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Semin Liver Dis 2010; 30(2): 160-177
DOI: 10.1055/s-0030-1253225
© Thieme Medical PublishersDOI: 10.1055/s-0030-1253225
Nuclear Receptor Regulation of the Adaptive Response of Bile Acid Transporters in Cholestasis
Weitere Informationen
Publikationsverlauf
Publikationsdatum:
26. April 2010 (online)
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
- 2 Boyer J L. It's all about bile. Hepatology. 2009; 49(3) 711-723
- 3 Wagner M, Zollner G, Trauner M. New molecular insights into the mechanisms of cholestasis. J Hepatol. 2009; 51(3) 565-580
- 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
- 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
- 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
- 7 Shulman A I, Mangelsdorf D J. Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med. 2005; 353(6) 604-615
- 8 Jensen E V. Estrogen receptor: ambiguities in the use of this term. Science. 1968; 159(820) 1261
- 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
- 10 Jansen P L, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport. Liver Int. 2003; 23(5) 315-322
- 11 Hofmann A F. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999; 159(22) 2647-2658
- 12 Chiang J Y. Bile acids: regulation of synthesis. J Lipid Res. 2009; , April 3 (Epub ahead of print)
- 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
- 14 Trauner M, Boyer J L. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev. 2003; 83(2) 633-671
- 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
- 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
- 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
- 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
- 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
- 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
- 21 Dawson P A, Lan T, Rao A. Bile acid transporters. J Lipid Res. 2009; 50(12) 2340-2357
- 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
- 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
- 24 Xia X, Francis H, Glaser S, Alpini G, LeSage G. Bile acid interactions with cholangiocytes. World J Gastroenterol. 2006; 12(22) 3553-3563
- 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
- 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
- 27 Arrese M, Trauner M. Molecular aspects of bile formation and cholestasis. Trends Mol Med. 2003; 9(12) 558-564
- 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
- 29 Anwer M S. Cellular regulation of hepatic bile acid transport in health and cholestasis. Hepatology. 2004; 39(3) 581-590
- 30 Mangelsdorf D J, Thummel C, Beato M et al.. The nuclear receptor superfamily: the second decade. Cell. 1995; 83(6) 835-839
- 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
- 32 Suchy F J, Ananthanarayanan M. Bile salt excretory pump: biology and pathobiology. J Pediatr Gastroenterol Nutr. 2006; 43(Suppl 1) S10-S16
- 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
- 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
- 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
- 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
- 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
- 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
MissingFormLabel
- 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
- 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
MissingFormLabel
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 87 Zollner G, Trauner M. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol. 2009; 156(1) 7-27
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 102 Brown J D, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation. 2007; 115(4) 518-533
- 103 Kota B P, Huang T H, Roufogalis B D. An overview on biological mechanisms of PPARs. Pharmacol Res. 2005; 51(2) 85-94
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 112 Tanaka H, Makino I. Ursodeoxycholic acid-dependent activation of the glucocorticoid receptor. Biochem Biophys Res Commun. 1992; 188(2) 942-948
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 121 Lee Y K, Moore D D. Liver receptor homolog-1, an emerging metabolic modulator. Front Biosci. 2008; 13 5950-5958
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 148 Paumgartner G, Pusl T. Medical treatment of cholestatic liver disease. Clin Liver Dis. 2008; 12(1) 53-80, viii , viii
- 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
- 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
- 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
- 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
- 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
- 154 Cullen S N, Chapman R W. The medical management of primary sclerosing cholangitis. Semin Liver Dis. 2006; 26(1) 52-61
- 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
- 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
- 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
- 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
- 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
- 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
- 161 Karpen S J. Exercising the nuclear option to treat cholestasis: CAR and PXR ligands. Hepatology. 2005; 42(2) 266-269
- 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
- 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
- 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
- 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
- 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
- 167 Fiorucci S, Baldelli F. Farnesoid X receptor agonists in biliary tract disease. Curr Opin Gastroenterol. 2009; 25(3) 252-259
- 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
- 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
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