

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ABSTRACT

Although hereditary or acquired defects in hepatobiliary transporter systems cause or predispose to cholestasis, adaptive bile acid transporter changes can counteract cholestasis by reducing hepatocellular and systemic concentrations of retained cholephiles. An important level in the regulation of adaptive bile acid transporters and overflow pathways is mediated at the transcriptional level by nuclear hormone receptors. Moreover, therapeutic approaches targeting nuclear receptors in cholestasis may stimulate these adaptive changes and open a new perspective for the treatment of cholestatic liver diseases. This review gives a comprehensive overview on bile acid transporters in the enterohepatic circulation and their adaptive changes in response to cholestasis as well as the regulatory networks underlying these adaptive mechanisms.

KEYWORDS

ABC transporters - bile acids - bilirubin - cholestasis - enterohepatic circulation - multidrug resistance (associated) proteins - nuclear receptors - adaptation

REFERENCES

  • 1 Trauner M, Meier P J, Boyer J L. Molecular pathogenesis of cholestasis.  N Engl J Med. 1998;  339(17) 1217-1227
    CrossrefPubMedGoogle Scholar
  • 2 Boyer J L. It's all about bile.  Hepatology. 2009;  49(3) 711-723
    CrossrefPubMedGoogle Scholar
  • 3 Wagner M, Zollner G, Trauner M. New molecular insights into the mechanisms of cholestasis.  J Hepatol. 2009;  51(3) 565-580
    CrossrefPubMedGoogle Scholar
  • 4 Geier A, Wagner M, Dietrich C G, Trauner M. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration.  Biochim Biophys Acta. 2007;  1773(3) 283-308
    CrossrefPubMedGoogle Scholar
  • 5 Zollner G, Marschall H U, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations.  Mol Pharm. 2006;  3(3) 231-251
    CrossrefPubMedGoogle Scholar
  • 6 Chawla A, Repa J J, Evans R M, Mangelsdorf D J. Nuclear receptors and lipid physiology: opening the X-files.  Science. 2001;  294(5548) 1866-1870
    CrossrefPubMedGoogle Scholar
  • 7 Shulman A I, Mangelsdorf D J. Retinoid X receptor heterodimers in the metabolic syndrome.  N Engl J Med. 2005;  353(6) 604-615
    CrossrefPubMedGoogle Scholar
  • 8 Jensen E V. Estrogen receptor: ambiguities in the use of this term.  Science. 1968;  159(820) 1261
    CrossrefPubMedGoogle Scholar
  • 9 Hollenberg S M, Weinberger C, Ong E S et al.. Primary structure and expression of a functional human glucocorticoid receptor cDNA.  Nature. 1985;  318(6047) 635-641
    CrossrefPubMedGoogle Scholar
  • 10 Jansen P L, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport.  Liver Int. 2003;  23(5) 315-322
    CrossrefPubMedGoogle Scholar
  • 11 Hofmann A F. The continuing importance of bile acids in liver and intestinal disease.  Arch Intern Med. 1999;  159(22) 2647-2658
    CrossrefPubMedGoogle Scholar
  • 12 Chiang J Y. Bile acids: regulation of synthesis.  J Lipid Res. 2009;  , April 3 (Epub ahead of print)
    CrossrefPubMedGoogle Scholar
  • 13 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
    CrossrefPubMedGoogle Scholar
  • 14 Trauner M, Boyer J L. Bile salt transporters: molecular characterization, function, and regulation.  Physiol Rev. 2003;  83(2) 633-671
    CrossrefPubMedGoogle Scholar
  • 15 Trauner M, Wagner M, Fickert P, Zollner G. Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis.  J Clin Gastroenterol. 2005;  39(4, Suppl 2) S111-S124
    CrossrefPubMedGoogle Scholar
  • 16 Wagner M, Trauner M. Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis.  Ann Hepatol. 2005;  4(2) 77-99
    PubMedGoogle Scholar
  • 17 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
    CrossrefPubMedGoogle Scholar
  • 18 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
    CrossrefPubMedGoogle Scholar
  • 19 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
    CrossrefPubMedGoogle Scholar
  • 20 Soroka C J, Mennone A, Hagey L R, Ballatori N, Boyer J L. Mouse organic solute transporter alpha deficiency enhances renal excretion of bile acids and attenuates cholestasis.  Hepatology. 2010;  51(1) 181-190
    PubMedGoogle Scholar
  • 21 Dawson P A, Lan T, Rao A. Bile acid transporters.  J Lipid Res. 2009;  50(12) 2340-2357
    CrossrefPubMedGoogle Scholar
  • 22 Hruz P, Zimmermann C, Gutmann H et al.. Adaptive regulation of the ileal apical sodium dependent bile acid transporter (ASBT) in patients with obstructive cholestasis.  Gut. 2006;  55(3) 395-402
    CrossrefPubMedGoogle Scholar
  • 23 Alpini G, Ueno Y, Glaser S S et al.. Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes.  Hepatology. 2001;  34(5) 868-876
    CrossrefPubMedGoogle Scholar
  • 24 Xia X, Francis H, Glaser S, Alpini G, LeSage G. Bile acid interactions with cholangiocytes.  World J Gastroenterol. 2006;  12(22) 3553-3563
    PubMedGoogle Scholar
  • 25 Fujino T, Murakami K, Ozawa I et al.. Hypoxia downregulates farnesoid X receptor via a hypoxia-inducible factor-independent but p38 mitogen-activated protein kinase-dependent pathway.  FEBS J. 2009;  276(5) 1319-1332
    CrossrefPubMedGoogle Scholar
  • 26 Fouassier L, Beaussier M, Schiffer E et al.. Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes.  Am J Physiol Gastrointest Liver Physiol. 2007;  293(1) G25-G35
    CrossrefPubMedGoogle Scholar
  • 27 Arrese M, Trauner M. Molecular aspects of bile formation and cholestasis.  Trends Mol Med. 2003;  9(12) 558-564
    CrossrefPubMedGoogle Scholar
  • 28 Kullak-Ublick G A, Stieger B, Meier P J. Enterohepatic bile salt transporters in normal physiology and liver disease.  Gastroenterology. 2004;  126(1) 322-342
    CrossrefPubMedGoogle Scholar
  • 29 Anwer M S. Cellular regulation of hepatic bile acid transport in health and cholestasis.  Hepatology. 2004;  39(3) 581-590
    CrossrefPubMedGoogle Scholar
  • 30 Mangelsdorf D J, Thummel C, Beato M et al.. The nuclear receptor superfamily: the second decade.  Cell. 1995;  83(6) 835-839
    CrossrefPubMedGoogle Scholar
  • 31 Perissi V, Rosenfeld M G. Controlling nuclear receptors: the circular logic of cofactor cycles.  Nat Rev Mol Cell Biol. 2005;  6(7) 542-554
    CrossrefPubMedGoogle Scholar
  • 32 Suchy F J, Ananthanarayanan M. Bile salt excretory pump: biology and pathobiology.  J Pediatr Gastroenterol Nutr. 2006;  43(Suppl 1) S10-S16
    PubMedGoogle Scholar
  • 33 Gineste R, Sirvent A, Paumelle R et al.. Phosphorylation of farnesoid X receptor by protein kinase C promotes its transcriptional activity.  Mol Endocrinol. 2008;  22(11) 2433-2447
    CrossrefPubMedGoogle Scholar
  • 34 Chen F, Ellis E, Strom S C, Shneider B L. ATPase Class I Type 8B Member 1 and protein kinase C zeta induce the expression of the canalicular bile salt export pump in human hepatocytes.  Pediatr Res. 2010;  67(2) 183-187
    CrossrefPubMedGoogle Scholar
  • 35 Parks D J, Blanchard S G, Bledsoe R K et al.. Bile acids: natural ligands for an orphan nuclear receptor.  Science. 1999;  284(5418) 1365-1368
    CrossrefPubMedGoogle Scholar
  • 36 Makishima M, Okamoto A Y, Repa J J et al.. Identification of a nuclear receptor for bile acids.  Science. 1999;  284(5418) 1362-1365
    CrossrefPubMedGoogle Scholar
  • 37 Wang H, Chen J, Hollister K, Sowers L C, Forman B M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.  Mol Cell. 1999;  3(5) 543-553
    PubMedGoogle Scholar
  • 38 Makishima M, Lu T T, Xie W et al.. Vitamin D receptor as an intestinal bile acid sensor.  Science. 2002;  296(5571) 1313-1316
    Google Scholar
  • 39 Staudinger J L, Goodwin B, Jones S A et al.. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.  Proc Natl Acad Sci U S A. 2001;  98(6) 3369-3374
    CrossrefPubMedGoogle Scholar
  • 40 Xie W, Radominska-Pandya A, Shi Y et al.. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.  Proc Natl Acad Sci U S A. 2001;  98(6) 3375-3380
    Google Scholar
  • 41 Huang W, Zhang J, Chua S S et al.. Induction of bilirubin clearance by the constitutive androstane receptor (CAR).  Proc Natl Acad Sci U S A. 2003;  100(7) 4156-4161
    CrossrefPubMedGoogle Scholar
  • 42 Moore D D, Kato S, Xie W et al.. International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor.  Pharmacol Rev. 2006;  58(4) 742-759
    CrossrefPubMedGoogle Scholar
  • 43 Song C, Hiipakka R A, Liao S. Selective activation of liver X receptor alpha by 6alpha-hydroxy bile acids and analogs.  Steroids. 2000;  65(8) 423-427
    CrossrefPubMedGoogle Scholar
  • 44 Lu T T, Repa J J, Mangelsdorf D J. Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism.  J Biol Chem. 2001;  276(41) 37735-37738
    PubMedGoogle Scholar
  • 45 Pellicciari R, Fiorucci S, Camaioni E et al.. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity.  J Med Chem. 2002;  45(17) 3569-3572
    CrossrefPubMedGoogle Scholar
  • 46 Maloney P R, Parks D J, Haffner C D et al.. Identification of a chemical tool for the orphan nuclear receptor FXR.  J Med Chem. 2000;  43(16) 2971-2974
    CrossrefPubMedGoogle Scholar
  • 47 Fiorucci S, Rizzo G, Donini A, Distrutti E, Santucci L. Targeting farnesoid X receptor for liver and metabolic disorders.  Trends Mol Med. 2007;  13(7) 298-309
    CrossrefPubMedGoogle Scholar
  • 48 Duran-Sandoval D, Mautino G, Martin G et al.. Glucose regulates the expression of the farnesoid X receptor in liver.  Diabetes. 2004;  53(4) 890-898
    CrossrefPubMedGoogle Scholar
  • 49 Wagner M, Zollner G, Trauner M. Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-kappaB: new insights into hepatic inflammation.  Hepatology. 2008;  48(5) 1383-1386
    CrossrefPubMedGoogle Scholar
  • 50 Goodwin B, Jones S A, Price R R et al.. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.  Mol Cell. 2000;  6(3) 517-526
    CrossrefPubMedGoogle Scholar
  • 51 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
    CrossrefPubMedGoogle Scholar
  • 52 Lee Y K, Dell H, Dowhan D H, Hadzopoulou-Cladaras M, Moore D D. The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression.  Mol Cell Biol. 2000;  20(1) 187-195
    CrossrefPubMedGoogle Scholar
  • 53 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
    CrossrefPubMedGoogle Scholar
  • 54 Jung D, Hagenbuch B, Fried M, Meier P J, Kullak-Ublick G A. Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene.  Am J Physiol Gastrointest Liver Physiol. 2004;  286(5) G752-G761
    CrossrefPubMedGoogle Scholar
  • 55 Eloranta J J, Jung D, Kullak-Ublick G A. The human Na+-taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism.  Mol Endocrinol. 2006;  20(1) 65-79
    CrossrefPubMedGoogle Scholar
  • 56 Gupta S, Stravitz R T, Dent P, Hylemon P B. Down-regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway.  J Biol Chem. 2001;  276(19) 15816-15822
    CrossrefPubMedGoogle Scholar
  • 57 Alvaro D, Gigliozzi A, Marucci L et al.. Corticosteroids modulate the secretory processes of the rat intrahepatic biliary epithelium.  Gastroenterology. 2002;  122(4) 1058-1069
    CrossrefPubMedGoogle Scholar
  • 58 Bochkis I M, Rubins N E, White P, Furth E E, Friedman J R, Kaestner K H. Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress.  Nat Med. 2008;  14(8) 828-836
    CrossrefPubMedGoogle Scholar
  • 59 Eloranta J J, Kullak-Ublick G A. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism.  Arch Biochem Biophys. 2005;  433(2) 397-412
    CrossrefPubMedGoogle Scholar
  • 60 Jung D, Kullak-Ublick G A. Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression.  Hepatology. 2003;  37(3) 622-631
    CrossrefPubMedGoogle Scholar
  • 61 Shih D Q, Bussen M, Sehayek E et al.. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism.  Nat Genet. 2001;  27(4) 375-382
    CrossrefPubMedGoogle Scholar
  • 62 Hayhurst G P, Lee Y H, Lambert G, Ward J M, Gonzalez F J. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.  Mol Cell Biol. 2001;  21(4) 1393-1403
    CrossrefPubMedGoogle Scholar
  • 63 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
    CrossrefPubMedGoogle Scholar
  • 64 Li H, Chen F, Shang Q et al.. FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade.  Am J Physiol Gastrointest Liver Physiol. 2005;  288(1) G60-G66
    CrossrefPubMedGoogle Scholar
  • 65 Neimark E, Chen F, Li X, Shneider B L. Bile acid-induced negative feedback regulation of the human ileal bile acid transporter.  Hepatology. 2004;  40(1) 149-156
    CrossrefPubMedGoogle Scholar
  • 66 Sinha J, Chen F, Miloh T, Burns R C, Yu Z, Shneider B L. beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes.  Am J Physiol Gastrointest Liver Physiol. 2008;  295(5) G996-G1003
    CrossrefPubMedGoogle Scholar
  • 67 Miao J, Xiao Z, Kanamaluru D et al.. Bile acid signaling pathways increase stability of small heterodimer partner (SHP) by inhibiting ubiquitin-proteasomal degradation.  Genes Dev. 2009;  23(8) 986-996
    CrossrefPubMedGoogle Scholar
  • 68 Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf D J, Suchy F J. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor.  J Biol Chem. 2001;  276(31) 28857-28865
    CrossrefPubMedGoogle Scholar
  • 69 Kast H R, Goodwin B, Tarr P T et al.. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor.  J Biol Chem. 2002;  277(4) 2908-2915
    CrossrefPubMedGoogle Scholar
  • 70 Denson L A, Auld K L, Schiek D S, McClure M H, Mangelsdorf D J, Karpen S J. Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation.  J Biol Chem. 2000;  275(12) 8835-8843
    CrossrefPubMedGoogle Scholar
  • 71 Huang L, Zhao A, Lew J L et al.. Farnesoid X receptor activates transcription of the phospholipid pump MDR3.  J Biol Chem. 2003;  278(51) 51085-51090
    CrossrefPubMedGoogle Scholar
  • 72 Moschetta A, Bookout A L, Mangelsdorf D J. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model.  Nat Med. 2004;  10(12) 1352-1358
    CrossrefPubMedGoogle Scholar
  • 73 Fickert P, Fuchsbichler A, Wagner M et al.. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.  Gastroenterology. 2004;  127(1) 261-274
    CrossrefPubMedGoogle Scholar
  • 74 Smit J J, Schinkel A H, Oude Elferink R P et al.. Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.  Cell. 1993;  75(3) 451-462
    CrossrefPubMedGoogle Scholar
  • 75 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-alpha and -beta genes.  Am J Physiol Gastrointest Liver Physiol. 2006;  290(3) G476-G485
    CrossrefPubMedGoogle Scholar
  • 76 Kim I, Ahn S H, Inagaki T et al.. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine.  J Lipid Res. 2007;  48(12) 2664-2672
    CrossrefPubMedGoogle Scholar
  • 77 Schaap F G, van der Gaag N A, Gouma D J, Jansen P L. 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
    CrossrefPubMedGoogle Scholar
  • 78 Lehmann J M, McKee D D, Watson M A, Willson T M, Moore J T, Kliewer S A. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.  J Clin Invest. 1998;  102(5) 1016-1023
    CrossrefPubMedGoogle Scholar
  • 79 Zhang H, LeCulyse E, Liu L et al.. Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation.  Arch Biochem Biophys. 1999;  368(1) 14-22
    CrossrefPubMedGoogle Scholar
  • 80 Moore L B, Parks D J, Jones S A et al.. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands.  J Biol Chem. 2000;  275(20) 15122-15127
    CrossrefPubMedGoogle Scholar
  • 81 Schuetz E G, Strom S, Yasuda K et al.. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450.  J Biol Chem. 2001;  276(42) 39411-39418
    CrossrefPubMedGoogle Scholar
  • 82 Frank C, Gonzalez M M, Oinonen C, Dunlop T W, Carlberg C. Characterization of DNA complexes formed by the nuclear receptor constitutive androstane receptor.  J Biol Chem. 2003;  278(44) 43299-43310
    CrossrefPubMedGoogle Scholar
  • 83 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
    CrossrefPubMedGoogle Scholar
  • 84 Marschall H U, Wagner M, Zollner G et al.. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans.  Gastroenterology. 2005;  129(2) 476-485
    CrossrefPubMedGoogle Scholar
  • 85 Teng S, Jekerle V, Piquette-Miller M. Induction of ABCC3 (MRP3) by pregnane X receptor activators.  Drug Metab Dispos. 2003;  31(11) 1296-1299
    CrossrefPubMedGoogle Scholar
  • 86 Jung D, Mangelsdorf D J, Meyer U A. Pregnane X receptor is a target of farnesoid X receptor.  J Biol Chem. 2006;  281(28) 19081-19091
    CrossrefPubMedGoogle Scholar
  • 87 Zollner G, Trauner M. Nuclear receptors as therapeutic targets in cholestatic liver diseases.  Br J Pharmacol. 2009;  156(1) 7-27
    CrossrefPubMedGoogle Scholar
  • 88 Gascon-Barré M, Demers C, Mirshahi A, Néron S, Zalzal S, Nanci A. The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells.  Hepatology. 2003;  37(5) 1034-1042
    CrossrefPubMedGoogle Scholar
  • 89 McCarthy T C, Li X, Sinal C J. Vitamin D receptor-dependent regulation of colon multidrug resistance-associated protein 3 gene expression by bile acids.  J Biol Chem. 2005;  280(24) 23232-23242
    CrossrefPubMedGoogle Scholar
  • 90 Echchgadda I, Song C S, Roy A K, Chatterjee B. Dehydroepiandrosterone sulfotransferase is a target for transcriptional induction by the vitamin D receptor.  Mol Pharmacol. 2004;  65(3) 720-729
    CrossrefPubMedGoogle Scholar
  • 91 Chen X, Chen F, Liu S et al.. Transactivation of rat apical sodium-dependent bile acid transporter and increased bile acid transport by 1alpha,25-dihydroxyvitamin D3 via the vitamin D receptor.  Mol Pharmacol. 2006;  69(6) 1913-1923
    CrossrefPubMedGoogle Scholar
  • 92 Honjo Y, Sasaki S, Kobayashi Y, Misawa H, Nakamura H. 1,25-dihydroxyvitamin D3 and its receptor inhibit the chenodeoxycholic acid-dependent transactivation by farnesoid X receptor.  J Endocrinol. 2006;  188(3) 635-643
    CrossrefPubMedGoogle Scholar
  • 93 Chow E C, Maeng H J, Liu S, Khan A A, Groothuis G M, Pang K S. 1alpha,25-Dihydroxyvitamin D(3) triggered vitamin D receptor and farnesoid X receptor-like effects in rat intestine and liver in vivo.  Biopharm Drug Dispos. 2009;  30(8) 457-475
    CrossrefPubMedGoogle Scholar
  • 94 Khan A A, Chow E C, Porte R J, Pang K S, Groothuis G M. Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver.  Biopharm Drug Dispos. 2009;  30(5) 241-258
    CrossrefPubMedGoogle Scholar
  • 95 Han S, Chiang J Y. Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes.  Drug Metab Dispos. 2009;  37(3) 469-478
    CrossrefPubMedGoogle Scholar
  • 96 Jiang W, Miyamoto T, Kakizawa T et al.. Inhibition of LXRalpha signaling by vitamin D receptor: possible role of VDR in bile acid synthesis.  Biochem Biophys Res Commun. 2006;  351(1) 176-184
    CrossrefPubMedGoogle Scholar
  • 97 D'Aldebert E, Biyeyeme Bi Mve M J, Mergey M et al.. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium.  Gastroenterology. 2009;  136(4) 1435-1443
    CrossrefPubMedGoogle Scholar
  • 98 Karpen S J, Sun A Q, Kudish B et al.. Multiple factors regulate the rat liver basolateral sodium-dependent bile acid cotransporter gene promoter.  J Biol Chem. 1996;  271(25) 15211-15221
    CrossrefPubMedGoogle Scholar
  • 99 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.  Hepatology. 2009;  49(1) 151-159
    CrossrefPubMedGoogle Scholar
  • 100 Chen W, Cai S Y, Xu S, Denson L A, Soroka C J, Boyer J L. Nuclear receptors RXRalpha:RARalpha are repressors for human MRP3 expression.  Am J Physiol Gastrointest Liver Physiol. 2007;  292(5) G1221-G1227
    CrossrefPubMedGoogle Scholar
  • 101 Gyamfi M A, Wan Y J. Mechanisms of resistance of hepatocyte retinoid X receptor alpha-null mice to WY-14,643-induced hepatocyte proliferation and cholestasis.  J Biol Chem. 2009;  284(14) 9321-9330
    CrossrefPubMedGoogle Scholar
  • 102 Brown J D, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets.  Circulation. 2007;  115(4) 518-533
    CrossrefPubMedGoogle Scholar
  • 103 Kota B P, Huang T H, Roufogalis B D. An overview on biological mechanisms of PPARs.  Pharmacol Res. 2005;  51(2) 85-94
    CrossrefPubMedGoogle Scholar
  • 104 Nakata K, Tanaka Y, Nakano T et al.. Nuclear receptor-mediated transcriptional regulation in phase I, II, and III xenobiotic metabolizing systems.  Drug Metab Pharmacokinet. 2006;  21(6) 437-457
    CrossrefPubMedGoogle Scholar
  • 105 Hunt M C, Yang Y Z, Eggertsen G et al.. The peroxisome proliferator-activated receptor alpha (PPARalpha) regulates bile acid biosynthesis.  J Biol Chem. 2000;  275(37) 28947-28953
    CrossrefPubMedGoogle Scholar
  • 106 Patel D D, Knight B L, Soutar A K, Gibbons G F, Wade D P. The effect of peroxisome-proliferator-activated receptor-alpha on the activity of the cholesterol 7 alpha-hydroxylase gene.  Biochem J. 2000;  351(Pt 3) 747-753
    CrossrefPubMedGoogle Scholar
  • 107 Barbier O, Villeneuve L, Bocher V et al.. The UDP-glucuronosyltransferase 1A9 enzyme is a peroxisome proliferator-activated receptor alpha and gamma target gene.  J Biol Chem. 2003;  278(16) 13975-13983
    CrossrefPubMedGoogle Scholar
  • 108 Fang H L, Strom S C, Cai H, Falany C N, Kocarek T A, Runge-Morris M. Regulation of human hepatic hydroxysteroid sulfotransferase gene expression by the peroxisome proliferator-activated receptor alpha transcription factor.  Mol Pharmacol. 2005;  67(4) 1257-1267
    CrossrefPubMedGoogle Scholar
  • 109 Marrapodi M, Chiang J Y. Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription.  J Lipid Res. 2000;  41(4) 514-520
    PubMedGoogle Scholar
  • 110 Kok T, Bloks V W, Wolters H et al.. Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice.  Biochem J. 2003;  369(Pt 3) 539-547
    CrossrefPubMedGoogle Scholar
  • 111 Jung D, Fried M, Kullak-Ublick G A. Human apical sodium-dependent bile salt transporter gene (SLC10A2) is regulated by the peroxisome proliferator-activated receptor alpha.  J Biol Chem. 2002;  277(34) 30559-30566
    CrossrefPubMedGoogle Scholar
  • 112 Tanaka H, Makino I. Ursodeoxycholic acid-dependent activation of the glucocorticoid receptor.  Biochem Biophys Res Commun. 1992;  188(2) 942-948
    CrossrefPubMedGoogle Scholar
  • 113 Miura T, Ouchida R, Yoshikawa N et al.. Functional modulation of the glucocorticoid receptor and suppression of NF-kappaB-dependent transcription by ursodeoxycholic acid.  J Biol Chem. 2001;  276(50) 47371-47378
    CrossrefPubMedGoogle Scholar
  • 114 Jung D, Fantin A C, Scheurer U, Fried M, Kullak-Ublick G A. Human ileal bile acid transporter gene ASBT (SLC10A2) is transactivated by the glucocorticoid receptor.  Gut. 2004;  53(1) 78-84
    CrossrefPubMedGoogle Scholar
  • 115 Courtois A, Payen L, Guillouzo A, Fardel O. Up-regulation of multidrug resistance-associated protein 2 (MRP2) expression in rat hepatocytes by dexamethasone.  FEBS Lett. 1999;  459(3) 381-385
    CrossrefPubMedGoogle Scholar
  • 116 Pułaski L, Kania K, Ratajewski M, Uchiumi T, Kuwano M, Bartosz G. Differential regulation of the human MRP2 and MRP3 gene expression by glucocorticoids.  J Steroid Biochem Mol Biol. 2005;  96(3-4) 229-234
    CrossrefPubMedGoogle Scholar
  • 117 Nishimura M, Koeda A, Suzuki E et al.. Regulation of mRNA expression of MDR1, MRP1, MRP2 and MRP3 by prototypical microsomal enzyme inducers in primary cultures of human and rat hepatocytes.  Drug Metab Pharmacokinet. 2006;  21(4) 297-307
    CrossrefPubMedGoogle Scholar
  • 118 Arenas F, Hervias I, Uriz M, Joplin R, Prieto J, Medina J F. Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells.  J Clin Invest. 2008;  118(2) 695-709
    PubMedGoogle Scholar
  • 119 Prieto J, Qian C, García N, Díez J, Medina J F. Abnormal expression of anion exchanger genes in primary biliary cirrhosis.  Gastroenterology. 1993;  105(2) 572-578
    CrossrefPubMedGoogle Scholar
  • 120 Drocourt L, Ourlin J C, Pascussi J M, Maurel P, Vilarem M J. Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes.  J Biol Chem. 2002;  277(28) 25125-25132
    CrossrefPubMedGoogle Scholar
  • 121 Lee Y K, Moore D D. Liver receptor homolog-1, an emerging metabolic modulator.  Front Biosci. 2008;  13 5950-5958
    PubMedGoogle Scholar
  • 122 Fayard E, Auwerx J, Schoonjans K. LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis.  Trends Cell Biol. 2004;  14(5) 250-260
    CrossrefPubMedGoogle Scholar
  • 123 Song X, Kaimal R, Yan B, Deng R. Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression.  J Lipid Res. 2008;  49(5) 973-984
    CrossrefPubMedGoogle Scholar
  • 124 Matsukuma K E, Wang L, Bennett M K, Osborne T F. A key role for orphan nuclear receptor liver receptor homologue-1 in activation of fatty acid synthase promoter by liver X receptor.  J Biol Chem. 2007;  282(28) 20164-20171
    CrossrefPubMedGoogle Scholar
  • 125 Iwaki M, Matsuda M, Maeda N et al.. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors.  Diabetes. 2003;  52(7) 1655-1663
    CrossrefPubMedGoogle Scholar
  • 126 Lee Y K, Moore D D. Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner.  J Biol Chem. 2002;  277(4) 2463-2467
    CrossrefPubMedGoogle Scholar
  • 127 Chen F, Ma L, Dawson P A et al.. Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter.  J Biol Chem. 2003;  278(22) 19909-19916
    CrossrefPubMedGoogle Scholar
  • 128 Inokuchi A, Hinoshita E, Iwamoto Y, Kohno K, Kuwano M, Uchiumi T. Enhanced expression of the human multidrug resistance protein 3 by bile salt in human enterocytes. A transcriptional control of a plausible bile acid transporter.  J Biol Chem. 2001;  276(50) 46822-46829
    CrossrefPubMedGoogle Scholar
  • 129 Frankenberg T, Rao A, Chen F, Haywood J, Shneider B L, Dawson P A. Regulation of the mouse organic solute transporter alpha-beta, Ostalpha-Ostbeta, by bile acids.  Am J Physiol Gastrointest Liver Physiol. 2006;  290(5) G912-G922
    PubMedGoogle Scholar
  • 130 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.  Mol Endocrinol. 2008;  22(6) 1345-1356
    CrossrefPubMedGoogle Scholar
  • 131 Mataki C, Magnier B C, Houten S M et al.. Compromised intestinal lipid absorption in mice with a liver-specific deficiency of liver receptor homolog 1.  Mol Cell Biol. 2007;  27(23) 8330-8339
    CrossrefPubMedGoogle Scholar
  • 132 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.  Mol Endocrinol. 2008;  22(6) 1345-1356
    CrossrefPubMedGoogle Scholar
  • 133 Zhang D D, Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress.  Mol Cell Biol. 2003;  23(22) 8137-8151
    CrossrefPubMedGoogle Scholar
  • 134 Itoh K, Chiba T, Takahashi S et al.. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.  Biochem Biophys Res Commun. 1997;  236(2) 313-322
    CrossrefPubMedGoogle Scholar
  • 135 Tan K P, Yang M, Ito S. Activation of nuclear factor (erythroid-2 like) factor 2 by toxic bile acids provokes adaptive defense responses to enhance cell survival at the emergence of oxidative stress.  Mol Pharmacol. 2007;  72(5) 1380-1390
    CrossrefPubMedGoogle Scholar
  • 136 Vollrath V, Wielandt A M, Iruretagoyena M, Chianale J. Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene.  Biochem J. 2006;  395(3) 599-609
    CrossrefPubMedGoogle Scholar
  • 137 Maher J M, Dieter M Z, Aleksunes L M et al.. Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway.  Hepatology. 2007;  46(5) 1597-1610
    CrossrefPubMedGoogle Scholar
  • 138 Weerachayaphorn J, Cai S Y, Soroka C J, Boyer J L. Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression.  Hepatology. 2009;  50(5) 1588-1596
    CrossrefPubMedGoogle Scholar
  • 139 Okada K, Shoda J, Taguchi K et al.. Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems.  Biochem Biophys Res Commun. 2009;  389(3) 431-436
    CrossrefPubMedGoogle Scholar
  • 140 Wang Y D, Chen W D, Wang M, Yu D, Forman B M, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response.  Hepatology. 2008;  48(5) 1632-1643
    CrossrefPubMedGoogle Scholar
  • 141 Zhou C, Tabb M M, Nelson E L et al.. Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation.  J Clin Invest. 2006;  116(8) 2280-2289
    CrossrefPubMedGoogle Scholar
  • 142 Farmer P K, He X, Schmitz M L, Rubin J, Nanes M S. Inhibitory effect of NF-kappaB on 1,25-dihydroxyvitamin D(3) and retinoid X receptor function.  Am J Physiol Endocrinol Metab. 2000;  279(1) E213-E220
    PubMedGoogle Scholar
  • 143 Fiorucci S, Antonelli E, Rizzo G et al.. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis.  Gastroenterology. 2004;  127(5) 1497-1512
    CrossrefPubMedGoogle Scholar
  • 144 Fickert P, Fuchsbichler A, Moustafa T et al.. Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts.  Am J Pathol. 2009;  175(6) 2392-2405
    CrossrefPubMedGoogle Scholar
  • 145 Marek C J, Tucker S J, Konstantinou D K et al.. Pregnenolone-16alpha-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms.  Biochem J. 2005;  387(Pt 3) 601-608
    CrossrefPubMedGoogle Scholar
  • 146 Fiorucci S, Rizzo G, Antonelli E et al.. Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis.  J Pharmacol Exp Ther. 2005;  315(1) 58-68
    CrossrefPubMedGoogle Scholar
  • 147 Fiorucci S, Rizzo G, Antonelli E et al.. A farnesoid X receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis.  J Pharmacol Exp Ther. 2005;  314(2) 584-595
    CrossrefPubMedGoogle Scholar
  • 148 Paumgartner G, Pusl T. Medical treatment of cholestatic liver disease.  Clin Liver Dis. 2008;  12(1) 53-80, viii , viii
    CrossrefPubMedGoogle Scholar
  • 149 Lew J L, Zhao A, Yu J et al.. The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion.  J Biol Chem. 2004;  279(10) 8856-8861
    CrossrefPubMedGoogle Scholar
  • 150 Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis.  Nat Clin Pract Gastroenterol Hepatol. 2006;  3(6) 318-328
    CrossrefPubMedGoogle Scholar
  • 151 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
    CrossrefPubMedGoogle Scholar
  • 152 Corpechot C, Abenavoli L, Rabahi N et al.. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis.  Hepatology. 2008;  48(3) 871-877
    CrossrefPubMedGoogle Scholar
  • 153 Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid.  Gastroenterology. 2006;  130(3) 715-720
    CrossrefPubMedGoogle Scholar
  • 154 Cullen S N, Chapman R W. The medical management of primary sclerosing cholangitis.  Semin Liver Dis. 2006;  26(1) 52-61
    Article in Thieme ConnectPubMedGoogle Scholar
  • 155 Lindor K D. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group . Ursodiol for primary sclerosing cholangitis.  N Engl J Med. 1997;  336(10) 691-695
    CrossrefPubMedGoogle Scholar
  • 156 Lindor K D, Kowdley K V, Luketic V A et al.. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.  Hepatology. 2009;  50(3) 808-814
    CrossrefPubMedGoogle Scholar
  • 157 Fickert P, Wagner M, Marschall H U et al.. 24-norursodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.  Gastroenterology. 2006;  130(2) 465-481
    CrossrefPubMedGoogle Scholar
  • 158 Yoon Y B, Hagey L R, Hofmann A F, Gurantz D, Michelotti E L, Steinbach J H. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents.  Gastroenterology. 1986;  90(4) 837-852
    PubMedGoogle Scholar
  • 159 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
    CrossrefPubMedGoogle Scholar
  • 160 Chen H L, Liu Y J, Chen H L et al.. Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia.  Pediatr Res. 2008;  63(6) 667-673
    CrossrefPubMedGoogle Scholar
  • 161 Karpen S J. Exercising the nuclear option to treat cholestasis: CAR and PXR ligands.  Hepatology. 2005;  42(2) 266-269
    CrossrefPubMedGoogle Scholar
  • 162 Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients?.  J Gastroenterol. 2003;  38(6) 573-578
    PubMedGoogle Scholar
  • 163 Nakai S, Masaki T, Kurokohchi K, Deguchi A, Nishioka M. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study.  Am J Gastroenterol. 2000;  95(1) 326-327
    CrossrefPubMedGoogle Scholar
  • 164 Ritzel U, Leonhardt U, Näther M, Schäfer G, Armstrong V W, Ramadori G. Simvastatin in primary biliary cirrhosis: effects on serum lipids and distinct disease markers.  J Hepatol. 2002;  36(4) 454-458
    CrossrefPubMedGoogle Scholar
  • 165 Ogura M, Nishida S, Ishizawa M et al.. Vitamin D3 modulates the expression of bile acid regulatory genes and represses inflammation in bile duct-ligated mice.  J Pharmacol Exp Ther. 2009;  328(2) 564-570
    CrossrefPubMedGoogle Scholar
  • 166 Tanaka A, Nezu S, Uegaki S et al.. Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations.  J Hepatol. 2009;  50(6) 1202-1209
    CrossrefPubMedGoogle Scholar
  • 167 Fiorucci S, Baldelli F. Farnesoid X receptor agonists in biliary tract disease.  Curr Opin Gastroenterol. 2009;  25(3) 252-259
    CrossrefPubMedGoogle Scholar
  • 168 Inagaki T, Moschetta A, Lee Y K et al.. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor.  Proc Natl Acad Sci U S A. 2006;  103(10) 3920-3925
    CrossrefPubMedGoogle Scholar
  • 169 Liu Y, Binz J, Numerick M J et al.. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.  J Clin Invest. 2003;  112(11) 1678-1687
    CrossrefPubMedGoogle Scholar

Michael TraunerM.D. 

Division of Gastroenterology and Hepatology, Department of Internal Medicine

Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria

Email: michael.trauner@meduni-graz.at

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