Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: An overview of their mechanisms of action

Raoul Poupon1
1Service d’Hépatologie et Centre de Référence des maladies inflammatoires des voies biliaires, Hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France; UPMC University Paris 06, INSERM, UMR-S 938, Paris, France

Tài liệu tham khảo

Makishima, 1999, Identification of a nuclear receptor for bile acids, Science, 284, 1362, 10.1126/science.284.5418.1362 Parks, 1999, Bile acids: natural ligands for an orphan nuclear receptor, Science, 284, 1365, 10.1126/science.284.5418.1365 Wang, 1999, Endogenous bile acids are ligands for the nuclear receptor FXR/BAR, Mol Cell, 3, 543, 10.1016/S1097-2765(00)80348-2 Maruyama, 2002, Identification of membranetype receptor for bile acids (M-BAR), Biochem Biophys Res Commun, 298, 714, 10.1016/S0006-291X(02)02550-0 Kawamata, 2003, A G protein-coupled receptor responsive to bile acids, J Biol Chem, 278, 9435, 10.1074/jbc.M209706200 Hofmann, 1984, Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem, J Lipid Res, 25, 1477, 10.1016/S0022-2275(20)34421-7 Hofmann, 1992, Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions, J Lipid Res, 33, 617, 10.1016/S0022-2275(20)41426-9 Holsti, 1956, Experimental cirrhosis of the liver in rabbits induced by gastric instillation of desiccated whole bile, Acta Pathol Microbiol Scand Suppl, 39, 1 Schmucker, 1990, Hepatic injury induced by bile salts: correlation between biochemical and morphological events, Hepatology, 12, 1216, 10.1002/hep.1840120523 Becker, 2007, Hydrophobic bile salts induce hepatocyte shrinkage via NADPH oxidase activation, Cell Physiol Biochem, 19, 89, 10.1159/000099197 Reinehr, 2005, Bile salt-induced apoptosis involves NADPH oxidase isoform activation, Gastroenterology, 129, 2009, 10.1053/j.gastro.2005.09.023 Allen, 2011, Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis, Am J Pathol, 178, 175, 10.1016/j.ajpath.2010.11.026 Calmus, 1992, Cholestasis induces major histocompatibility complex class I expression in hepatocytes, Gastroenterology, 102, 1371, 10.1016/0016-5085(92)90778-W Hillaire, 1994, Effects of bile acids and cholestasis on major histocompatibility complex class I in human and rat hepatocytes, Gastroenterology, 107, 781, 10.1016/0016-5085(94)90127-9 Arvieux, 1993, Immunogenicity of rat hepatocytes in vivo: effect of cholestasis-induced changes in major histocompatibility complex expression, J Hepatol, 18, 335, 10.1016/S0168-8278(05)80278-8 Calmus, 1992, Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes, Hepatology, 16, 719, 10.1002/hep.1840160317 Podevin, 1995, Effect of cholestasis and bile acids on interferoninduced 2’,5’-adenylate synthetase and NK cell activities, Gastroenterology, 108, 1192, 10.1016/0016-5085(95)90219-8 Podevin, 1999, Bile acids modulate the interferon signalling pathway, Hepatology, 29, 1840, 10.1002/hep.510290617 Fiorucci, 2010, Counter-regulatory role of bile acid activated receptors in immunity and inflammation, Curr Mol Med, 10, 579 Poupon, 1987, Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis?, Lancet, 1, 834, 10.1016/S0140-6736(87)91610-2 Poupon, 1994, Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group, N Engl J Med, 330, 1342, 10.1056/NEJM199405123301903 Poupon, 1997, Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis, Gastroenterology, 113, 884, 10.1016/S0016-5085(97)70183-5 Lindor, 2009, High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis, Hepatology, 50, 808, 10.1002/hep.23082 Crosignani, 1996, Clinical pharmacokinetics of therapeutic bile acids, Clin Pharmacokinet, 30, 333, 10.2165/00003088-199630050-00002 Bachrach, 1982, Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Part II, Dig Dis Sci, 27, 833, 10.1007/BF01391378 Lanzini, 2003, Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration, Gut, 52, 1371, 10.1136/gut.52.9.1371 Chazouilleres, 1996, Ileal absorption of bile acids in patients with chronic cholestasis: SeHCAT test results and effect of ursodeoxycholic acid (UDCA), Dig Dis Sci, 41, 2417, 10.1007/BF02100137 Stiehl, 1995, Intestinal absorption of bile acids: effect of ursodeoxycholic acid treatment, Ital J Gastroenterol, 27, 193 Jazrawi, 1994, Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid, Gastroenterology, 106, 134, 10.1016/S0016-5085(94)94899-2 Beuers, 1992, Effect of ursodeoxycholic acid on the kinetics of the major hydrophobic bile acids in health and in chronic cholestatic liver disease, Hepatology, 15, 603, 10.1002/hep.1840150409 Poupon, 1995, Ursodeoxycholic acid therapy of chronic cholestatic conditions in adults and children, Pharmacol Ther, 66, 1, 10.1016/0163-7258(94)00073-C Spirli, 2003, Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes, Gastroenterology, 124, 737, 10.1053/gast.2003.50100 Spirli, 2001, Proinflammatory cytokines inhibit secretion in rat bile duct epithelium, Gastroenterology, 121, 156, 10.1053/gast.2001.25516 Prieto, 1993, Abnormal expression of anion exchanger genes in primary biliary cirrhosis, Gastroenterology, 105, 572, 10.1016/0016-5085(93)90735-U Prieto, 1999, Assessment of biliary bicarbonate secretion in humans by positron emission tomography, Gastroenterology, 117, 167, 10.1016/S0016-5085(99)70564-0 Arenas, 2008, Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells, J Clin Invest, 118, 695 Paumgartner, 2004, Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease, Clin Liver Dis, 8, 67, 10.1016/S1089-3261(03)00135-1 Uriz, 2011, Ursodeoxycholic acid is conjugated with taurine to promote secretinstimulated biliary hydrocholeresis in the normal rat, PLoS One, 6, e28717, 10.1371/journal.pone.0028717 Ikebuchi Y, Shimizu H, Ito K, Yoshikado T, Yamanashi Y, Takada T, Suzuki H. Ursodeoxycholic acid stimulates the formation of the bile canalicular network. Biochem Pharmacol 2012;In press. Guldutuna, 1993, Molecular aspects of membrane stabilization by ursodeoxycholate [see comment], Gastroenterology, 104, 1736, 10.1016/0016-5085(93)90653-T Rodrigues, 1998, Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production, Mol Med, 4, 165, 10.1007/BF03401914 Mitsuyoshi, 1999, Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants, Biochem Biophys Res Commun, 263, 537, 10.1006/bbrc.1999.1403 Ljubuncic, 2000, Ursodeoxycholic acid suppresses extent of lipid peroxidation in diseased liver in experimental cholestatic liver disease, Dig Dis Sci, 45, 1921, 10.1023/A:1005615306596 Rodriguez-Ortigosa, 2002, Effect of ursodeoxycholic acid on methionine adenosyltransferase activity and hepatic glutathione metabolism in rats, Gut, 50, 701, 10.1136/gut.50.5.701 Bernstein, 2002, Activation of the metallothionein IIA promoter and other key stress response elements by ursodeoxycholate in HepG2 cells: relevance to the cytoprotective function of ursodeoxycholate, Pharmacology, 65, 2, 10.1159/000056179 Lapenna, 2002, Antioxidant properties of ursodeoxycholic acid, Biochem Pharmacol, 64, 1661, 10.1016/S0006-2952(02)01391-6 Kawata, 2010, Enhanced hepatic Nrf2 activation after ursodeoxycholic acid treatment in patients with primary biliary cirrhosis, Antioxid Redox Signal, 13, 259, 10.1089/ars.2009.2903 Yang, 2009, Dysregulation of glutathione synthesis during cholestasis in mice: molecular mechanisms and therapeutic implications, Hepatology, 49, 1982, 10.1002/hep.22908 Arisawa, 2009, Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells, Biochem Pharmacol, 77, 858, 10.1016/j.bcp.2008.11.012 Okada, 2008, Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice, Am J Physiol Gastrointest Liver Physiol, 295, G735, 10.1152/ajpgi.90321.2008 Koga, 1997, Nuclear DNA fragmentation and expression of Bcl-2 in primary biliary cirrhosis, Hepatology, 25, 1077, 10.1002/hep.510250505 Allina, 2006, T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis, J Autoimmun, 27, 232, 10.1016/j.jaut.2006.11.004 Xie, 2002, Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation, Hepatology, 36, 592, 10.1053/jhep.2002.35441 Qiao, 2002, Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes, Hepatology, 35, 779, 10.1053/jhep.2002.32533 Schoemaker, 2004, Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways, Hepatology, 39, 1563, 10.1002/hep.20246 Sola, 2004, Modulation of nuclear steroid receptors by ursodeoxycholic acid inhibits TGF-beta1-induced E2F-1/p53-mediated apoptosis of rat hepatocytes, Biochemistry, 43, 8429, 10.1021/bi049781x Amaral, 2010, The role of p53 in apoptosis, Discov Med, 9, 145 Calmus, 1990, Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid, Hepatology, 11, 12, 10.1002/hep.1840110104 Tanaka, 1996, Ligand-independent activation of the glucocorticoid receptor by ursodeoxycholic acid. Repression of IFN-gamma-induced MHC class II gene expression via a glucocorticoid receptor-dependent pathway, J Immunol, 156, 1601, 10.4049/jimmunol.156.4.1601 Takahashi, 2012, Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis, Hepatology, 55, 846, 10.1002/hep.24757 Kikuchi, 2009, Ursodeoxycholic acid reduces CpG-induced IgM production in patients with primary biliary cirrhosis, Hepatol Res, 39, 448, 10.1111/j.1872-034X.2008.00474.x Yoshikawa, 1992, Immunomodulatory effects of ursodeoxycholic acid on immune responses, Hepatology, 16, 358, 10.1002/hep.1840160213 Ishizaki, 2008, Ursodeoxycholic acid protects concanavalin A-induced mouse liver injury through inhibition of intrahepatic tumor necrosis factor-alpha and macrophage inflammatory protein-2 production, Eur J Pharmacol, 578, 57, 10.1016/j.ejphar.2007.08.031 Unitt, 2011, Plant lectins are novel Toll-like receptor agonists, Biochem Pharmacol, 81, 1324, 10.1016/j.bcp.2011.03.010 Tu, 2012, Curcumin attenuates Concanavalin A-induced liver injury in mice by inhibition of Toll-like receptor (TLR) 2, TLR4 and TLR9 expression, Int Immunopharmacol, 12, 151, 10.1016/j.intimp.2011.11.005 Ogawa, 2005, Molecular determinants of crosstalk between nuclear receptors and toll-like receptors, Cell, 122, 707, 10.1016/j.cell.2005.06.029 D’Aldebert, 2009, Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium, Gastroenterology, 136, 1435, 10.1053/j.gastro.2008.12.040 Sadeghi, 2006, Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogenassociated molecular patterns, Eur J Immunol, 36, 361, 10.1002/eji.200425995 Mattner, 2008, Liver autoimmunity triggered by microbial activation of natural killer T cells, Cell Host Microbe, 3, 304, 10.1016/j.chom.2008.03.009 Nishigaki, 1996, Ursodeoxycholic acid corrects defective natural killer activity by inhibiting prostaglandin E2 production in primary biliary cirrhosis, Dig Dis Sci, 41, 1487, 10.1007/BF02088577 Mimura, 1995, Role of hepatocytes in direct clearance of lipopolysaccharide in rats, Gastroenterology, 109, 1969, 10.1016/0016-5085(95)90765-3 Tuin, 2006, On the role and fate of LPS-dephosphorylating activity in the rat liver, Am J Physiol Gastrointest Liver Physiol, 290, G377, 10.1152/ajpgi.00147.2005 Sasatomi, 1998, Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis, J Hepatol, 29, 409, 10.1016/S0168-8278(98)80058-5 Harada, 2010, Biliary innate immunity in the pathogenesis of biliary diseases, Inflamm Allergy Drug Targets, 9, 83, 10.2174/187152810791292809 Harada, 2009, Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis, Clin Exp Immunol, 157, 261, 10.1111/j.1365-2249.2009.03947.x Harada, 2012, Cholangiopathy with respect to biliary innate immunity, Int J Hepatol, 2012, 793569, 10.1155/2012/793569 Ide, 1997, Increased serum IgM class anti-lipid A antibody and therapeutic effect of ursodeoxycholic acid in primary biliary cirrhosis, Hepatogastroenterology, 44, 1569 Ballot, 2004, Immune response to lipopolysaccharide in primary biliary cirrhosis and autoimmune diseases, J Autoimmun, 22, 153, 10.1016/j.jaut.2003.11.002 Fiorotto, 2011, Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-kappaB-mediated inflammatory response in mice, Gastroenterology, 141, 1498, 10.1053/j.gastro.2011.06.052 Hagmann, 1984, Role of peptide leukotrienes and their hepatobiliary elimination in endotoxin action, Circ Shock, 14, 223 Schwarzenberg, 1994, Ursodeoxycholic acid modifies gut-derived endotoxemia in neonatal rats, Pediatr Res, 35, 214, 10.1203/00006450-199402000-00018 Hori, 1997, Protective effect of the intravenous administration of ursodeoxycholic acid against endotoxemia in rats with obstructive jaundice, Surg Today, 27, 140, 10.1007/BF02385903 Miura, 2001, Functional modulation of the glucocorticoid receptor and suppression of NF-kappaBdependent transcription by ursodeoxycholic acid, J Biol Chem, 276, 47371, 10.1074/jbc.M107098200 Treede, 2007, Anti-inflammatory effects of phosphatidylcholine, J Biol Chem, 282, 27155, 10.1074/jbc.M704408200 Van Nieuwkerk, 1996, Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene, Gastroenterology, 111, 165, 10.1053/gast.1996.v111.pm8698195 Tsuboi, 2004, Partial characterization of cytoprotective mechanisms of lecithin against bile salt-induced bile duct damage, J Gastroenterol, 39, 955, 10.1007/s00535-003-1432-0 Stiehl, 1995, Biliary secretion of bile acids and lipids in primary sclerosing cholangitis. Influence of cholestasis and effect of ursodeoxycholic acid treatment, J Hepatol, 23, 283 Kano, 1998, Effects of long-term ursodeoxycholate administration on expression levels of secretory low-molecular-weight phospholipases A2 and mucin genes in gallbladders and biliary composition in patients with multiple cholesterol stones, Hepatology, 28, 302, 10.1002/hep.510280204 Rosmorduc, 2007, Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene, Orphanet J Rare Dis, 2, 29, 10.1186/1750-1172-2-29 Hofmann, 2005, Novel biotransformation and physiological properties of norursodeoxycholic acid in humans, Hepatology, 42, 1391, 10.1002/hep.20943 Fickert, 2006, 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice, Gastroenterology, 130, 465, 10.1053/j.gastro.2005.10.018 Denk, 2010, Conjugation is essential for the anticholestatic effect of NorUrsodeoxycholic acid in taurolithocholic acid-induced cholestasis in rat liver, Hepatology, 52, 1758, 10.1002/hep.23911 Schote, 2007, Nuclear receptors in human immune cells: expression and correlations, Mol Immunol, 44, 1436, 10.1016/j.molimm.2006.04.021 Campana, 2005, Regulation of ileal bile acid-binding protein expression in Caco-2 cells by ursodeoxycholic acid: role of the farnesoid X receptor, Biochem Pharmacol, 69, 1755, 10.1016/j.bcp.2005.03.019 Sinha, 2008, beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes, Am J Physiol Gastrointest Liver Physiol, 295, G996, 10.1152/ajpgi.90343.2008 Inagaki, 2005, Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis, Cell Metab, 2, 217, 10.1016/j.cmet.2005.09.001 Goodwin, 2000, A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis, Mol Cell, 6, 517, 10.1016/S1097-2765(00)00051-4 Denson, 2001, The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp, Gastroenterology, 121, 140, 10.1053/gast.2001.25503 Ananthanarayanan, 2001, Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor, J Biol Chem, 276, 28857, 10.1074/jbc.M011610200 Liu, 2003, Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis, J Clin Invest, 112, 1678, 10.1172/JCI18945 Kast, 2002, 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, 277, 2908, 10.1074/jbc.M109326200 Gnerre, 2004, Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene, Pharmacogenetics, 14, 635, 10.1097/00008571-200410000-00001 Barbier, 2003, FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity, Gastroenterology, 124, 1926, 10.1016/S0016-5085(03)00388-3 Song, 2001, Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor, J Biol Chem, 276, 42549, 10.1074/jbc.M107557200 Wagner, 2003, Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice, Gastroenterology, 125, 825, 10.1016/S0016-5085(03)01068-0 Modica, 2012, Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis, Gastroenterology, 142, 355, 10.1053/j.gastro.2011.10.028 Baghdasaryan, 2011, Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/-(Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO(-)(3) output, Hepatology, 54, 1303, 10.1002/hep.24537 Eloranta, 2006, 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, 20, 65, 10.1210/me.2005-0159 Inagaki, 2006, Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor, Proc Natl Acad Sci U S A, 103, 3920, 10.1073/pnas.0509592103 Wang, 2008, X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response, Hepatology, 48, 1632, 10.1002/hep.22519 Mencarelli, 2009, The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis, J Immunol, 183, 6657, 10.4049/jimmunol.0901347 Chignard, 2005, VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium, Hepatology, 42, 549, 10.1002/hep.20806 Lee, 2005, Alpha-crystallin is a target gene of the farnesoid X-activated receptor in human livers, J Biol Chem, 280, 31792, 10.1074/jbc.M503182200 Pellicciari, 2002, 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity, J Med Chem, 45, 3569, 10.1021/jm025529g Kowdley, 2011, The first new monotherapy therapeutic PBC study in a decade? An international study evaluating the farnesoid X receptor agonist obeticholic acid in PBC, 416A Kowdley, 2011, An international study evaluating the farnesoid X receptor agonist obeticholic acid as monotherapy in PBC, J Hepatol, S13, 10.1016/S0168-8278(11)60030-5 Sharma, 2011, Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators, J Med Chem, 54, 122, 10.1021/jm100860s