Review article: Nuclear receptors and liver disease - Current understanding and new therapeutic implications

Alimentary Pharmacology and Therapeutics

Volumn 30, Issue 8, 2009, Pages 816-825

  Elfaki, D A H ^a   Bjornsson, E ^a   Lindor, K D ^a  

^a MAYO CLINIC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; 3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY]PHENYL]VINYL]BENZOIC ACID; 6ALPHA ETHYLCHENODEOXYCHOLIC ACID; ALKALINE PHOSPHATASE; AMINOTRANSFERASE; BEZAFIBRATE; BILE ACID; CELL NUCLEUS RECEPTOR; CHENODEOXYCHOLIC ACID DERIVATIVE; FARNESOID X RECEPTOR; FENOFIBRATE; FEXARAMINE; FIBRIC ACID DERIVATIVE; GAMMA GLUTAMYLTRANSFERASE; HISTAMINE H4 RECEPTOR; HYPOCHOLESTEROLEMIC AGENT; IMMUNOGLOBULIN M; INT 747; LIVER X RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 1; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIOGLITAZONE; PLACEBO; PREGNANE X RECEPTOR; ROSIGLITAZONE; TROGLITAZONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; URSODEOXYCHOLIC ACID;

AMINOTRANSFERASE BLOOD LEVEL; ANGINA PECTORIS; BILE ACID BLOOD LEVEL; CHOLESTASIS; CLINICAL TRIAL; CONGESTIVE HEART FAILURE; DIABETES MELLITUS; DRUG EFFICACY; DRUG TARGETING; DYSLIPIDEMIA; EDEMA; FATTY LIVER; GENE EXPRESSION; GLYCEMIC CONTROL; HOMEOSTASIS; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTRIGLYCERIDEMIA; INSULIN RESISTANCE; INSULIN SENSITIVITY; INTROSPECTION; LIVER DISEASE; LIVER FIBROSIS; LIVER TOXICITY; LOW CALORY DIET; MOLECULAR MECHANICS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; PANCREATITIS; PLEURA EFFUSION; PREDICTION; PRIMARY BILIARY CIRRHOSIS; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; RHABDOMYOLYSIS; SIDE EFFECT; TREATMENT DURATION; WEIGHT GAIN;

CLOFIBRIC ACID; HUMANS; LIGANDS; LIVER DISEASES; RECEPTORS, CYTOPLASMIC AND NUCLEAR; THIAZOLIDINEDIONES;

EID: 70349421143     PISSN: 02692813     EISSN: 13652036     Source Type: Journal    
DOI: 10.1111/j.1365-2036.2009.04104.x     Document Type: Review

References (130)

1. Makishima M. Nuclear receptors as targets for drug development: regulation of cholesterol and bile acid metabolism by nuclear receptors. J Pharmacol Sci 2005 97 : 177 183.
2. Boyer JL. Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease? Gastroenterology 2005 129 : 735 740.
3. Tobin JF, Freedman LP. Nuclear receptors as drug targets in metabolic diseases: new approaches to therapy. Trends Endocrinol Metab 2006 17 : 284 290.
4. McEwan IJ. Nuclear receptors: one big family. Methods Mol Biol 2009 505 : 3 18.
5. Eloranta JJ, Kullak-Ublick GA. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys 2005 433 : 397 412.
6. Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 2000 14 : 121 141.
7. Karpen SJ. Nuclear receptor regulation of hepatic function. J Hepatol 2002 36 : 832 850.
8. Tirona RG, Kim RB. Nuclear receptors and drug disposition gene regulation. J Pharm Sci 2005 94 : 1169 1186.
9. Chen HL, Liu YJ, Chen HL, et al. Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. Pediatr Res 2008 63 : 667 673.
10. Caron S, Cariou B, Staels B. FXR: More than a bile acid receptor? Endocrinology 2006 147 : 4022 4024.
11. Francis GA, Fayard E, Picard F, Auwerx J. Nuclear receptors and the control of metabolism. Annu Rev Physiol 2003 65 : 261 311.
12. Hansen MK, Connolly TM. Nuclear receptors as drug targets in obesity, dyslipidemia and atherosclerosis. Curr Opin Investig Drugs 2008 9 : 247 255.
13. Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009 89 : 147 191.
14. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003 72 : 137 174.
15. Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. CMLS, Cell Mol Life Sci 2008 65 : 2461 2483.
16. 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 : S111 24.
17. Zhang Y, Lee FY, Barrera G, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 2006 103 : 1006 1011.
18. Huang W, Zhang J, Moore DD. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest 2004 113 : 137 143.
19. Russell DW. 50 years of advances in bile acid synthesis and metabolism. J Lipid Res 2008 50 (Suppl S120 5.
20. Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev 2008 60 : 311 357.
21. Schaffner F, Thaler H. Nonalcoholic fatty liver disease. Prog Liver Dis 1986 8 : 283 298.
22. Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990 11 : 74 80.
23. Adams LA, Angulo P. Treatment of nonalcoholic steatohepatitis: antioxidants or insulin sensitizers? Clin Gastroenterol Hepatol 2004 2 : 1059 1060. (Pubitemid 40037634)
24. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003 37 : 1202 1219.
25. McCullough AJ. Update on nonalcoholic fatty liver disease. J Clin Gastroenterol 2002 34 : 255 262.
26. Contos MJ, Sanyal AJ. The clinicopathologic spectrum and management of nonalcoholic fatty liver disease. Adv Anat Pathol 2002 9 : 37 51.
27. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000 118 : 1117 1123.
28. Ahima RS. The natural history of nonalcoholic fatty liver disease: insights from children and mice.[comment]. Gastroenterology 2008 135 : 1860 1862
29. Peraza MA, Burdick AD, Marin HE, Gonzalez FJ, Peters JM. The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicol Sci 2006 90 : 269 295.
30. Chehab FF. Obesity and lipodystrophy - where do the circles intersect? Endocrinology 2008 149 : 925 934.
31. Beltowski J. Liver X receptors (LXR) as therapeutic targets in dyslipidemia. Cardiovasc Ther 2008 26 : 297 316.
32. Yoneda M, Hotta K, Nozaki Y, et al. Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterology 2008 8 : 27.
33. Adams LA, Lindor KD. Nonalcoholic fatty liver disease. Ann Epidemiol 2007 17 : 863 869.
34. Wang Q, Jiang L, Wang J, et al. Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice. Hepatology 2007 49 : 116 175.
35. Buque X, Aspichueta P, Ochoa B. [Molecular basis of obesity-related hepatic steatosis]. Rev Esp Enferm Dig 2008 100 : 565 578.
36. Tsai CH, Li TC, Lin CC. Metabolic syndrome as a risk factor for nonalcoholic fatty liver disease.[see comment]. South Med J 2008 101 : 900 905.
37. Wilfred de Alwis NM, Day CP. Genes and nonalcoholic fatty liver disease. Curr Diab Rep 2008 8 : 156 163.
38. G Z, M T. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol 2009 156 : 7 27.
39. Diep QN, Amiri F, Touyz RM, et al. PPARalpha activator effects on Ang II-induced vascular oxidative stress and inflammation. Hypertension 2002 40 : 866 871.
40. Bocher V, Chinetti G, Fruchart JC, Staels B. [Role of the peroxisome proliferator-activated receptors (PPARS) in the regulation of lipids and inflammation control]. Journal de la Societe de biologie 2002 196 : 47 52.
41. Paumelle R, Staels B. Cross-talk between statins and PPARalpha in cardiovascular diseases: clinical evidence and basic mechanisms. Trends Cardiovasc Med 2008 18 : 73 8.
42. Devchand PR, Keller H, Peters JM, et al. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 1996 384 : 39 43.
43. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A 1997 94 : 4318 4323.
44. Marra F. Nuclear factor-kappaB inhibition and non-alcoholic steatohepatitis: inflammation as a target for therapy. Gut 2008 57 : 570 572.
45. Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007 45 : 1366 1374.
46. Marra F, Pastacaldi S. [Thiazolidinediones and PPARgamma system in repair of liver damage]. Recenti Prog Med 2002 93 : 9 15.
47. Westin S, Kurokawa R, Nolte RT, et al. Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators. Nature 1998 395 : 199 202.
48. Nolte RT, Wisely GB, Westin S, et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998 395 : 137 143.
49. Marx N, Kehrle B, Kohlhammer K, et al. PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis. Circ Res 2002 90 : 703 710.
50. Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008 135 : 100 110.
51. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis. J Hepatol 2003 38 : 434 440.
52. Sutinen J. The Effects of Thiazolidinediones on Metabolic Complications and Lipodystrophy in HIV-Infected Patients. PPAR Res 2009 2009 : 373524
53. Beaven SW, Tontonoz P. Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia. Annu Rev Med 2006 57 : 313 329.
54. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003 38 : 1008 1017.
55. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008 135 : 1176 1184.
56. Schinner S, Kratzner R, Baun D, et al. Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor gamma and thiazolidinedione oral antidiabetic drugs. Br J Pharmacol 2009 157 : 736 735.
57. Smith MT. Mechanisms of troglitazone hepatotoxicity. Chem Res Toxicol 2003 16 : 679 687.
58. Kohlroser J, Mathai J, Reichheld J, Banner BF, Bonkovsky HL. Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration. Am j gastroenterol 2000 95 : 272 276.
59. Pfutzner A, Marx N, Lubben G, et al. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. J Am Coll Cardiol 2005 45 : 1925 1931
60. El-Naggar MH, Helmy A, Moawad M, et al. Late-onset rosiglitazone- associated acute liver failure in a patient with Hodgkin's lymphoma. Ann Pharmacother 2008 42 : 713 718.
61. Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet 1999 354 : 141 148.
62. Chawla A, Barak Y, Nagy L, et al. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation.[see comment]. Nat Med 2001 7 : 48 52.
63. Puri V, Ranjit S, Konda S, et al. Cidea is associated with lipid droplets and insulin sensitivity in humans. Proc Natl Acad Sci U S A 2008 105 : 7833 7838.
64. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006 355 : 2297 2307.
65. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.[see comment]. J Hepatol 2005 42 : 132 138.
66. Lutchman G, Modi A, Kleiner DE, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 2007 46 : 424 429.
67. Stafylas PC, Sarafidis PA, Lasaridis AN. The controversial effects of thiazolidinediones on cardiovascular morbidity and mortality. Int J Cardiol 2009 131 : 298 304.
68. Henriksen JH, Ring-Larsen H. Rosiglitazone: possible complications and treatment of non-alcoholic steatohepatitis (NASH). J Hepatol 2008 48 : 174 176.
69. Hofmann AF. Pathogenesis of cholesterol gallstones. J Clin Gastroenterol 1988 10 (Suppl. 2 S1 11.
70. Vitek L, Carey MC. Enterohepatic cycling of bilirubin as a cause of 'black' pigment gallstones in adult life. Eur J Clin Invest 2003 33 : 799 810.
71. Stieger B, Meier Y, Meier PJ. The bile salt export pump. Pflugers Arch 2007 453 : 611 620.
72. Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick GA, Meier PJ. Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol 2005 43 : 342 357.
73. Baghdasaryan A, Fickert P, Fuchsbichler A, et al. Role of hepatic phospholipids in development of liver injury in Mdr2 (Abcb4) knockout mice. Liver Int 2008 28 : 948 958.
74. Nagengast FM, Grubben MJ, van Munster IP. Role of bile acids in colorectal carcinogenesis. Eur J Cancer 1995 31A : 1067 1070.
75. Barbier O, Trottier J, Kaeding J, Caron P, Verreault M. Lipid-activated transcription factors control bile acid glucuronidation. Mol Cell Biochem 2009 326 : 3 8.
76. Wagner M, Fickert P, Zollner G, et al. Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology 2003 125 : 825 838.
77. Stedman C, Liddle C, Coulter S, et al. Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci U S A 2006 103 : 11323 11328.
78. Wagner M, Halilbasic E, Marschall HU, et al. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 2005 42 : 420 430.
79. Jung D, Mangelsdorf DJ, Meyer UA. Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem 2006 281 : 19081 19091.
80. Zollner G, Marschall HU, 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 : 231 251.
81. Zollner G, Trauner M. Mechanisms of cholestasis. Clin Liver Dis 2008 12 : 1 26.
82. 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 : S111 24.
83. Denson LA, 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 : 140 147.
84. Sinal CJ, Tohkin M, Miyata M, et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000 102 : 731 744.
85. Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 2001 276 : 28857 28865.
86. Kast HR, Goodwin B, Tarr PT, 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 : 2908 2915.
87. Jansen PL, Muller M, Sturm E. Genes and cholestasis. Hepatology 2001 34 : 1067 1074.
88. 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 : 3569 3572
89. Rizzo G, Renga B, Mencarelli A, Pellicciari R, Fiorucci S. Role of FXR in regulating bile acid homeostasis and relevance for human diseases. Curr Drug Targets 2005 5 : 289 303.
90. Song KH, Li T, Owsley E, Strom S, Chiang JY. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression. Hepatology 2009 49 : 297 305.
91. Holt JA, Luo G, Billin AN, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 2003 17 : 1581 1591.
92. 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 : 217 225.
93. Chiang JY. Bile acids: regulation of synthesis. J Lipid Res 2009 (Epub ahead of print).
94. Huang W, Ma K, Zhang J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.[see comment]. Science 2006 312 : 233 236.
95. Inagaki T, Moschetta A, Lee YK, 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 : 3920 3925.
96. Kim I, Morimura K, Shah Y, et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 2007 28 : 940 946.
97. Yang F, Huang X, Yi T, et al. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 2007 67 : 863 867.
98. Scholtes C, Diaz O, Icard V, et al. Enhancement of genotype 1 hepatitis C virus replication by bile acids through FXR. J Hepatol 2008 48 : 192 199.
99. Pineda Torra I, Claudel T, Duval C, et al. Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 2003 17 : 259 272.
100. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 2006 116 : 1102 1109.
101. Jiang T, Wang XX, Scherzer P, et al. Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy. Diabetes 2007 56 : 2485 2493.
102. Fiorucci S, Clerici C, Antonelli E, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther 2005 313 : 604 612.
103. Akwabi-Ameyaw A, Bass JY, Caldwell RD, et al. Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064. Bioorg Med Chem Lett 2008 18 : 4339 4343.
104. Maloney PR, Parks DJ, Haffner CD, et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 2000 43 : 2971 2974.
105. Liu Y, Binz J, Numerick MJ, et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 2003 112 : 1678 1687.
106. Nishimaki-Mogami T, Une M, Fujino T, et al. Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor. J Lipid Res 2004 45 : 1538 1545.
107. Martinez-Fernandez P, Hierro L, Jara P, Alvarez L. Knockdown of ATP8B1 expression leads to specific down-regulation of the bile acid sensor FXR in HepG2 cells. Effect of the FXR agonist GW4064. Am J Physiol 2009 296 : G1119 29.
108. Yu J, Lo JL, Huang L, et al. Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem 2002 277 : 31441 31447.
109. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology 1988 94 : 488 493.
110. Podesta A, Lopez P, Terg R, et al. Treatment of pruritus of primary biliary cirrhosis with rifampin. Dig Dis Sci 1991 36 : 216 220.
111. Bachs L, Pares A, Elena M, Piera C, Rodes J. Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet 1989 1 : 574 576.
112. Zhang B, Xie W, Krasowski MD. PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics. Pharmacogenomics 2008 9 : 1695 1709.
113. Marschall HU, Wagner M, Zollner G, et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 2005 129 : 476 485.
114. Maglich JM, Lobe DC, Moore JT. The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress. J Lipid Res 2009 50 : 439 445.
115. Yamazaki Y, Kakizaki S, Horiguchi N, et al. The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Gut 2007 56 : 565 574.
116. Zollner G, Trauner M. Mechanisms of cholestasis. Clin Liver Dis. 2008 12 : 1 26
117. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998 339 : 1217 1227.
118. Zollner G, Fickert P, Silbert D, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 2003 38 : 717 727.
119. Yamada T, Arai T, Nagino M, et al. Impaired expression of hepatic multidrug resistance protein 2 is associated with posthepatectomy hyperbilirubinemia in patients with biliary cancer. Langenbecks Archiv Surg 2005 390 : 421 429.
120. Zollner G, Fickert P, Zenz R, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 2001 33 : 633 646.
121. Dohmen K, Mizuta T, Nakamuta M, et al. Fenofibrate for patients with asymptomatic primary biliary cirrhosis. World J Gastroenterol 2004 10 : 894 898.
122. Iwasaki S, Akisawa N, Saibara T, Onishi S. Fibrate for treatment of primary biliary cirrhosis. Hepatol Res 2007 37 (Suppl. 3 S515 7.
123. 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 : 326 327.
124. Miyaguchi S, Ebinuma H, Imaeda H, et al. A novel treatment for refractory primary biliary cirrhosis? Hepatogastroenterology 2000 47 : 1518 1521.
125. Kurihara T, Niimi A, Maeda A, Shigemoto M, Yamashita K. Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid. Am J Gastroenterol 2000 95 : 2990 2992.
126. Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol 2003 38 : 573 578.
127. Nakamuta M, Enjoji M, Kotoh K, Shimohashi N, Tanabe Y. Long-term fibrate treatment for PBC. J Gastroenterol 2005 40 : 546 547.
128. Tachibana K, Yamasaki D, Ishimoto K, Doi T. The role of PPARs in cancer. PPAR research. 2008 2008 : 102737.
129. Ashby J, Brady A, Elcombe CR, et al. Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis. Hum Exp Toxicol 1994 13 (Suppl. 2 S1 117. (Pubitemid 2162129)
130. Corton JC. Evaluation of the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver tumor induction by trichloroethylene and metabolites. Crit Rev Toxicol 2008 38 : 857 875.